Neurobiological effects of physical exercise: Difference between revisions

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Addiction and dependence glossary
	addiction – a biopsychosocial disorder characterized by persistent use of drugs (including alcohol) despite substantial harm and adverse consequences; addictive drug – psychoactive substances that with repeated use are associated with significantly higher rates of substance use disorders, due in large part to the drug's effect on brain reward systems; dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake); drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose; drug withdrawal – symptoms that occur upon cessation of repeated drug use; physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens); psychological dependence – dependence socially seen as being extremely mild compared to physical dependence (e.g., with enough willpower it could be overcome); reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them; rewarding stimuli – stimuli that the brain interprets as intrinsically positive and desirable or as something to approach; sensitization – an amplified response to a stimulus resulting from repeated exposure to it; substance use disorder – a condition in which the use of substances leads to clinically and functionally significant impairment or distress; tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose;
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neurobiological effects of physical exercise
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Neurobiological effects of
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ICD-9-CM	93.19
MeSH	D005081
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The neurobiological effects of physical exercise are numerous and involve a wide range of interrelated neuropsychological changes. A large body of research in humans has demonstrated that consistent aerobic exercise (e.g., 30 minutes every day) induces persistent beneficial behavioral and neural plasticity as well as healthy alterations in gene expression in the brain; some of these long-term effects include: increased neuron growth, increased neurological activity (c-Fos and BDNF signaling), improved stress coping, enhanced cognitive control over behavior, improved declarative and working memory, and structural and functional improvements in brain structures and pathways associated with cognitive control and memory. The effects of exercise on cognition have important implications for improving academic performance in children and college students, improving adult productivity, preserving cognitive function in old age, preventing or treating certain neurological disorders, and improving overall quality of life.

People who regularly participate in aerobic exercise have greater scores on neuropsychological function and performance tests. Examples of aerobic exercise that produce these changes are running, jogging, brisk walking, swimming, and cycling. Exercise intensity and duration are positively correlated with the release of neurotrophic factors and the magnitude of nearly all forms of exercise-induced behavioral and neural plasticity; consequently, more pronounced improvements in measures of neuropsychological performance are observed in endurance athletes as compared with recreational athletes or sedentary individuals. Aerobic exercise is also a potent long-term antidepressant and a short-term euphoriant; consequently, consistent exercise has also been shown to produce general improvements in mood and self-esteem in all individuals.

Long-term effects

Neuroplasticity and neurogenesis

Neuroplasticity is essentially the ability of neurons in the brain to adapt over time, and most often occurs in response to repeated exposure to stimuli;^[1] whereas neurogenesis is the postnatal (after-birth) growth of new neurons, a beneficial form of neuroplasticity.^[1] Aerobic exercise promotes neurogenesis by increasing the production of neurotrophic factors (compounds which promote the growth or survival of neurons), such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF).^[2]^[3]^[4] Consistent aerobic exercise over a period of several months induces marked clinically significant improvements in executive function (i.e., the "cognitive control" of behavior) and increased gray matter volume in multiple brain regions, particularly those which give rise to cognitive control.^[4]^[5]^[6]^[7] The brain structures that show the greatest improvements in gray matter volume in response to aerobic exercise are the prefrontal cortex and hippocampus;^[4]^[5]^[8] moderate improvements seen in the anterior cingulate cortex, parietal cortex, cerebellum, caudate nucleus, and nucleus accumbens.^[4]^[5]^[8] The prefrontal cortex, caudate nucleus, and anterior cingulate cortex are among the most significant brain structures in the dopamine and norepinephrine systems that give rise to cognitive control.^[5]^[9] Exercise-induced neurogenesis (i.e., the increases in gray matter volume) in the hippocampus is associated with measurable improvements in spatial memory.^[5]^[8]^[10]^[11] Higher physical fitness scores (measured by VO₂ max) are associated with better executive function, faster processing speed, and greater volume of the hippocampus, caudate nucleus, and nucleus accumbens.^[5] Long-term aerobic exercise is also associated with persistent beneficial epigenetic changes that result in improved stress coping, improved cognitive function, and increased neuronal activity (c-Fos and BDNF signaling).^[12]^[13]

BDNF signaling

One of the most significant effects of exercise on the brain is the increased synthesis and expression of BDNF, a neuropeptide hormone, in the brain and periphery, resulting in increased signaling through its tyrosine kinase receptor, tropomyosin receptor kinase B (TrkB).^[12]^[14]^[15] Since BDNF is capable of crossing the blood–brain barrier, higher peripheral BDNF synthesis also increases BDNF signaling in the brain.^[2] Exercise-induced increases in brain BDNF signaling are associated with beneficial epigenetic changes, improved cognitive function, improved mood, and improved memory.^[3]^[8]^[12]^[14] Furthermore, research has provided a great deal of support for the role of BDNF in hippocampal neurogenesis, synaptic plasticity, and neural repair.^[4]^[14] Engaging in moderate-high intensity aerobic exercise such as running, swimming and cycling, increases BDNF biosynthesis through myokine signaling, resulting in up to a threefold increase in blood plasma and brain BDNF levels;^[12]^[14]^[15] exercise intensity affects the magnitude of increased BDNF synthesis and expression.^[12]^[14]^[15] A meta-analysis of studies involving the effect of exercise on BDNF levels found that consistent exercise modestly increases resting BDNF levels as well.^[3]

Antidepressant effect

A number of medical reviews have indicated that exercise has a marked and persistent antidepressant effect in humans,^[4]^[16]^[17]^[18]^[19]^[20] an effect believed to be mediated through enhanced BDNF signaling in the brain.^[8]^[17] Several systematic reviews have analyzed the potential for physical exercise in the treatment of depressive disorders. The 2013 Cochrane Collaboration review on physical exercise for depression noted that, based upon limited evidence, it is more effective than a control intervention and comparable to psychological or antidepressant drug therapies.^[16] Three subsequent 2014 systematic reviews that included the Cochrane review in their analysis concluded with similar findings: one indicated that that physical exercise is effective as an adjunct treatment (i.e., treatments that are used together) with antidepressant medication;^[17] the other two indicated that physical exercise has marked antidepressant effects and recommended the inclusion of physical activity as an adjunct treatment for mild–moderate depression^[18] and mental illness in general.^[19] One review asserted that evidence from clinical trials supports the efficacy of physical exercise as a treatment for depression over 2–4 months.^[4]

IGF-1 signaling

IGF-1 is a peptide that mediates some of the effects of growth hormone and acts through the IGF-1 receptor to control body growth and tissue remodeling.^[21] In the brain, IGF-1 functions as a neurotrophic factor that, like BDNF, plays a significant role in cognition, neurogenesis, and neuronal survival.^[14]^[22]^[23] Physical activity is associated with increased levels of serum IGF-1, which is known to contribute to neuroplasticity along with locally produced IGF-1 in the brain due to its capacity to cross the blood–brain barrier in the capillary bed and blood–cerebrospinal fluid barrier;^[4]^[14]^[21]^[22] consequently one review noted that IGF-1 is a key mediator of exercise-induced adult neurogenesis, while a second review characterized it as a factor which links "body fitness" with "brain fitness".^[21]^[22] The amount of IGF-1 released during exercise is positively correlated with exercise intensity and duration.^[24]

VEGF signaling

VEGF is a neurotrophic and angiogenic (i.e., blood vessel growth promoting) signaling protein that binds to two receptor tyrosine kinases, VEGFR1 and VEGFR2, which are expressed in neurons and glial cells the brain.^[23] Hypoxia, or inadequate cellular oxygen supply, strongly upregulates VEGF expression and VEGF exerts a neuroprotective effect in hypoxic neurons.^[23] Like BDNF and IGF-1, aerobic exercise has been shown to increase VEGF biosynthesis in peripheral tissue which subsequently crosses the blood–brain barrier and promotes neurogenesis and blood vessel formation the central nervous system.^[2]^[25]^[26] Exercise-induced increases in VEGF signaling have been shown to improve cerebral blood volume and contribute to exercise-induced neurogenesis in the hippocampus.^[4]^[25]^[26]

ΔFosB and addiction

Similar to other natural rewards and addictive drugs, consistent aerobic exercise increases gene expression of the gene transcription factor that causes and maintains addiction, ΔFosB, in the nucleus accumbens;^[27]^[28] however, exercise also increases c-Fos expression as well, thereby opposing the long-term accumulation of ΔFosB.^[12]^[29]^[30] Clinical and preclinical evidence indicate that consistent aerobic exercise, especially endurance exercise (e.g., marathon running), actually prevents the development of certain drug addictions and is an effective adjunct treatment for drug addiction, and for psychostimulant addiction in particular.^[28]^[31]^[32] Consistent aerobic exercise magnitude-dependently (i.e., by duration and intensity) reduces drug addiction risk, which appears to occur through the reversal of drug induced addiction-related neuroplasticity.^[28]^[31] In particular, aerobic exercise decreases psychostimulant self-administration, reduces the reinstatement (i.e., relapse) of drug-seeking, and induces opposite effects on striatal dopamine receptor D₂ (DRD2) signaling (increased DRD2 density) to those induced by pathological stimulant use (decreased DRD2 density).^[28]^[31] Consequently, consistent aerobic exercise leads to better treatment outcomes when used as an adjunct treatment for addiction.^[31]^[32]

Protein fosB, also known as FosB and G0/G1 switch regulatory protein 3 (G0S3), is a protein that in humans is encoded by the FBJ murine osteosarcoma viral oncogene homolog B (FOSB) gene.^[33]^[34]^[35]

The FOS gene family consists of four members: FOS, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family (e.g., c-Jun, JunD), thereby forming the transcription factor complex AP-1. As such, the FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation.^[33] FosB and its truncated splice variants, ΔFosB and further truncated Δ2ΔFosB, are all involved in osteosclerosis, although Δ2ΔFosB lacks a known transactivation domain, in turn preventing it from affecting transcription through the AP-1 complex.^[36]

The ΔFosB splice variant has been identified as playing a central, crucial^[37]^[27] role in the development and maintenance of addiction.^[37]^[28]^[38] ΔFosB overexpression (i.e., an abnormally and excessively high level of ΔFosB expression which produces a pronounced gene-related phenotype) triggers the development of addiction-related neuroplasticity throughout the reward system and produces a behavioral phenotype that is characteristic of an addiction.^[37]^[38]^[39] ΔFosB differs from the full length FosB and further truncated Δ2ΔFosB in its capacity to produce these effects, as only accumbal ΔFosB overexpression is associated with pathological responses to drugs.^[40]

DeltaFosB

DeltaFosB – more commonly written as ΔFosB – is a truncated splice variant of the FOSB gene.^[41] ΔFosB has been implicated as a critical factor in the development of virtually all forms of behavioral and drug addictions.^[27]^[28]^[42] In the brain's reward system, it is linked to changes in a number of other gene products, such as CREB and sirtuins.^[43]^[44]^[45] In the body, ΔFosB regulates the commitment of mesenchymal precursor cells to the adipocyte or osteoblast lineage.^[46]

In the nucleus accumbens, ΔFosB functions as a "sustained molecular switch" and "master control protein" in the development of an addiction.^[37]^[47]^[48] In other words, once "turned on" (sufficiently overexpressed) ΔFosB triggers a series of transcription events that ultimately produce an addictive state (i.e., compulsive reward-seeking involving a particular stimulus); this state is sustained for months after cessation of drug use due to the abnormal and exceptionally long half-life of ΔFosB isoforms.^[37]^[47]^[48] ΔFosB expression in D1-type nucleus accumbens medium spiny neurons directly and positively regulates drug self-administration and reward sensitization through positive reinforcement while decreasing sensitivity to aversion.^[37]^[38] Based upon the accumulated evidence, a medical review from late 2014 argued that accumbal ΔFosB expression can be used as an addiction biomarker and that the degree of accumbal ΔFosB induction by a drug is a metric for how addictive it is relative to others.^[37]

Chronic administration of anandamide, or N-arachidonylethanolamide (AEA), an endogenous cannabinoid, and additives such as sucralose, a noncaloric sweetener used in many food products of daily intake, are found to induce an overexpression of ΔFosB in the infralimbic cortex (Cx), nucleus accumbens (NAc) core, shell, and central nucleus of amygdala (Amy), that induce long-term changes in the reward system.^[49]

Role in addiction

Signaling cascade in the nucleus accumbens that results in psychostimulant addiction

The signaling cascade involved in psychostimulant addiction

Note: colored text contains article links.

G_s

cAMP

ΔFosB

JunD

c-Fos

SIRT1

HDAC1

^{[Color legend 1]}

This diagram depicts the signaling events in the brain's reward center that are induced by chronic high-dose exposure to psychostimulants that increase the concentration of synaptic dopamine, like amphetamine, methamphetamine, and phenethylamine. Following presynaptic dopamine and glutamate co-release by such psychostimulants,^[52]^[53] postsynaptic receptors for these neurotransmitters trigger internal signaling events through a cAMP-dependent pathway and a calcium-dependent pathway that ultimately result in increased CREB phosphorylation.^[52]^[54]^[55] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;^[52]^[47]^[56] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.^[30] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for 1–2 months, slowly accumulates following repeated high-dose exposure to stimulants through this process.^[47]^[56] ΔFosB functions as "one of the master control proteins" that produces addiction-related structural changes in the brain, and upon sufficient accumulation, with the help of its downstream targets (e.g., nuclear factor kappa B), it induces an addictive state.^[47]^[56]

Chronic addictive drug use causes alterations in gene expression in the mesocorticolimbic projection, which arise through transcriptional and epigenetic mechanisms.^[27]^[57]^[58] The most important transcription factors that produce these alterations are ΔFosB, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and nuclear factor kappa B (NF-κB).^[27] ΔFosB is the most significant biomolecular mechanism in addiction because the overexpression of ΔFosB in the D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient for many of the neural adaptations and behavioral effects (e.g., expression-dependent increases in drug self-administration and reward sensitization) seen in drug addiction.^[37]^[27]^[38] ΔFosB overexpression has been implicated in addictions to alcohol (ethanol), cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.^[37]^[27]^[57]^[59]^[60] ΔJunD, a transcription factor, and G9a, a histone methyltransferase, both oppose the function of ΔFosB and inhibit increases in its expression.^[27]^[38]^[61] Increases in nucleus accumbens ΔJunD expression (via viral vector-mediated gene transfer) or G9a expression (via pharmacological means) reduces, or with a large increase can even block, many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).^[39]^[27] Repression of c-Fos by ΔFosB, which consequently further induces expression of ΔFosB, forms a positive feedback loop that serves to indefinitely perpetuate the addictive state.

ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.^[27]^[42] Natural rewards, similar to drugs of abuse, induce gene expression of ΔFosB in the nucleus accumbens, and chronic acquisition of these rewards can result in a similar pathological addictive state through ΔFosB overexpression.^[27]^[28]^[42] Consequently, ΔFosB is the key mechanism involved in addictions to natural rewards (i.e., behavioral addictions) as well;^[27]^[28]^[42] in particular, ΔFosB in the nucleus accumbens is critical for the reinforcing effects of sexual reward.^[42] Research on the interaction between natural and drug rewards suggests that dopaminergic psychostimulants (e.g., amphetamine) and sexual behavior act on similar biomolecular mechanisms to induce ΔFosB in the nucleus accumbens and possess bidirectional reward cross-sensitization effects^{[note 1]} that are mediated through ΔFosB.^[28]^[62] This phenomenon is notable since, in humans, a dopamine dysregulation syndrome, characterized by drug-induced compulsive engagement in natural rewards (specifically, sexual activity, shopping, and gambling), has also been observed in some individuals taking dopaminergic medications.^[28]

ΔFosB inhibitors (drugs or treatments that oppose its action or reduce its expression) may be an effective treatment for addiction and addictive disorders.^[63] Current medical reviews of research involving lab animals have identified a drug class – class I histone deacetylase inhibitors^{[note 2]} – that indirectly inhibits the function and further increases in the expression of accumbal ΔFosB by inducing G9a expression in the nucleus accumbens after prolonged use.^[39]^[61]^[64]^[65] These reviews and subsequent preliminary evidence which used oral administration or intraperitoneal administration of the sodium salt of butyric acid or other class I HDAC inhibitors for an extended period indicate that these drugs have efficacy in reducing addictive behavior in lab animals^{[note 3]} that have developed addictions to ethanol, psychostimulants (i.e., amphetamine and cocaine), nicotine, and opiates;^[61]^[65]^[66]^[67] however, as of August 2015^[update], few clinical trials involving humans with addiction and any HDAC class I inhibitors have been conducted to test for treatment efficacy in humans or identify an optimal dosing regimen.^{[note 4]}

Plasticity in cocaine addiction

ΔFosB accumulation from excessive drug use

Top: this depicts the initial effects of high dose exposure to an addictive drug on gene expression in the nucleus accumbens for various Fos family proteins (i.e., c-Fos, FosB, ΔFosB, Fra1, and Fra2).
Bottom: this illustrates the progressive increase in ΔFosB expression in the nucleus accumbens following repeated twice daily drug binges, where these phosphorylated (35–37 kilodalton) ΔFosB isoforms persist in the D1-type medium spiny neurons of the nucleus accumbens for up to 2 months.^[48]^[56]

ΔFosB levels have been found to increase upon the use of cocaine.^[69] Each subsequent dose of cocaine continues to increase ΔFosB levels with no apparent ceiling of tolerance.^{[citation needed]} Elevated levels of ΔFosB leads to increases in brain-derived neurotrophic factor (BDNF) levels, which in turn increases the number of dendritic branches and spines present on neurons involved with the nucleus accumbens and prefrontal cortex areas of the brain. This change can be identified rather quickly, and may be sustained weeks after the last dose of the drug.

Transgenic mice exhibiting inducible expression of ΔFosB primarily in the nucleus accumbens and dorsal striatum exhibit sensitized behavioural responses to cocaine.^[70] They self-administer cocaine at lower doses than control,^[71] but have a greater likelihood of relapse when the drug is withheld.^[48]^[71] ΔFosB increases the expression of AMPA receptor subunit GluR2^[70] and also decreases expression of dynorphin, thereby enhancing sensitivity to reward.^[48]

Neural and behavioral effects of validated ΔFosB transcriptional targets^[37]^[43]
Target gene	Target expression	Neural effects	Behavioral effects
c-Fos	↓	Molecular switch enabling the chronic induction of ΔFosB^{[note 5]}	–
dynorphin	↓ ^{[note 6]}	• Downregulation of κ-opioid feedback loop	• Diminished self-extinguishing response to drug
NF-κB	↑	• Expansion of Nacc dendritic processes • NF-κB inflammatory response in the NAcc • NF-κB inflammatory response in the CPTooltip caudate putamen	• Increased drug reward • Locomotor sensitization
GluR2	↑	• Decreased sensitivity to glutamate	• Increased drug reward
Cdk5	↑	• GluR1 synaptic protein phosphorylation • Expansion of NAcc dendritic processes	• Decreased drug reward (net effect)

Summary of addiction-related plasticity


Form of neuroplasticity or behavioral plasticity	Type of reinforcer						Sources
Form of neuroplasticity or behavioral plasticity	Opiates	Psychostimulants	High fat or sugar food	Sexual intercourse	Physical exercise (aerobic)	Environmental enrichment	Sources
ΔFosB expression in nucleus accumbens D1-type MSNsTooltip medium spiny neurons	↑	↑	↑	↑	↑	↑	^[28]
Behavioral plasticity
Escalation of intake	Yes	Yes	Yes				^[28]
Psychostimulant cross-sensitization	Yes	Not applicable	Yes	Yes	Attenuated	Attenuated	^[28]
Psychostimulant self-administration	↑	↑	↓		↓	↓	^[28]
Psychostimulant conditioned place preference	↑	↑	↓	↑	↓	↑	^[28]
Reinstatement of drug-seeking behavior	↑	↑			↓	↓	^[28]
Neurochemical plasticity
CREBTooltip cAMP response element-binding protein phosphorylation in the nucleus accumbens	↓	↓	↓		↓	↓	^[28]
Sensitized dopamine response in the nucleus accumbens	No	Yes	No	Yes			^[28]
Altered striatal dopamine signaling	↓DRD2, ↑DRD3	↑DRD1, ↓DRD2, ↑DRD3	↑DRD1, ↓DRD2, ↑DRD3		↑DRD2	↑DRD2	^[28]
Altered striatal opioid signaling	No change or ↑μ-opioid receptors	↑μ-opioid receptors ↑κ-opioid receptors	↑μ-opioid receptors	↑μ-opioid receptors	No change	No change	^[28]
Changes in striatal opioid peptides	↑dynorphin No change: enkephalin	↑dynorphin	↓enkephalin		↑dynorphin	↑dynorphin	^[28]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens	↓	↑		↑			^[28]
Dendritic spine density in the nucleus accumbens	↓	↑		↑			^[28]

Other functions in the brain

Viral overexpression of ΔFosB in the output neurons of the nigrostriatal dopamine pathway (i.e., the medium spiny neurons in the dorsal striatum) induces levodopa-induced dyskinesias in animal models of Parkinson's disease.^[72]^[73] Dorsal striatal ΔFosB is overexpressed in rodents and primates with dyskinesias;^[73] postmortem studies of individuals with Parkinson's disease that were treated with levodopa have also observed similar dorsal striatal ΔFosB overexpression.^[73] Levetiracetam, an antiepileptic drug, has been shown to dose-dependently decrease the induction of dorsal striatal ΔFosB expression in rats when co-administered with levodopa;^[73] the signal transduction involved in this effect is unknown.^[73]

ΔFosB expression in the nucleus accumbens shell increases resilience to stress and is induced in this region by acute exposure to social defeat stress.^[74]^[75]^[76]

Antipsychotic drugs have been shown to increase ΔFosB as well, more specifically in the prefrontal cortex. This increase has been found to be part of pathways for the negative side effects that such drugs produce.^[77]

Notes

^ In simplest terms, this means that when either amphetamine or sex is perceived as "more alluring or desirable" through reward sensitization, this effect occurs with the other as well.
^ Inhibitors of class I histone deacetylase (HDAC) enzymes are drugs that inhibit four specific histone-modifying enzymes: HDAC1, HDAC2, HDAC3, and HDAC8. Most of the animal research with HDAC inhibitors has been conducted with four drugs: butyrate salts (mainly sodium butyrate), trichostatin A, valproic acid, and SAHA;^[64]^[65] butyric acid is a naturally occurring short-chain fatty acid in humans, while the latter two compounds are FDA-approved drugs with medical indications unrelated to addiction.
^ Specifically, prolonged administration of a class I HDAC inhibitor appears to reduce an animal's motivation to acquire and use an addictive drug without affecting an animals motivation to attain other rewards (i.e., it does not appear to cause motivational anhedonia) and reduce the amount of the drug that is self-administered when it is readily available.^[61]^[65]^[66]
^ Among the few clinical trials that employed a class I HDAC inhibitor, one utilized valproate for methamphetamine addiction.^[68]
^ In other words, c-Fos repression allows ΔFosB to accumulate within nucleus accumbens medium spiny neurons more rapidly because it is selectively induced in this state.^[38]
^ ΔFosB has been implicated in causing both increases and decreases in dynorphin expression in different studies;^[37]^[43] this table entry reflects only a decrease.

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  Ion channel
  G proteins & linked receptors
  (Text color) Transcription factors

References

^ ^a ^b Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY (ed.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 5, 351. ISBN 9780071481274. The clinical actions of fluoxetine, like those of many neuropharmacologic agents, reflect drug-induced neural plasticity, which is the process by which neurons adapt over time in response to chronic disturbance. ... For example, evidence indicates that prolonged increases in cortisol may be damaging to hippocampal neurons and can suppress hippocampal neurogenesis (the generation of new neurons postnatally).{{cite book}}: CS1 maint: multiple names: authors list (link)
^ ^a ^b ^c Tarumi T, Zhang R (January 2014). "Cerebral hemodynamics of the aging brain: risk of Alzheimer disease and benefit of aerobic exercise". Front Physiol. 5: 6. doi:10.3389/fphys.2014.00006. PMC 3896879. PMID 24478719. Exercise-related improvements in brain function and structure may be conferred by the concurrent adaptations in vascular function and structure. Aerobic exercise increases the peripheral levels of growth factors (e.g., BDNF, IFG-1, and VEGF) which cross the blood-brain barrier (BBB) and stimulate neurogenesis and angiogenesis (Trejo et al., 2001; Lee et al., 2002; Fabel et al., 2003; Lopez-Lopez et al., 2004).{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ ^a ^b ^c Szuhany KL, Bugatti M, Otto MW (October 2014). "A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor". J Psychiatr Res. 60C: 56–64. doi:10.1016/j.jpsychires.2014.10.003. PMC 4314337. PMID 25455510. Consistent evidence indicates that exercise improves cognition and mood, with preliminary evidence suggesting that brain-derived neurotrophic factor (BDNF) may mediate these effects. The aim of the current meta-analysis was to provide an estimate of the strength of the association between exercise and increased BDNF levels in humans across multiple exercise paradigms. We conducted a meta-analysis of 29 studies (N = 1111 participants) examining the effect of exercise on BDNF levels in three exercise paradigms: (1) a single session of exercise, (2) a session of exercise following a program of regular exercise, and (3) resting BDNF levels following a program of regular exercise. Moderators of this effect were also examined. Results demonstrated a moderate effect size for increases in BDNF following a single session of exercise (Hedges' g = 0.46, p < 0.001). Further, regular exercise intensified the effect of a session of exercise on BDNF levels (Hedges' g = 0.59, p = 0.02). Finally, results indicated a small effect of regular exercise on resting BDNF levels (Hedges' g = 0.27, p = 0.005). ... Effect size analysis supports the role of exercise as a strategy for enhancing BDNF activity in humans{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ Gomez-Pinilla F, Hillman C (January 2013). "The influence of exercise on cognitive abilities". Compr Physiol. 3 (1): 403–428. doi:10.1002/cphy.c110063. PMC 3951958. PMID 23720292. A second recent meta-analysis (162) corroborated Colcombe and Kramer's (30) findings, in that aerobic exercise was related to attention, processing speed, memory, and cognitive control. ... Normal aging results in the loss of brain tissue (31), with markedly larger tissue loss evidenced in the frontal, temporal, and parietal cortices (16, 58, 149). As such, cognitive functions subserved by these brain regions (such as those involved in cognitive control and memory) are expected to decay more dramatically than other aspects of cognition. Specifically, age-related decreases in gray matter volume have been associated with decrements in a variety of cognitive control processes. ... Decreases in gray matter volume may result from several factors including loss in the number of neurons, neuronal shrinkage, reduction in dendritic arborization, and alterations in glia (158). Further, decreases in white matter (brain tissue composed primarily of myelinated nerve fibers) volume, which represent changes in connectivity between neurons, also occur as a result of aging. Loss of white matter volume further relates to performance decrements on a host of cognitive tasks ... aerobic fitness relates to larger hippocampal volume (23) and better relational memory performance (24), during preadolescent childhood. ... Specifically, those assigned to the aerobic training group demonstrated increases in gray matter in the frontal lobes, including the dorsal anterior cingulate cortex (ACC), supplementary motor area, middle frontal gyrus, dorsolateral region of the right inferior frontal gyrus, and the left superior temporal lobe (32). White matter volume changes were also evidenced for the aerobic fitness group with increases in white matter tracts within the anterior third of the corpus callosum (32). ... In addition, aerobic fitness has been shown to promote better functioning of brain, especially in neural networks involved in cognitive control of inhibition and attention (33). ... In addition to BDNF, the actions of IGF-1 and vascular endothelial growth factor (VEGF) (54) are considered essential for the angiogenic and neurogenic effects of exercise in the brain. ... Randomized and crossover clinical trials demonstrate the efficacy of aerobic or resistance training exercise (2–4 months) as a treatment for depression in both young and older individuals. ... exercise seems to have both preventative and therapeutic effects on the course of depression
^ ^a ^b ^c ^d ^e ^f Erickson KI, Leckie RL, Weinstein AM (September 2014). "Physical activity, fitness, and gray matter volume". Neurobiol. Aging. 35 Suppl 2: S20–528. doi:10.1016/j.neurobiolaging.2014.03.034. PMC 4094356. PMID 24952993. Retrieved 9 December 2014. We conclude that higher cardiorespiratory fitness levels are routinely associated with greater gray matter volume in the prefrontal cortex and hippocampus and less consistently in other regions. We also conclude that physical activity is associated with greater gray matter volume in the same regions that are associated with cardiorespiratory fitness including the prefrontal cortex and hippocampus. ... Meta-analyses (Colcombe and Kramer, 2003; Smith et al., 2010) suggest that the effects of exercise on the brain might not be uniform across all regions and that some brain areas, specifically those areas supporting executive functions, might be more influenced by participation in exercise than areas not as critically involved in executive functions. ... The effects appear to be general in the sense that many different cognitive domains are improved after several months of aerobic exercise, but specific in the sense that executive functions are improved more than other cognitive domains. ... physical activity and exercise may reduce the risk for AD (Barnes and Yaffe, 2011; Podewils et al., 2005; Sofi et al., 2011) ... Erickson et al. (2010) reported that greater amounts of physical activity were associated with greater gray matter volume 9-years later in the prefrontal cortex, anterior cingulate, parietal cortex, cerebellum, and hippocampus. ... higher fitness levels (VO2max) were associated with larger hippocampal volumes, better executive function, and faster processing speed. ... Verstynen et al. (2012) examined the association between cardiorespiratory fitness levels (VO2max) and the size of the basal ganglia ... Verstynen et al. (2012) found that higher fitness levels were associated with greater volume of the caudate nucleus and nucleus accumbens, and in turn, greater volumes were associated with better performance on a task-switching paradigm. ... That is, higher physical activity levels mitigated the detrimental effects of lifetime stress on the size of the hippocampus. ... The few randomized interventions published thus far have found results highly overlapping with the cross-sectional studies and suggest that the prefrontal cortex and hippocampus remain pliable in late life and that moderate intensity exercise for 6 months–1 year is sufficient for changing the size of these areas.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ Cite error: The named reference exercise benefits was invoked but never defined (see the help page).
^ Cite error: The named reference cognitive control of exercise was invoked but never defined (see the help page).
^ ^a ^b ^c ^d ^e Cite error: The named reference BDNF depression was invoked but never defined (see the help page).
^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY (ed.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 147–148, 154–157. ISBN 9780071481274. Neurons from the SNc densely innervate the dorsal striatum where they play a critical role in the learning and execution of motor programs. Neurons from the VTA innervate the ventral striatum (nucleus accumbens), olfactory bulb, amygdala, hippocampus, orbital and medial prefrontal cortex, and cingulate cortex. VTA DA neurons play a critical role in motivation, reward-related behavior, attention, and multiple forms of memory. ... Thus, acting in diverse terminal fields, dopamine confers motivational salience ("wanting") on the reward itself or associated cues (nucleus accumbens shell region), updates the value placed on different goals in light of this new experience (orbital prefrontal cortex), helps consolidate multiple forms of memory (amygdala and hippocampus), and encodes new motor programs that will facilitate obtaining this reward in the future (nucleus accumbens core region and dorsal striatum). ... DA has multiple actions in the prefrontal cortex. It promotes the "cognitive control" of behavior: the selection and successful monitoring of behavior to facilitate attainment of chosen goals. Aspects of cognitive control in which DA plays a role include working memory, the ability to hold information "on line" in order to guide actions, suppression of prepotent behaviors that compete with goal-directed actions, and control of attention and thus the ability to overcome distractions. ... Noradrenergic projections from the LC thus interact with dopaminergic projections from the VTA to regulate cognitive control. ...{{cite book}}: CS1 maint: multiple names: authors list (link)
^ Lees C, Hopkins J (2013). "Effect of aerobic exercise on cognition, academic achievement, and psychosocial function in children: a systematic review of randomized control trials". Prev Chronic Dis. 10: E174. doi:10.5888/pcd10.130010. PMC 3809922. PMID 24157077. This omission is relevant, given the evidence that aerobic-based physical activity generates structural changes in the brain, such as neurogenesis, angiogenesis, increased hippocampal volume, and connectivity (12,13). In children, a positive relationship between aerobic fitness, hippocampal volume, and memory has been found (12,13). ... Mental health outcomes included reduced depression and increased self-esteem, although no change was found in anxiety levels (18). ... This systematic review of the literature found that APA is positively associated with cognition, academic achievement, behavior, and psychosocial functioning outcomes. Importantly, Shephard also showed that curriculum time reassigned to APA still results in a measurable, albeit small, improvement in academic performance (24). ... The actual aerobic-based activity does not appear to be a major factor; interventions used many different types of APA and found similar associations. In positive association studies, intensity of the aerobic activity was moderate to vigorous. The amount of time spent in APA varied significantly between studies; however, even as little as 45 minutes per week appeared to have a benefit.
^ Carvalho A, Rea IM, Parimon T, Cusack BJ (2014). "Physical activity and cognitive function in individuals over 60 years of age: a systematic review". Clin Interv Aging. 9: 661–682. doi:10.2147/CIA.S55520. PMC 3990369. PMID 24748784.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ ^a ^b ^c ^d ^e ^f Denham J, Marques FZ, O'Brien BJ, Charchar FJ (February 2014). "Exercise: putting action into our epigenome". Sports Med. 44 (2): 189–209. doi:10.1007/s40279-013-0114-1. PMID 24163284. Aerobic physical exercise produces numerous health benefits in the brain. Regular engagement in physical exercise enhances cognitive functioning, increases brain neurotrophic proteins, such as brain-derived neurotrophic factor (BDNF), and prevents cognitive diseases [76–78]. Recent findings highlight a role for aerobic exercise in modulating chromatin remodelers [21, 79–82]. ... These results were the first to demonstrate that acute and relatively short aerobic exercise modulates epigenetic modifications. The transient epigenetic modifications observed due to chronic running training have also been associated with improved learning and stress-coping strategies, epigenetic changes and increased c-Fos-positive neurons ... Nonetheless, these studies demonstrate the existence of epigenetic changes after acute and chronic exercise and show they are associated with improved cognitive function and elevated markers of neurotrophic factors and neuronal activity (BDNF and c-Fos). ... The aerobic exercise training-induced changes to miRNA profile in the brain seem to be intensity-dependent [164]. These few studies provide a basis for further exploration into potential miRNAs involved in brain and neuronal development and recovery via aerobic exercise.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ Ehlert T, Simon P, Moser DA (February 2013). "Epigenetics in sports". Sports Med. 43 (2): 93–110. doi:10.1007/s40279-012-0012-y. PMID 23329609. Alterations in epigenetic modification patterns have been demonstrated to be dependent on exercise and growth hormone (GH), insulin-like growth factor 1 (IGF-1), and steroid administration. ... the authors observed improved stress coping in exercised subjects. Investigating the dentate gyrus, a brain region which is involved in learning and coping with stressful and traumatic events, they could show that this effect is mediated by increased phosphorylation of serine 10 combined with H3K14 acetylation, which is associated with local opening of condensed chromatin. Consequently, they found increased immediate early gene expression as shown for c-FOS (FBJ murine osteosarcoma viral oncogene homologue).{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ ^a ^b ^c ^d ^e ^f ^g Phillips C, Baktir MA, Srivatsan M, Salehi A (2014). "Neuroprotective effects of physical activity on the brain: a closer look at trophic factor signaling". Front Cell Neurosci. 8: 170. doi:10.3389/fncel.2014.00170. PMC 4064707. PMID 24999318. Moreover, recent evidence suggests that myokines released by exercising muscles affect the expression of brain-derived neurotrophic factor synthesis in the dentate gyrus of the hippocampus, a finding that could lead to the identification of new and therapeutically important mediating factors. ... Studies have demonstrated the intensity of exercise training is positively correlated with BDNF plasma levels in young, healthy individuals (Ferris et al., 2007). Resistance exercise has also been shown to elevate serum BDNF levels in young individuals (Yarrow et al., 2010). Moreover, it has been shown that moderate levels of physical activity in people with AD significantly increased plasma levels of BDNF (Coelho et al., 2014). ... In humans, it has been shown that 4 h of rowing activity leads to increased levels of plasma BDNF from the internal jugular (an indicator of central release from the brain) and radial artery (an indicator of peripheral release; Rasmussen et al., 2009). Seifert et al. (2010) reported that basal release of BDNF increases following 3 months endurance training in young and healthy individuals, as measured from the jugular vein. These trends are augmented by rodent studies showing that endurance training leads to increased synthesis of BDNF in the hippocampal formation (Neeper et al., 1995, 1996). ... Both BDNF and IGF-1 play a significant role in cognition and motor function in humans. ... Multiple large-scale studies in humans have shown that serum levels of IGF-1 are correlated with fitness and as well as body mass indices (Poehlman and Copeland, 1990). Furthermore, animal studies have shown that exercise in rats is associated with increased amounts of IGF-1 in the CSF.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
^ ^a ^b ^c Heinonen I, Kalliokoski KK, Hannukainen JC, Duncker DJ, Nuutila P, Knuuti J (November 2014). "Organ-Specific Physiological Responses to Acute Physical Exercise and Long-Term Training in Humans". Physiology (Bethesda). 29 (6): 421–436. doi:10.1152/physiol.00067.2013. PMID 25362636. The Effects of Acute Exercise
Studies in humans and animals have shown that brain blood flow remains largely unchanged in response to acute exercise[,] ... does not increase with increasing exercise intensity[, and] ... increased metabolic demands of active brain parts are mostly met by redistributing oxygen supply, although changes in oxygen extraction may also contribute. During exercise, blood flow is directed to the areas controlling locomotor, vestibular, cardiorespiratory, and visual functions (8, 91), facilitated by direct communication of neurons and vascular cells (94, 134). ... with increasing exercise intensity, brain glucose uptake decreases (75) as the uptake and utilization of lactate is enhanced (65, 139, 182). Regional differences in brain glucose uptake are also evident, which is furthermore influenced by the level of physical fitness. Thus the decrease in glucose uptake in the dorsal part of the anterior cingulate cortex during exercise is significantly more pronounced in subjects with higher exercise capacity (75) ...
The Effects of Long-Term Exercise Training
[A] physically active lifestyle has been shown to lead to higher cognitive performance and delayed or prevented neurological conditions in humans (71, 101, 143, 191). ... The production of brain-derived neurotrophic factor (BDNF), a key protein regulating maintenance and growth of neurons, is known to be stimulated by acute exercise (145), which may contribute to learning and memory. BDNF is released from brain already at rest but increases two- to threefold during exercise, which contributes 70–80% of circulating BDNF (145).{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ ^a ^b Cooney GM, Dwan K, Greig CA, Lawlor DA, Rimer J, Waugh FR, McMurdo M, Mead GE (2013). "Exercise for depression". Cochrane Database Syst Rev. 9: CD004366. doi:10.1002/14651858.CD004366.pub6. PMID 24026850. Exercise is moderately more effective than a control intervention for reducing symptoms of depression, but analysis of methodologically robust trials only shows a smaller effect in favour of exercise. When compared to psychological or pharmacological therapies, exercise appears to be no more effective, though this conclusion is based on a few small trials.
^ ^a ^b ^c Mura G, Moro MF, Patten SB, Carta MG (2014). "Exercise as an add-on strategy for the treatment of major depressive disorder: a systematic review". CNS Spectr. 19 (6): 496–508. doi:10.1017/S1092852913000953. PMID 24589012. Considered overall, the studies included in the present review showed a strong effectiveness of exercise combined with antidepressants. ... Conclusions
This is the first review to have focused on exercise as an add-on strategy in the treatment of MDD. Our findings corroborate some previous observations that were based on few studies and which were difficult to generalize.^{41,51,73,92,93} Given the results of the present article, it seems that exercise might be an effective strategy to enhance the antidepressant effect of medication treatments. Moreover, we hypothesize that the main role of exercise on treatment-resistant depression is in inducing neurogenesis by increasing BDNF expression, as was demonstrated by several recent studies.
^ ^a ^b Josefsson T, Lindwall M, Archer T (2014). "Physical exercise intervention in depressive disorders: meta-analysis and systematic review". Scand J Med Sci Sports. 24 (2): 259–272. doi:10.1111/sms.12050. PMID 23362828. Physical activity has also become increasingly and firmly associated with improvements in mental health and psychological well-being (Mutrie, 2000; Landers & Arent, 2007). In particular, exercise is believed to be effective in preventing depression and also to significantly reduce depressive symptoms in clinical as well as in nonclinical populations (O'Neal et al., 2000; Landers & Arent, 2007). Several correlational studies show that exercise is negatively related to depressive symptoms (e.g., Galper et al., 2006; Hassmén et al., 2000). Moreover, a considerably large number of intervention studies have by now investigated the effect of various exercise programs on depression and the vast majority of them indicate that exercise significantly reduces depression (e.g., Blumenthal et al., 2007; Martinsen et al., 1985; Singh et al., 1997). ... To date, it is not possible to determine exactly how effective exercise is in reducing depression symptoms in clinical and nonclinical depressed populations, respectively. However, the results from the present meta-analysis as well as from seven earlier meta-analyses (North et al., 1990; Craft & Landers, 1998; Lawlor & Hopker, 2001; Stathopoulou et al., 2006; Mead et al., 2009; Rethorst et al., 2009; Krogh et al., 2011) indicate that exercise has a moderate to large antidepressant effect. Some meta-analytic results (e.g., Rethorst et al., 2009) suggest that exercise may be even more efficacious for clinically depressed people. ... In short, our final conclusion is that exercise may well be recommended for people with mild and moderate depression who are willing, motivated, and physically healthy enough to engage in such a program.
^ ^a ^b Rosenbaum S, Tiedemann A, Sherrington C, Curtis J, Ward PB (2014). "Physical activity interventions for people with mental illness: a systematic review and meta-analysis". J Clin Psychiatry. 75 (9): 964–974. doi:10.4088/JCP.13r08765. PMID 24813261. This systematic review and meta-analysis found that physical activity reduced depressive symptoms among people with a psychiatric illness. The current meta-analysis differs from previous studies, as it included participants with depressive symptoms with a variety of psychiatric diagnoses (except dysthymia and eating disorders). ... This review provides strong evidence for the antidepressant effect of physical activity; however, the optimal exercise modality, volume, and intensity remain to be determined. ... Conclusion
Few interventions exist whereby patients can hope to achieve improvements in both psychiatric symptoms and physical health simultaneously without significant risks of adverse effects. Physical activity offers substantial promise for improving outcomes for people living with mental illness, and the inclusion of physical activity and exercise programs within treatment facilities is warranted given the results of this review.
^ Brené S, Bjørnebekk A, Aberg E, Mathé AA, Olson L, Werme M (2007). "Running is rewarding and antidepressive". Physiol. Behav. 92 (1–2): 136–140. doi:10.1016/j.physbeh.2007.05.015. PMC 2040025. PMID 17561174.
^ ^a ^b ^c Torres-Aleman I (2010). "Toward a comprehensive neurobiology of IGF-I". Dev Neurobiol. 70 (5): 384–96. doi:10.1002/dneu.20778. PMID 20186710. However, the adult brain appears to have an external input from serum IGF-I, where this anabolic peptide is abundant. Thus, serum IGF-I has been proven to be an important modulator of brain activity, including higher functions such as cognition. Many of these functions can be ascribed to its tissue-remodeling activity as IGF-I modulates adult neurogenesis and angiogenesis. Other activities are cytoprotective; indeed, IGF-I can be considered a key neuroprotective peptide. Still others pertain to the functional characteristics of brain cells, such as cell excitability. Through modulation of membrane channels and neurotransmission, IGF-I impinges directly on neuronal plasticity, the cellular substrate of cognition. However, to fully understand the role of IGF-I in the brain, we have to sum the actions of locally produced IGF-I to those of serum IGF-I ... An operational approach to overcome this limitation would be to consider IGF-I as a signal coupling environmental influences on body metabolism with brain function. Or in a more colloquial way, we may say that IGF-I links body "fitness" with brain fitness
^ ^a ^b ^c Aberg D (2010). "Role of the growth hormone/insulin-like growth factor 1 axis in neurogenesis". Endocr Dev. 17: 63–76. doi:10.1159/000262529. PMID 19955757. The growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis is not only involved in brain growth, development and myelination, but also in brain plasticity as indexed by neurogenesis. This may have links to various cognitive effects of GH and IGF-1. GH and IGF-1 affect the genesis of neurons, astrocytes, endothelial cells and oligodendrocytes. Specifically, IGF-1 increases progenitor cell proliferation and numbers of new neurons, oligodendrocytes, and blood vessels in the dentate gyrus of the hippocampus. In the adult cerebral cortex IGF-1 only affects oligodendrogenesis. ... Altogether, data suggest that both exogenous and endogenous GH and/or IGF-1 may be used as agents to enhance cell genesis and neurogenesis in the adult brain. ... GH and IGF-1 have been shown to affect a multitude of mechanisms, including neurogenesis, oligodendrogenesis, angiogenesis, glutamate receptor activation, cholinergic system, dopaminergic reward system, monoamine abundance, dendritic arborization, astrocyte communication via connexin 43, and opioid receptor abundance ... IGF-1 also reaches the brain via both the capillary bed BBB and via the blood-CSF barrier. It appears that IGF-1 uptake is mediated by a specific carrier both in the capillary bed BBB [40] and in the blood-CSF barrier [41, 42]. Moreover, IGF-1 transport across the BBB can be either increased, such as by exercise [43] ... Thus, although not fully characterized, there appear to be mechanisms for transport of both GH and IGF-1 across the BBB. ... Interestingly, exercise is a factor known to enhance cell genesis in the brain, and it appears that IGF-1 is a key mediator of the effect of exercise in terms of cell genesis in the adult brain [52, 53]. ... IGF-1 treatment enhances neurogenesis [52, 53, 55], oligodendrogenesis [56, 58] and angiogenesis [59]. ... As physical exercise has positive effects in many diseases as well as in normal health, it is of interest that circulating IGF-1 as been shown to be one of the mediators of enhanced neurogenesis in the hippocampus.
^ ^a ^b ^c Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY (ed.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 221, 412. ISBN 9780071481274. BDNF, CNTF, insulin-like growth factor-1 (IGF-1), and VEGF have been proven to support motor neuron survival in vitro and in vivo. ... VEGF exerts its effects through two receptor tyrosine kinases, VEGFR1 (also known as flt-1) and VEGFR2 (or flk-1). VEGF and its receptors are expressed in neurons and glia, and this expression is highly up-regulated by hypoxia. The neurotrophic properties of VEGF were first identified when mutations in the VEGF promoter of mice resulted in ALS-like symptoms. Subsequently, VEGF was found to rescue hypoxia-induced motor neuron death both in vivo and in vitro. Recently, a polymorphism in the VEGF promoter sequence was identified in a subset of ALS patients. It is thought that low VEGF levels may underlie motor neuron degeneration in at least one group of patients, but measurement of VEGF in ALS patients has proven difficult. VEGF may also be important for response to stroke and other forms of neural injury. ... One of the prototypical triggers for apoptosis, at least in vitro, is the withdrawal of neurotrophic factors. Neurotrophic factor receptors, such as the TrkA receptor for NGF or the IGF-I receptor for insulin-like growth factor, activate prosurvival signaling cascades{{cite book}}: CS1 maint: multiple names: authors list (link)
^ Gatti R, De Palo EF, Antonelli G, Spinella P (2012). "IGF-I/IGFBP system: metabolism outline and physical exercise". J. Endocrinol. Invest. 35 (7): 699–707. doi:10.3275/8456. PMID 22714057.
^ ^a ^b Cite error: The named reference Fitness mechanism was invoked but never defined (see the help page).
^ ^a ^b Bouchard J, Villeda SA (2015). "Aging and brain rejuvenation as systemic events". J. Neurochem. 132 (1): 5–19. doi:10.1111/jnc.12969. PMC 4301186. PMID 25327899. The beneficial effects of exercise extend beyond peripheral tissues to also include the brain. ... Because of the blood–brain barrier, it was traditionally thought that the beneficial effects of exercise on the CNS were not orchestrated through systemic changes in the periphery. However, recent studies suggest that the effects of exercise are, in part, mediated by changes in the systemic environment. Investigations looking at magnetic resonance imaging (MRI) measurements of cerebral blood volume in the hippocampus have demonstrated that exercise selectively increased the cerebral blood volume of the dentate gyrus, correlating with post-mortem increase in neurogenesis (Pereira et al. 2007). From a molecular perspective, elevated systemic levels of circulating growth factors such as vascular endothelial growth factor and insulin-like growth factor 1 (IGF-1) in blood elicited by increased exercise have been shown to mediate, in part, enhancements in neurogenesis (Trejo et al. 2001; Fabel et al. 2003). Coincidently, circulating levels of IGF-1 decrease with age and the restoration to levels resembling a younger systemic environment up-regulate neurogenesis and improve learning and memory (Lichtenwalner et al. 2001; Darnaudery et al. 2006).
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure^14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption^14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. Cite error: The named reference "Nestler" was defined multiple times with different content (see the help page).
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t ^u ^v ^w Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–1122. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader, 2008). Cite error: The named reference "Natural and drug addictions" was defined multiple times with different content (see the help page).
^ Zlebnik NE, Hedges VL, Carroll ME, Meisel RL (2014). "Chronic wheel running affects cocaine-induced c-Fos expression in brain reward areas in rats". Behav. Brain Res. 261: 71–78. doi:10.1016/j.bbr.2013.12.012. PMID 24342748.
^ ^a ^b Nestler EJ (October 2008). "Review. Transcriptional mechanisms of addiction: role of DeltaFosB". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 363 (1507): 3245–3255. doi:10.1098/rstb.2008.0067. PMC 2607320. PMID 18640924. Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure—cited earlier (Renthal et al. in press). The mechanism responsible for ΔFosB repression of c-fos expression is complex and is covered below. ...
Examples of validated targets for ΔFosB in nucleus accumbens ... GluR2 ... dynorphin ... Cdk5 ... NFκB ... c-Fos
Table 3 Cite error: The named reference "c-Fos repression" was defined multiple times with different content (see the help page).
^ ^a ^b ^c ^d Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA (September 2013). "Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis". Neurosci Biobehav Rev. 37 (8): 1622–44. doi:10.1016/j.neubiorev.2013.06.011. PMC 3788047. PMID 23806439. [exercise] efficacy may be related to its ability to normalize glutamatergic and dopaminergic signaling and reverse drug-induced changes in chromatin via epigenetic interactions with brain-derived neurotrophic factor (BDNF) in the reward pathway. ... these data show that exercise can affect dopaminergic signaling at many different levels, which may underlie its ability to modify vulnerability during drug use initiation. Exercise also produces neuroadaptations that may influence an individual's vulnerability to initiate drug use. Consistent with this idea, chronic moderate levels of forced treadmill running blocks not only subsequent methamphetamine-induced conditioned place preference, but also stimulant-induced increases in dopamine release in the NAc (Chen et al., 2008) and striatum (Marques et al., 2008). ... [These] findings indicate the efficacy of exercise at reducing drug intake in drug-dependent individuals ... wheel running [reduces] methamphetamine self-administration under extended access conditions (Engelmann et al., 2013) ... These findings suggest that exercise may "magnitude"-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuro-adaptive changes that develop during and following extended access to the drug. ... Exercise has been proposed as a treatment for drug addiction that may reduce drug craving and risk of relapse. Although few clinical studies have investigated the efficacy of exercise for preventing relapse, the few studies that have been conducted generally report a reduction in drug craving and better treatment outcomes (see Table 4). ... Taken together, these data suggest that the potential benefits of exercise during relapse, particularly for relapse to psychostimulants, may be mediated via chromatin remodeling and possibly lead to greater treatment outcomes.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ ^a ^b Linke SE, Ussher M (2015). "Exercise-based treatments for substance use disorders: evidence, theory, and practicality". Am J Drug Alcohol Abuse. 41 (1): 7–15. doi:10.3109/00952990.2014.976708. PMID 25397661. The limited research conducted suggests that exercise may be an effective adjunctive treatment for SUDs. In contrast to the scarce intervention trials to date, a relative abundance of literature on the theoretical and practical reasons supporting the investigation of this topic has been published. ... numerous theoretical and practical reasons support exercise-based treatments for SUDs, including psychological, behavioral, neurobiological, nearly universal safety profile, and overall positive health effects.
^ ^a ^b "Entrez Gene: FOSB FBJ murine osteosarcoma viral oncogene homolog B".
^ Siderovski DP, Blum S, Forsdyke RE, Forsdyke DR (October 1990). "A set of human putative lymphocyte G0/G1 switch genes includes genes homologous to rodent cytokine and zinc finger protein-encoding genes". DNA and Cell Biology. 9 (8): 579–87. doi:10.1089/dna.1990.9.579. PMID 1702972.
^ Martin-Gallardo A, McCombie WR, Gocayne JD, FitzGerald MG, Wallace S, Lee BM, Lamerdin J, Trapp S, Kelley JM, Liu LI (April 1992). "Automated DNA sequencing and analysis of 106 kilobases from human chromosome 19q13.3". Nature Genetics. 1 (1): 34–9. doi:10.1038/ng0492-34. PMID 1301997. S2CID 1986255.
^ Sabatakos G, Rowe GC, Kveiborg M, Wu M, Neff L, Chiusaroli R, Philbrick WM, Baron R (May 2008). "Doubly truncated FosB isoform (Delta2DeltaFosB) induces osteosclerosis in transgenic mice and modulates expression and phosphorylation of Smads in osteoblasts independent of intrinsic AP-1 activity". Journal of Bone and Mineral Research. 23 (5): 584–95. doi:10.1359/jbmr.080110. PMC 2674536. PMID 18433296.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". The American Journal of Drug and Alcohol Abuse. 40 (6): 428–37. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711.
ΔFosB as a therapeutic biomarker
The strong correlation between chronic drug exposure and ΔFosB provides novel opportunities for targeted therapies in addiction (118), and suggests methods to analyze their efficacy (119). Over the past two decades, research has progressed from identifying ΔFosB induction to investigating its subsequent action (38). It is likely that ΔFosB research will now progress into a new era – the use of ΔFosB as a biomarker. If ΔFosB detection is indicative of chronic drug exposure (and is at least partly responsible for dependence of the substance), then its monitoring for therapeutic efficacy in interventional studies is a suitable biomarker (Figure 2). Examples of therapeutic avenues are discussed herein. ...

Conclusions
ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades, involving effectors such as GluR2 (87,88), Cdk5 (93) and NFkB (100). Moreover, many of these molecular changes identified are now directly linked to the structural, physiological and behavioral changes observed following chronic drug exposure (60,95,97,102). New frontiers of research investigating the molecular roles of ΔFosB have been opened by epigenetic studies, and recent advances have illustrated the role of ΔFosB acting on DNA and histones, truly as a molecular switch (34). As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much needed in addiction.
^ ^a ^b ^c ^d ^e ^f ^g Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.⁴¹ ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.
^ ^a ^b ^c Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T (2012). "Epigenetic regulation in drug addiction". Annals of Agricultural and Environmental Medicine. 19 (3): 491–6. PMID 23020045. For these reasons, ΔFosB is considered a primary and causative transcription factor in creating new neural connections in the reward centre, prefrontal cortex, and other regions of the limbic system. This is reflected in the increased, stable and long-lasting level of sensitivity to cocaine and other drugs, and tendency to relapse even after long periods of abstinence. These newly constructed networks function very efficiently via new pathways as soon as drugs of abuse are further taken ... In this way, the induction of CDK5 gene expression occurs together with suppression of the G9A gene coding for dimethyltransferase acting on the histone H3. A feedback mechanism can be observed in the regulation of these 2 crucial factors that determine the adaptive epigenetic response to cocaine. This depends on ΔFosB inhibiting G9a gene expression, i.e. H3K9me2 synthesis which in turn inhibits transcription factors for ΔFosB. For this reason, the observed hyper-expression of G9a, which ensures high levels of the dimethylated form of histone H3, eliminates the neuronal structural and plasticity effects caused by cocaine by means of this feedback which blocks ΔFosB transcription
^ Ohnishi YN, Ohnishi YH, Vialou V, Mouzon E, LaPlant Q, Nishi A, Nestler EJ (January 2015). "Functional role of the N-terminal domain of ΔFosB in response to stress and drugs of abuse". Neuroscience. 284: 165–70. doi:10.1016/j.neuroscience.2014.10.002. PMC 4268105. PMID 25313003.
^ Nakabeppu Y, Nathans D (February 1991). "A naturally occurring truncated form of FosB that inhibits Fos/Jun transcriptional activity". Cell. 64 (4): 751–9. doi:10.1016/0092-8674(91)90504-R. PMID 1900040. S2CID 23904956.
^ ^a ^b ^c ^d ^e Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M (2012). "Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms". Journal of Psychoactive Drugs. 44 (1): 38–55. doi:10.1080/02791072.2012.662112. PMC 4040958. PMID 22641964.
^ ^a ^b ^c Nestler EJ (October 2008). "Review. Transcriptional mechanisms of addiction: role of DeltaFosB". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 363 (1507): 3245–55. doi:10.1098/rstb.2008.0067. PMC 2607320. PMID 18640924. Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure—cited earlier (Renthal et al. in press). The mechanism responsible for ΔFosB repression of c-fos expression is complex and is covered below. ...
Examples of validated targets for ΔFosB in nucleus accumbens ... GluR2 ... dynorphin ... Cdk5 ... NFκB ... c-Fos
Table 3
^ Renthal W, Nestler EJ (August 2008). "Epigenetic mechanisms in drug addiction". Trends in Molecular Medicine. 14 (8): 341–50. doi:10.1016/j.molmed.2008.06.004. PMC 2753378. PMID 18635399.
^ Renthal W, Kumar A, Xiao G, Wilkinson M, Covington HE, Maze I, Sikder D, Robison AJ, LaPlant Q, Dietz DM, Russo SJ, Vialou V, Chakravarty S, Kodadek TJ, Stack A, Kabbaj M, Nestler EJ (May 2009). "Genome-wide analysis of chromatin regulation by cocaine reveals a role for sirtuins". Neuron. 62 (3): 335–48. doi:10.1016/j.neuron.2009.03.026. PMC 2779727. PMID 19447090.
^ Sabatakos G, Sims NA, Chen J, Aoki K, Kelz MB, Amling M, Bouali Y, Mukhopadhyay K, Ford K, Nestler EJ, Baron R (September 2000). "Overexpression of DeltaFosB transcription factor(s) increases bone formation and inhibits adipogenesis". Nature Medicine. 6 (9): 985–90. doi:10.1038/79683. PMID 10973317. S2CID 20302360.
^ ^a ^b ^c ^d ^e Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nature Reviews Neuroscience. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB serves as one of the master control proteins governing this structural plasticity. ... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. ... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net result is c-fos gene repression.
Figure 4: Epigenetic basis of drug regulation of gene expression
^ ^a ^b ^c ^d ^e Nestler EJ, Barrot M, Self DW (September 2001). "DeltaFosB: a sustained molecular switch for addiction". Proceedings of the National Academy of Sciences of the United States of America. 98 (20): 11042–6. Bibcode:2001PNAS...9811042N. doi:10.1073/pnas.191352698. PMC 58680. PMID 11572966.
^ Salaya-Velazquez NF, López-Muciño LA, Mejía-Chávez S, Sánchez-Aparicio P, Domínguez-Guadarrama AA, Venebra-Muñoz A (February 2020). "Anandamide and sucralose change ΔFosB expression in the reward system". NeuroReport. 31 (3): 240–244. doi:10.1097/WNR.0000000000001400. PMID 31923023. S2CID 210149592.
^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. ISBN 978-0-07-148127-4.
^ Volkow ND, Koob GF, McLellan AT (January 2016). "Neurobiologic Advances from the Brain Disease Model of Addiction". New England Journal of Medicine. 374 (4): 363–371. doi:10.1056/NEJMra1511480. PMC 6135257. PMID 26816013. Substance-use disorder: A diagnostic term in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other drugs that causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home. Depending on the level of severity, this disorder is classified as mild, moderate, or severe.
Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder.
^ ^a ^b ^c Renthal W, Nestler EJ (September 2009). "Chromatin regulation in drug addiction and depression". Dialogues in Clinical Neuroscience. 11 (3): 257–268. doi:10.31887/DCNS.2009.11.3/wrenthal. PMC 2834246. PMID 19877494. [Psychostimulants] increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein (CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes including fosB and c-fos in response to psychostimulant exposure. ΔFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg, c-fos) where it recruits HDAC1 as a corepressor. ... Chronic exposure to psychostimulants increases glutamatergic [signaling] from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5.
Figure 2: Psychostimulant-induced signaling events
^ Broussard JI (January 2012). "Co-transmission of dopamine and glutamate". The Journal of General Physiology. 139 (1): 93–96. doi:10.1085/jgp.201110659. PMC 3250102. PMID 22200950. Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.
^ Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014. Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the "brain reward circuit". Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. ... Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain.
^ Cadet JL, Brannock C, Jayanthi S, Krasnova IN (2015). "Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat". Molecular Neurobiology. 51 (2): 696–717 (Figure 1). doi:10.1007/s12035-014-8776-8. PMC 4359351. PMID 24939695.
^ ^a ^b ^c ^d Nestler EJ (December 2012). "Transcriptional mechanisms of drug addiction". Clinical Psychopharmacology and Neuroscience. 10 (3): 136–143. doi:10.9758/cpn.2012.10.3.136. PMC 3569166. PMID 23430970. The 35-37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. ... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. ... ΔFosB overexpression in nucleus accumbens induces NFκB ... In contrast, the ability of ΔFosB to repress the c-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase
^ ^a ^b Hyman SE, Malenka RC, Nestler EJ (2006). "Neural mechanisms of addiction: the role of reward-related learning and memory". Annual Review of Neuroscience. 29: 565–98. doi:10.1146/annurev.neuro.29.051605.113009. PMID 16776597.
^ Steiner H, Van Waes V (January 2013). "Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants". Progress in Neurobiology. 100: 60–80. doi:10.1016/j.pneurobio.2012.10.001. PMC 3525776. PMID 23085425.
^ Kanehisa Laboratories (29 October 2014). "Alcoholism – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014.
^ Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P (February 2009). "Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens". Proceedings of the National Academy of Sciences of the United States of America. 106 (8): 2915–20. Bibcode:2009PNAS..106.2915K. doi:10.1073/pnas.0813179106. PMC 2650365. PMID 19202072.
^ ^a ^b ^c ^d Nestler EJ (January 2014). "Epigenetic mechanisms of drug addiction". Neuropharmacology. 76 Pt B: 259–268. doi:10.1016/j.neuropharm.2013.04.004. PMC 3766384. PMID 23643695. Short-term increases in histone acetylation generally promote behavioral responses to the drugs, while sustained increases oppose cocaine's effects, based on the actions of systemic or intra-NAc administration of HDAC inhibitors. ... Genetic or pharmacological blockade of G9a in the NAc potentiates behavioral responses to cocaine and opiates, whereas increasing G9a function exerts the opposite effect (Maze et al., 2010; Sun et al., 2012a). Such drug-induced downregulation of G9a and H3K9me2 also sensitizes animals to the deleterious effects of subsequent chronic stress (Covington et al., 2011). Downregulation of G9a increases the dendritic arborization of NAc neurons, and is associated with increased expression of numerous proteins implicated in synaptic function, which directly connects altered G9a/H3K9me2 in the synaptic plasticity associated with addiction (Maze et al., 2010).
G9a appears to be a critical control point for epigenetic regulation in NAc, as we know it functions in two negative feedback loops. It opposes the induction of ΔFosB, a long-lasting transcription factor important for drug addiction (Robison and Nestler, 2011), while ΔFosB in turn suppresses G9a expression (Maze et al., 2010; Sun et al., 2012a). ... Also, G9a is induced in NAc upon prolonged HDAC inhibition, which explains the paradoxical attenuation of cocaine's behavioral effects seen under these conditions, as noted above (Kennedy et al., 2013). GABAA receptor subunit genes are among those that are controlled by this feedback loop. Thus, chronic cocaine, or prolonged HDAC inhibition, induces several GABAA receptor subunits in NAc, which is associated with increased frequency of inhibitory postsynaptic currents (IPSCs). In striking contrast, combined exposure to cocaine and HDAC inhibition, which triggers the induction of G9a and increased global levels of H3K9me2, leads to blockade of GABAA receptor and IPSC regulation.
^ Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (February 2013). "Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator". The Journal of Neuroscience. 33 (8): 3434–42. doi:10.1523/JNEUROSCI.4881-12.2013. PMC 3865508. PMID 23426671.
^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and addictive disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 384–385. ISBN 9780071481274.
^ ^a ^b McCowan TJ, Dhasarathy A, Carvelli L (February 2015). "The Epigenetic Mechanisms of Amphetamine". J. Addict. Prev. 2015 (Suppl 1). PMC 4955852. PMID 27453897. Epigenetic modifications caused by addictive drugs play an important role in neuronal plasticity and in drug-induced behavioral responses. Although few studies have investigated the effects of AMPH on gene regulation (Table 1), current data suggest that AMPH acts at multiple levels to alter histone/DNA interaction and to recruit transcription factors which ultimately cause repression of some genes and activation of other genes. Importantly, some studies have also correlated the epigenetic regulation induced by AMPH with the behavioral outcomes caused by this drug, suggesting therefore that epigenetics remodeling underlies the behavioral changes induced by AMPH. If this proves to be true, the use of specific drugs that inhibit histone acetylation, methylation or DNA methylation might be an important therapeutic alternative to prevent and/or reverse AMPH addiction and mitigate the side effects generate by AMPH when used to treat ADHD.
^ ^a ^b ^c ^d Walker DM, Cates HM, Heller EA, Nestler EJ (February 2015). "Regulation of chromatin states by drugs of abuse". Curr. Opin. Neurobiol. 30: 112–121. doi:10.1016/j.conb.2014.11.002. PMC 4293340. PMID 25486626. Studies investigating general HDAC inhibition on behavioral outcomes have produced varying results but it seems that the effects are specific to the timing of exposure (either before, during or after exposure to drugs of abuse) as well as the length of exposure
^ ^a ^b Primary references involving sodium butyrate:

• Kennedy PJ, Feng J, Robison AJ, Maze I, Badimon A, Mouzon E, Chaudhury D, Damez-Werno DM, Haggarty SJ, Han MH, Bassel-Duby R, Olson EN, Nestler EJ (April 2013). "Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation". Nat. Neurosci. 16 (4): 434–440. doi:10.1038/nn.3354. PMC 3609040. PMID 23475113. While acute HDAC inhibition enhances the behavioral effects of cocaine or amphetamine^1,3,4,13,14, studies suggest that more chronic regimens block psychostimulant-induced plasticity^3,5,11,12. ... The effects of pharmacological inhibition of HDACs on psychostimulant-induced plasticity appear to depend on the timecourse of HDAC inhibition. Studies employing co-administration procedures in which inhibitors are given acutely, just prior to psychostimulant administration, report heightened behavioral responses to the drug^1,3,4,13,14. In contrast, experimental paradigms like the one employed here, in which HDAC inhibitors are administered more chronically, for several days prior to psychostimulant exposure, show inhibited expression³ or decreased acquisition of behavioral adaptations to drug^5,11,12. The clustering of seemingly discrepant results based on experimental methodologies is interesting in light of our present findings. Both HDAC inhibitors and psychostimulants increase global levels of histone acetylation in NAc. Thus, when co-administered acutely, these drugs may have synergistic effects, leading to heightened transcriptional activation of psychostimulant-regulated target genes. In contrast, when a psychostimulant is given in the context of prolonged, HDAC inhibitor-induced hyperacetylation, homeostatic processes may direct AcH3 binding to the promoters of genes (e.g., G9a) responsible for inducing chromatin condensation and gene repression (e.g., via H3K9me2) in order to dampen already heightened transcriptional activation. Our present findings thus demonstrate clear cross talk among histone PTMs and suggest that decreased behavioral sensitivity to psychostimulants following prolonged HDAC inhibition might be mediated through decreased activity of HDAC1 at H3K9 KMT promoters and subsequent increases in H3K9me2 and gene repression.

• Simon-O'Brien E, Alaux-Cantin S, Warnault V, Buttolo R, Naassila M, Vilpoux C (July 2015). "The histone deacetylase inhibitor sodium butyrate decreases excessive ethanol intake in dependent animals". Addict Biol. 20 (4): 676–689. doi:10.1111/adb.12161. PMID 25041570. S2CID 28667144. Altogether, our results clearly demonstrated the efficacy of NaB in preventing excessive ethanol intake and relapse and support the hypothesis that HDACi may have a potential use in alcohol addiction treatment.

• Castino MR, Cornish JL, Clemens KJ (April 2015). "Inhibition of histone deacetylases facilitates extinction and attenuates reinstatement of nicotine self-administration in rats". PLOS ONE. 10 (4): e0124796. Bibcode:2015PLoSO..1024796C. doi:10.1371/journal.pone.0124796. PMC 4399837. PMID 25880762. treatment with NaB significantly attenuated nicotine and nicotine + cue reinstatement when administered immediately ... These results provide the first demonstration that HDAC inhibition facilitates the extinction of responding for an intravenously self-administered drug of abuse and further highlight the potential of HDAC inhibitors in the treatment of drug addiction.
^ Kyzar EJ, Pandey SC (August 2015). "Molecular mechanisms of synaptic remodeling in alcoholism". Neurosci. Lett. 601: 11–9. doi:10.1016/j.neulet.2015.01.051. PMC 4506731. PMID 25623036. Increased HDAC2 expression decreases the expression of genes important for the maintenance of dendritic spine density such as BDNF, Arc, and NPY, leading to increased anxiety and alcohol-seeking behavior. Decreasing HDAC2 reverses both the molecular and behavioral consequences of alcohol addiction, thus implicating this enzyme as a potential treatment target (Fig. 3). HDAC2 is also crucial for the induction and maintenance of structural synaptic plasticity in other neurological domains such as memory formation [115]. Taken together, these findings underscore the potential usefulness of HDAC inhibition in treating alcohol use disorders ... Given the ability of HDAC inhibitors to potently modulate the synaptic plasticity of learning and memory [118], these drugs hold potential as treatment for substance abuse-related disorders. ... Our lab and others have published extensively on the ability of HDAC inhibitors to reverse the gene expression deficits caused by multiple models of alcoholism and alcohol abuse, the results of which were discussed above [25,112,113]. This data supports further examination of histone modifying agents as potential therapeutic drugs in the treatment of alcohol addiction ... Future studies should continue to elucidate the specific epigenetic mechanisms underlying compulsive alcohol use and alcoholism, as this is likely to provide new molecular targets for clinical intervention.
^ Kheirabadi GR, Ghavami M, Maracy MR, Salehi M, Sharbafchi MR (2016). "Effect of add-on valproate on craving in methamphetamine depended patients: A randomized trial". Advanced Biomedical Research. 5: 149. doi:10.4103/2277-9175.187404. PMC 5025910. PMID 27656618.
^ Hope BT (May 1998). "Cocaine and the AP-1 transcription factor complex". Annals of the New York Academy of Sciences. 844 (1): 1–6. Bibcode:1998NYASA.844....1H. doi:10.1111/j.1749-6632.1998.tb08216.x. PMID 9668659. S2CID 11683570.
^ ^a ^b Kelz MB, Chen J, Carlezon WA, Whisler K, Gilden L, Beckmann AM, Steffen C, Zhang YJ, Marotti L, Self DW, Tkatch T, Baranauskas G, Surmeier DJ, Neve RL, Duman RS, Picciotto MR, Nestler EJ (September 1999). "Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine". Nature. 401 (6750): 272–6. Bibcode:1999Natur.401..272K. doi:10.1038/45790. PMID 10499584. S2CID 4390717.
^ ^a ^b Colby CR, Whisler K, Steffen C, Nestler EJ, Self DW (March 2003). "Striatal cell type-specific overexpression of DeltaFosB enhances incentive for cocaine". The Journal of Neuroscience. 23 (6): 2488–93. doi:10.1523/JNEUROSCI.23-06-02488.2003. PMC 6742034. PMID 12657709.
^ Cao X, Yasuda T, Uthayathas S, Watts RL, Mouradian MM, Mochizuki H, Papa SM (May 2010). "Striatal overexpression of DeltaFosB reproduces chronic levodopa-induced involuntary movements". The Journal of Neuroscience. 30 (21): 7335–43. doi:10.1523/JNEUROSCI.0252-10.2010. PMC 2888489. PMID 20505100.
^ ^a ^b ^c ^d ^e Du H, Nie S, Chen G, Ma K, Xu Y, Zhang Z, Papa SM, Cao X (2015). "Levetiracetam Ameliorates L-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats Inducing Critical Molecular Changes in the Striatum". Parkinson's Disease. 2015: 253878. doi:10.1155/2015/253878. PMC 4322303. PMID 25692070. Furthermore, the transgenic overexpression of ΔFosB reproduces AIMs in hemiparkinsonian rats without chronic exposure to L-DOPA [13]. ... FosB/ΔFosB immunoreactive neurons increased in the dorsolateral part of the striatum on the lesion side with the used antibody that recognizes all members of the FosB family. All doses of levetiracetam decreased the number of FosB/ΔFosB positive cells (from 88.7 ± 1.7/section in the control group to 65.7 ± 0.87, 42.3 ± 1.88, and 25.7 ± 1.2/section in the 15, 30, and 60 mg groups, resp.; Figure 2). These results indicate dose-dependent effects of levetiracetam on FosB/ΔFosB expression. ... In addition, transcription factors expressed with chronic events such as ΔFosB (a truncated splice variant of FosB) are overexpressed in the striatum of rodents and primates with dyskinesias [9, 10]. ... Furthermore, ΔFosB overexpression has been observed in postmortem striatal studies of Parkinsonian patients chronically treated with L-DOPA [26]. ... Of note, the most prominent effect of levetiracetam was the reduction of ΔFosB expression, which cannot be explained by any of its known actions on vesicular protein or ion channels. Therefore, the exact mechanism(s) underlying the antiepileptic effects of levetiracetam remains uncertain.
^ "ROLE OF ΔFOSB IN THE NUCLEUS ACCUMBENS". Mount Sinai School of Medicine. NESTLER LAB: LABORATORY OF MOLECULAR PSYCHIATRY. Archived from the original on 28 June 2017. Retrieved 6 September 2014.
^ Furuyashiki T, Deguchi Y (August 2012). "[Roles of altered striatal function in major depression]". Brain and Nerve = Shinkei Kenkyū No Shinpo (in Japanese). 64 (8): 919–26. PMID 22868883.
^ Nestler EJ (April 2015). "∆FosB: a transcriptional regulator of stress and antidepressant responses". European Journal of Pharmacology. 753: 66–72. doi:10.1016/j.ejphar.2014.10.034. PMC 4380559. PMID 25446562. In more recent years, prolonged induction of ∆FosB has also been observed within NAc in response to chronic administration of certain forms of stress. Increasing evidence indicates that this induction represents a positive, homeostatic adaptation to chronic stress, since overexpression of ∆FosB in this brain region promotes resilience to stress, whereas blockade of its activity promotes stress susceptibility. Chronic administration of several antidepressant medications also induces ∆FosB in the NAc, and this induction is required for the therapeutic-like actions of these drugs in mouse models. Validation of these rodent findings is the demonstration that depressed humans, examined at autopsy, display reduced levels of ∆FosB within the NAc. As a transcription factor, ΔFosB produces this behavioral phenotype by regulating the expression of specific target genes, which are under current investigation. These studies of ΔFosB are providing new insight into the molecular basis of depression and antidepressant action, which is defining a host of new targets for possible therapeutic development.
^ Dietz DM, Kennedy PJ, Sun H, Maze I, Gancarz AM, Vialou V, Koo JW, Mouzon E, Ghose S, Tamminga CA, Nestler EJ (February 2014). "ΔFosB induction in prefrontal cortex by antipsychotic drugs is associated with negative behavioral outcomes". Neuropsychopharmacology. 39 (3): 538–44. doi:10.1038/npp.2013.255. PMC 3895248. PMID 24067299.

External links

ROLE OF ΔFOSB IN THE NUCLEUS ACCUMBENS Archived 28 June 2017 at the Wayback Machine
KEGG Pathway – human alcohol addiction
KEGG Pathway – human amphetamine addiction
KEGG Pathway – human cocaine addiction
FOSB+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

Structural growth

Reviews of neuroimaging studies indicate that consistent aerobic exercise increases gray matter volume in several brain regions associated with memory, cognitive control, motor function, and reward processing;^[1]^[2]^[3] the most prominent gains are seen in the prefrontal cortex and hippocampus, which are primarily associated with cognitive control and memory processing respectively.^[2]^[4]^[3] Moreover, the left and right halves of the prefrontal cortex, which is divided by the medial longitudinal fissure, appear to become more interconnected in response to consistent aerobic exercise.^[5] Two reviews indicate that marked improvements in prefrontal and hippocampal gray matter volume occur in healthy adults that engage in medium intensity exercise for several months.^[2]^[6] Other regions of the brain that demonstrate moderate or less significant gains in gray matter volume during neuroimaging include the anterior cingulate cortex, parietal cortex, cerebellum, caudate nucleus, and nucleus accumbens.^[1]^[2]^[3]^[7]

Regular exercise has been shown to counter the shrinking of the hippocampus and memory impairment that naturally occurs in late adulthood.^[1]^[2]^[3] Sedentary adults over age 55 show a 1–2% decline in hippocampal volume annually.^[3]^[8] A neuroimaging study with a sample of 120 adults revealed that participating in regular aerobic exercise increased the volume of the left hippocampus by 2.12% and the right hippocampus by 1.97% over a one-year period.^[3]^[8] Subjects in the low intensity stretching group who had higher fitness levels at baseline showed less hippocampal volume loss, providing evidence for exercise being protective against age-related cognitive decline.^[8] In general, individuals that exercise more over a given period have greater hippocampal volumes and better memory function.^[1]^[3] Aerobic exercise has also been shown to induce growth in the white matter tracts in the anterior corpus callosum, which normally shrink with age.^[1]^[6]

The various functions of the brain structures that show exercise-induced increases in gray matter volume include:

Prefrontal and anterior cingulate cortices – required for the cognitive control of behavior, particularly: working memory, attentional control, decision-making, cognitive flexibility, social cognition, and inhibitory control of behavior;^[9]^[10] implicated in attention deficit hyperactivity disorder (ADHD) and addiction^[9]
Nucleus accumbens – responsible for reward perception, motivation, and positive reinforcement; implicated in addiction^[11]
Hippocampus – responsible for storage and consolidation of declarative memory and spatial memory;^[2]^[12] implicated in depression^[3]
Cerebellum – responsible for motor coordination and motor learning^[13]
Caudate nucleus – responsible for stimulus-response learning and inhibitory control; implicated in Parkinson's disease, Huntington's disease and ADHD^[9]^[12]
Parietal cortex – responsible for sensory perception, working memory, and attention^[9]^[14]

Cognitive control and memory

Concordant with the functional roles of the brain structures that exhibit increased gray matter volumes, exercise has been shown to improve numerous aspects of cognitive control and memory function.^[1]^[5]^[4]^[15]^[16] In particular, consistent aerobic exercise has been shown to improve attentional control,^{[note 1]} attention span, information processing speed, cognitive flexibility (e.g., task switching), inhibitory control,^{[note 2]} working memory updating and capacity,^{[note 3]} declarative memory,^{[note 4]} and spatial memory.^[1]^[2]^[5]^[4]^[15]^[16] Individuals who have a sedentary lifestyle tend to have impaired cognitive control relative to other more physically active non-exercisers.^[4]^[15] A reciprocal relationship between exercise and cognitive control has also been noted: improvements in control processes, such as attentional control and inhibitory control, increase an individual's tendency to exercise.^[4] A systematic review of studies conducted on children suggests that some of the exercise-induced improvements in executive function are apparent after single bouts of exercise, while other aspects (e.g., attentional control) only improve following consistent exercise on a regular basis.^[16]

ADHD is a developmental neuropsychiatric disorder in which there are deficits in certain aspects of cognitive control, particularly attentional control and inhibitory control.^[9] Regular physical exercise, particularly aerobic exercise, is an effective adjunct treatment for ADHD, although the best type and intensity is not currently known.^[19]^[20] In non-randomized trials, physical exercise has been shown to result in better behavior and motor abilities without causing any side effects in ADHD populations.^[19]^[20]

Short-term effects

Psychological stress and cortisol

The "stress hormone", cortisol, is a glucocorticoid that binds to glucocorticoid receptors.^[21]^[22]^[23] Psychological stress induces the release of cortisol from the adrenal gland by activating the hypothalamic–pituitary–adrenal axis (HPA axis).^[21]^[22]^[23] Short-term increases in cortisol levels are associated with adaptive cognitive improvements, such as enhanced inhibitory control;^[24]^[22]^[23] however, excessively high exposure or prolonged exposure to high levels of cortisol causes impairments in cognitive control and has neurotoxic effects in the human brain.^[24]^[15]^[23] For example, chronic psychological stress decreases BDNF expression which has detrimental effects on hippocampal volume and can lead to depression.^[24]^[21]

As a physical stressor, aerobic exercise stimulates cortisol secretion in an intensity-dependent manner;^[22] however, it does not result in long-term increases in cortisol production since this exercise-induced effect on cortisol is a response to transient negative energy balance.^{[note 5]}^[22] Individuals who have recently exercised exhibit improvements in stress coping behaviors.^[25]^[26]^[24] Aerobic exercise increases physical fitness and lowers neuroendocrine (i.e., HPA axis) reactivity and therefore reduces the biological response to psychological stress in humans (e.g., reduced cortisol release and attenuated heart rate response).^[24]^[27] Exercise also reverses stress-induced decreases in BDNF expression and signaling in the brain, thereby acting as a buffer against stress-related diseases like depression.^[24]^[21]^[27]

Euphoria

Continuous exercise can produce short-term euphoria, an affective state associated with feelings of profound contentment, elation, and well-being, which is colloquially known as a "runner's high" in distance running or a "rower's high" in crew.^[28]^[29] Current medical reviews indicate that several endogenous euphoriants are responsible for producing exercise-related euphoria, specifically phenethylamine (a stimulant), β-endorphin (an opioid), and anandamide (a cannabinoid).^[30]^[31]^[32]^[33]^[34]

Neurotransmitters, neuromodulators, and neuropeptides

β-Phenylethylamine

β-Phenylethylamine, commonly referred to as phenethylamine, is a potent endogenous trace amine neuromodulator which has the same biomolecular targets as amphetamine;^[35]^[36] consequently, both compounds interact with monoamine neurons in the central nervous system in an identical manner. Thirty minutes of moderate to high intensity physical exercise has been shown to induce an enormous increase in urinary β-phenylacetic acid, the primary metabolite of phenethylamine.^[30]^[31]^[32] Two reviews noted a study where the mean 24 hour urinary β-phenylacetic acid concentration following just 30 minutes of intense exercise rose 77% above its base level;^[30]^[31]^[32] the reviews suggest that phenethylamine synthesis sharply increases during physical exercise during which it is rapidly metabolized due to its short half-life of roughly 30 seconds.^[30]^[31]^[32]^[37] In a resting state, phenethylamine is synthesized in catecholamine neurons from L-phenylalanine by aromatic amino acid decarboxylase at approximately the same rate at which dopamine is produced.^[37]

In light of this observation, the original paper and both reviews suggest that phenethylamine plays a prominent role in mediating the mood-enhancing euphoric effects of a runner's high, as both phenethylamine and amphetamine are potent euphoriants.^[30]^[31]^[32]

β-Endorphin

β-Endorphins (contracted from "endogenous morphine") are endogenous opioid neuropeptides that bind to μ-opioid receptors, in turn producing euphoria and pain relief.^[33] A meta-analytic review found that exercise significantly increases the secretion of β-endorphins and that this secretion is correlated with improved mood states.^[33] Moderate intensity exercise produces the greatest increase in β-endorphin synthesis, while higher and lower intensity forms of exercise are associated with smaller increases in β-endorphin synthesis.^[33]

A review on β-endorphins and exercise noted that an individual's mood improves for the remainder of the day following physical exercise and that one's mood is positively correlated with overall daily physical activity level.^[33] Exercise-induced improvements in mood occur in sedentary individuals, recreational exercisers, and marathoner runners, but recreational athletes and marathon runners experience more pronounced mood-lifting effects from exercising.^[33]

Anandamide

Anandamide is an endogenous cannabinoid neurotransmitter that binds to cannabinoid receptors.^[34] It has been shown that aerobic exercise causes an increase in plasma anandamide levels, where the magnitude of this increase is highest at moderate exercise intensity (i.e., exercising at ~70–80% maximum heart rate).^[34] Increases in plasma anandamide levels are associated with psychoactive effects because anandamide is able to cross the blood–brain barrier and act within the central nervous system.^[34] Thus, because anandamide is a euphoriant and aerobic exercise is associated with euphoric effects, it has been proposed that anandamide partly mediates the short-term mood-lifting effects of exercise (e.g., the euphoria of a runner's high) via exercise-induced increases in its synthesis.^[28]^[34]

Classical monoamines

Glutamate

Glutamate, one of the most common neurochemicals in the brain, is an excitatory neurotransmitter involved in many aspects of brain function, including learning and memory.^[38] Glutamate regulates certain exercise-related memory processes primarily via cotransmission with dopamine in the dopaminergic projections from the ventral tegmental area;^[39]^[40] in particular, exercise has been shown to modulate (normalize) glutamatergic cotransmission in the mesocorticolimbic dopamine pathway.^[41]

Children

Education and learning implications

Physical activity has contributed to reducing childhood obesity and the incidences of cardiovascular disease, colon & breast cancer, and depression & anxiety across the adult lifespan.^[42] The connection between physical activity and cognitive performance has been investigated in a number of studies, many of which observed a positive correlation between the two. Sibley and Etnier (2003) performed a meta-analysis that looked at the relationship in children. They reported a beneficial relationship in the categories of perceptual skills, intelligence quotient, achievement, verbal tests, mathematic tests, developmental level/academic readiness and other, with the exception of memory, that was found to be unrelated to physical activity.^[43] The correlation was strongest for the age ranges of 4–7 and 11–13 years.^[43] On the other hand, Chaddock and colleagues (2011) found results that contrasted Sibley and Etnier's meta-analysis. In their study, the hypothesis was that lower-fit children would perform poorly in executive control of memory and have smaller hippocampal volumes compared to higher-fit children.^[44] Instead of physical activity being unrelated to memory in children between 4 and 18 years of age, it may be that preadolescents of higher fitness have larger hippocampal volumes, than preadolescents of lower fitness. According to a previous study done by Chaddock and colleagues (Chaddock et al. 2010), a larger hippocampal volume would result in better executive control of memory.^[45] They concluded that hippocampal volume was positively associated with performance on relational memory tasks.^[45] Their findings are the first to indicate that aerobic fitness may relate to the structure and function of the preadolescent human brain.^[45] In Best’s (2010) meta-analysis of the effect of activity on children’s executive function, there are two distinct experimental designs used to assess aerobic exercise on cognition. The first is chronic exercise, in which children are randomly assigned to a schedule of aerobic exercise over several weeks and later assessed at the end.^[46] The second is acute exercise, which examines the immediate changes in cognitive functioning after each session.^[46] The results of both suggest that aerobic exercise may briefly aid children’s executive function and also influence more lasting improvements to executive function.^[46] Other studies have suggested that exercise is unrelated to academic performance, perhaps due to the parameters used to determine exactly what academic achievement is.^[42] This area of study has been a focus for education boards that make decisions on whether physical education should be implemented in the school curriculum, how much time should be dedicated to physical education, and its impact on other academic subjects.^[43]

Animal studies have also shown that exercise can impact brain development early on in life. Mice that had access to running wheels and other such exercise equipment had better neuronal growth in the neural systems involved in learning and memory.^[42] Neuroimaging of the human brain has yielded similar results, where exercise leads to changes in brain structure and function.^[42] Some investigations have linked low levels of aerobic fitness in children with impaired executive function in older adults, but there is mounting evidence it may also be associated with a lack of selective attention, response inhibition, and interference control.^[44]

Elderly and neurodegenerative disorders

Signs of cognitive decline become more evident with age. Cross-sectional studies have shown a positive link between exercise and general cognitive function in older individuals.^[47] Fitness is associated with better cognitive performance in individuals with cardiovascular disease,^[48] which is associated with an increased rate of cognitive decline during aging. The protective effects of fitness may be relevant to the prevention of cognitive decline due to neurodegenerative disorders. Summarized below are the effects that physical activity is thought to have on three neurodegenerative conditions that usually manifest in mid-to-late adulthood causing cognitive symptoms (Alzheimer's disease, Huntington's disease and Parkinson's disease).

Alzheimer's disease

Alzheimer's Disease is a cortical neurodegenerative disorder and the most prevalent form of dementia, representing approximately 65% of all cases of dementia; it is characterized by impaired cognitive function, behavioral abnormalities, and a reduced capacity to perform basic activities of daily life.^[49]^[50] Two meta-analytic systematic reviews of randomized controlled trials with durations of 3–12 months have examined the effects of physical exercise on the aforementioned characteristics of Alzheimer's disease.^[49]^[50] The reviews found beneficial effects of physical exercise on cognitive function, the rate of cognitive decline, and the ability to perform activities of daily living in individuals with Alzheimer's disease.^[49]^[50] One review suggested that, based upon transgenic mouse models, the cognitive effects of exercise on Alzheimer's disease may result from a reduction in the quantity of amyloid plaque.^[49]^[51]

The Caerphilly Prospective study followed 2,375 male subjects over 30 years and examined the association between healthy lifestyles and dementia, among other factors.^[52] Analyses of the Caerphilly study data have found that exercise is associated with a lower incidence of dementia and a reduction in cognitive impairment.^[52]^[53] A subsequent systematic review of longitudinal studies also found higher levels of physical activity to be associated with a reduction in the risk of dementia and cognitive decline;^[54] this review further asserted that increased physical activity appears to be causally related with these reduced risks.^[54]

Huntington's disease

Huntington's Disease (HD) is an autosomal dominant neurodegenerative disorder leading to a decline in motor skills, chorea, subcortical dementia, and other psychiatric symptoms.^[55]

Physical therapy can be sought to help improve the motor impairments of the disease. The conclusions about the effects of exercise on cognitive function in HD patients have varied across the literature. Pang and colleagues (2006) studied R6/1 transgenic mice models of HD, with results that showed exercise delayed the onset of symptoms and slowed cognitive decline.^[55] On the other hand, another study by Kohl and colleagues (2007) used the R6/2 transgenic mouse model of HDstrain to see if physical activity could stimulate hippocampal neurogenesis from neural stem cells.^[56] Their study found that physical exercise did stimulate cell proliferation and survival in normal healthy mice, but did not enhance hippocampal neurogenesis in the transgenic mice.^[56] They speculated that this result may be due to an effect the mutated Huntingtin gene, and by extension the mutated Huntingtin protein, has on the mechanisms needed for successful hippocampal neurogenesis in HD patients.^[56]

Parkinson's disease

Parkinson's disease (PD) is a movement disorder that produces symptoms such as bradykinesia, rigidity, shaking, and impaired gait.^[57]

A review by Kramer and colleagues (2006) found that some neurotransmitter systems are affected by exercise in a positive way.^[58] A few studies reported seeing an improvement in brain health and cognitive function due to exercise.^[58] One particular study by Kramer and colleagues (1999) found that aerobic training improved executive control processes supported by frontal and prefrontal regions of the brain.^[59] These regions are responsible for the cognitive deficits in PD patients, however there was speculation that the difference in the neurochemical environment in the frontal lobes of PD patients may inhibit the benefit of aerobic exercise.^[60] Nocera and colleagues (2010) performed a case study based on this literature where they gave participants with early-to mid-staged PD, and the control group cognitive/language assessments with exercise regimens. Individuals performed 20 minutes of aerobic exercise three times a week for 8 weeks on a stationary exercise cycle. It was found that aerobic exercise improved several measures of cognitive function,^[60] providing evidence that such exercise regimens may be beneficial to patients with PD.

Notes

^ Attentional control allows an individual to focus their attention on a specific source and ignore other stimuli that compete for one's attention,^[17] such as in the cocktail party effect.
^ Inhibitory control is the process of altering one's learned behavioral responses, sometimes called "prepotent responses", in a way that makes it easier to complete a particular goal.^[9]^[18] Inhibitory control allows individuals to control their impulses and habits when necessary or desired,^[9]^[15]^[18] e.g., to overcome procrastination.
^ Working memory is the form of memory used by an individual at any given moment for active information processing,^[17] such as when reading or writing an encyclopedia article. Working memory has a limited capacity and functions as an information buffer, analogous to a computer's data buffer, that permits the manipulation of information for comprehension, decision-making, and guidance of behavior.^[9]
^ Declarative memory, also known as explicit memory, is the form of memory that pertains to facts and events.^[12]
^ In healthy individuals, this energy deficit resolves simply from eating and drinking a sufficient amount of food and beverage after exercising.

Reference notes

References

^ ^a ^b ^c ^d ^e ^f ^g Cite error: The named reference Comprehensive review was invoked but never defined (see the help page).
^ ^a ^b ^c ^d ^e ^f ^g Cite error: The named reference gray matter was invoked but never defined (see the help page).
^ ^a ^b ^c ^d ^e ^f ^g ^h Erickson KI, Miller DL, Roecklein KA (2012). "The aging hippocampus: interactions between exercise, depression, and BDNF". Neuroscientist. 18 (1): 82–97. doi:10.1177/1073858410397054. PMC 3575139. PMID 21531985. Late adulthood is associated with increased hippocampal atrophy and dysfunction. ... However, there is strong evidence that decreased BDNF is associated with age-related hippocampal dysfunction, memory impairment, and increased risk for depression, whereas increasing BDNF by aerobic exercise appears to ameliorate hippocampal atrophy, improve memory function, and reduce depression. ... For example, longitudinal studies have reported between 1% and 2% annual hippocampal atrophy in adults older than 55 years without dementia ... Over a nine-year period, greater amounts of physical activity in the form of walking are associated with greater gray matter volume in several regions including prefrontal, temporal, and hippocampal areas. ... The prefrontal cortex and hippocampus deteriorate in late adulthood, preceding and leading to deficits in executive and memory function. We examined in this review the evidence that age-related changes in BDNF might at least partially explain hippocampal atrophy and increased risk for memory impairment. We can conclude that 1) decreases in BDNF protein expression are associated with poorer hippocampal function and increased rates of geriatric depression and AD. ... 3) Aerobic exercise enhances executive and memory function and reduces hippocampal atrophy in late adulthood, and this may be partially mediated through a BDNF pathway.
^ ^a ^b ^c ^d ^e Buckley J, Cohen JD, Kramer AF, McAuley E, Mullen SP (2014). "Cognitive control in the self-regulation of physical activity and sedentary behavior". Front Hum Neurosci. 8: 747. doi:10.3389/fnhum.2014.00747. PMC 4179677. PMID 25324754. Recent theory (e.g., Temporal Self-Regulation Theory; Hall and Fong, 2007, 2010, 2013) and evidence suggest that the relation between physical activity and cognitive control is reciprocal (Daly et al., 2013). Most research has focused on the beneficial effects of regular physical activity on executive functions-the set of neural processes that define cognitive control. Considerable evidence shows that regular physical activity is associated with enhanced cognitive functions, including attention, processing speed, task switching, inhibition of prepotent responses and declarative memory (for reviews see Colcombe and Kramer, 2003; Smith et al., 2010; Guiney and Machado, 2013; McAuley et al., 2013). Recent research demonstrates a dose-response relationship between fitness and spatial memory (Erickson et al., 2011) ... The effects of physical activity on cognitive control appear to be underpinned by a variety of brain processes including: increased hippocampal volume, increased gray matter density in the prefrontal cortex (PFC), upregulation of neurotrophins and greater microvascular density ... Together, this research suggests that an improvement in control processes, such as attention and inhibition or interference control, is associated with an improvement in self-regulation of physical activity. ... Hoang et al. (2013) found that young adults who initially exhibited low levels of physical activity and remained relatively inactive for 25 years had nearly twofold greater odds of impaired executive function compared with those who exhibited higher activity levels; very-low physical activity patterns were associated with even more pronounced declines in executive functioning. … sedentary behavior indirectly led to poor executive function through depressive symptoms (Vance et al., 2005). … sedentary individuals display less capacity to quickly and accurately switch between tasks.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
^ ^a ^b ^c Guiney H, Machado L (February 2013). "Benefits of regular aerobic exercise for executive functioning in healthy populations". Psychon Bull Rev. 20 (1): 73–86. doi:10.3758/s13423-012-0345-4. PMID 23229442. Executive functions are strategic in nature and depend on higher-order cognitive processes that underpin planning, sustained attention, selective attention, resistance to interference, volitional inhibition, working memory, and mental flexibility ... Data to date from studies of aging provide strong evidence of exercise-linked benefits related to task switching, selective attention, inhibition of prepotent responses, and working memory capacity; furthermore, cross-sectional fitness data suggest that working memory updating could potentially benefit as well. In young adults, working memory updating is the main executive function shown to benefit from regular exercise, but cross-sectional data further suggest that task-switching and post-error performance may also benefit. In children, working memory capacity has been shown to benefit, and cross-sectional data suggest potential benefits for selective attention and inhibitory control. ... Support for the idea that higher levels of aerobic activity may be associated with superior brain structure has been gained through cross-sectional studies in older adults and children (for a recent review, see Voss, Nagamatsu, et al., 2011). ... only those in the aerobic exercise group exhibited improved connectivity between the left and right prefrontal cortices, two areas that are crucial to the effective functioning of the fronto-executive network. ... Together, these studies provide evidence that regular aerobic exercise benefits control over responses during selective attention in older adults. ... aerobic fitness is a good predictor of performance on tasks that rely relatively heavily on inhibitory control over prepotent responses (e.g., Colcombe et al., 2004, Study 1; Prakash et al., 2011) and also that regular aerobic exercise improves performance on such tasks ... Overall, the results from the span and Sternberg tasks suggest that regular exercise can also confer benefits for the volume of information that children and older adults can hold in mind at one time.
^ ^a ^b Valkanova V, Eguia Rodriguez R, Ebmeier KP (June 2014). "Mind over matter—what do we know about neuroplasticity in adults?". Int Psychogeriatr. 26 (6): 891–909. doi:10.1017/S1041610213002482. PMID 24382194. Control group: Active
Intervention: Aerobic exercise
[Increased GMV in:] Lobes (dorsal anterior cingulate cortex, supplementary motor area, middle frontal gyrus bilaterally); R inferior frontal gyrus, middle frontal gyrus and L superior temporal lobe; increase in the volume of anterior white matter tracts ... ↑GMV anterior hippocampus
^ Ruscheweyh R, Willemer C, Krüger K, Duning T, Warnecke T, Sommer J, Völker K, Ho HV, Mooren F, Knecht S, Flöel A (July 2011). "Physical activity and memory functions: an interventional study". Neurobiol. Aging. 32 (7): 1304–19. doi:10.1016/j.neurobiolaging.2009.08.001. PMID 19716631.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ ^a ^b ^c Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, Kim JS, Heo S, Alves H, White SM, Wojcicki TR, Mailey E, Vieira VJ, Martin SA, Pence BD, Woods JA, McAuley E, Kramer AF (February 2011). "Exercise training increases size of hippocampus and improves memory". Proc. Natl. Acad. Sci. U.S.A. 108 (7): 3017–22. doi:10.1073/pnas.1015950108. PMC 3041121. PMID 21282661.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ ^a ^b ^c ^d ^e ^f ^g ^h Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY (ed.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 313–321. ISBN 9780071481274. • Executive function, the cognitive control of behavior, depends on the prefrontal cortex, which is highly developed in higher primates and especially humans.
• Working memory is a short-term, capacity-limited cognitive buffer that stores information and permits its manipulation to guide decision-making and behavior. ...
These diverse inputs and back projections to both cortical and subcortical structures put the prefrontal cortex in a position to exert what is often called "top-down" control or cognitive control of behavior. ... The prefrontal cortex receives inputs not only from other cortical regions, including association cortex, but also, via the thalamus, inputs from subcortical structures subserving emotion and motivation, such as the amygdala (Chapter 14) and ventral striatum (or nucleus accumbens; Chapter 15). ...
In conditions in which prepotent responses tend to dominate behavior, such as in drug addiction, where drug cues can elicit drug seeking (Chapter 15), or in attention deficit hyperactivity disorder (ADHD; described below), significant negative consequences can result. ... ADHD can be conceptualized as a disorder of executive function; specifically, ADHD is characterized by reduced ability to exert and maintain cognitive control of behavior. Compared with healthy individuals, those with ADHD have diminished ability to suppress inappropriate prepotent responses to stimuli (impaired response inhibition) and diminished ability to inhibit responses to irrelevant stimuli (impaired interference suppression). ... Functional neuroimaging in humans demonstrates activation of the prefrontal cortex and caudate nucleus (part of the striatum) in tasks that demand inhibitory control of behavior. ... Early results with structural MRI show thinning of the cerebral cortex in ADHD subjects compared with age-matched controls in prefrontal cortex and posterior parietal cortex, areas involved in working memory and attention.{{cite book}}: CS1 maint: multiple names: authors list (link)
^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY (ed.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 315. ISBN 9780071481274. However, damage to the prefrontal cortex has a significant deleterious effect on social behavior, decision making, and adaptive responding to the changing circumstances of life. ... Several subregions of the prefrontal cortex have been implicated in partly distinct aspects of cognitive control, although these distinctions remain somewhat vaguely defined. The anterior cingulate cortex is involved in processes that require correct decision-making, as seen in conflict resolution (eg, the Stroop test, see in Chapter 16), or cortical inhibition (eg, stopping one task and switching to another). The medial prefrontal cortex is involved in supervisory attentional functions (eg, action-outcome rules) and behavioral flexibility (the ability to switch strategies). The dorsolateral prefrontal cortex, the last brain area to undergo myelination during development in late adolescence, is implicated in matching sensory inputs with planned motor responses. The ventromedial prefrontal cortex seems to regulate social cognition, including empathy. The orbitofrontal cortex is involved in social decision making and in representing the valuations assigned to different experiences.{{cite book}}: CS1 maint: multiple names: authors list (link)
^ Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY (ed.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 147, 266, 376. ISBN 9780071481274. VTA DA neurons play a critical role in motivation, reward-related behavior (Chapter 15), attention, and multiple forms of memory. This organization of the DA system, wide projection from a limited number of cell bodies, permits coordinated responses to potent new rewards. Thus, acting in diverse terminal fields, dopamine confers motivational salience ("wanting") on the reward itself or associated cues (nucleus accumbens shell region) ... Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward. ... The NAc and VTA are central components of the circuitry underlying reward and memory of reward. As previously mentioned, the activity of dopaminergic neurons in the VTA appears to be linked to reward prediction. The NAc is involved in learning associated with reinforcement ... The shell of the NAc appears to be particularly important to initial drug actions within reward circuitry; addictive drugs appear to have a greater effect on dopamine release in the shell than in the core of the NAc.{{cite book}}: CS1 maint: multiple names: authors list (link)
^ ^a ^b ^c Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY (ed.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 148, 324–328, 438. ISBN 9780071481274. [dopamine] helps consolidate multiple forms of memory (amygdala and hippocampus) ... the specific crucial structures underlying the ability to store declarative memories are the hippocampus, the subicular complex, and the entorhinal cortex ... These findings strongly suggest that LTP in the hippocampus is required for at least some forms of learning and memory known to be dependent on this brain region. ... Evidence that the caudate nucleus and putamen influence stimulus-response learning comes from lesion studies in rodents and primates and from neuroimaging studies in humans and from studies of human disease. In Parkinson disease, the dopaminergic innervation of the caudate and putamen is severely compromised by the death of dopamine neurons in the substantia nigra pars compacta (Chapter 17). Patients with Parkinson disease have normal declarative memory ... However, they have marked impairments of stimulus-response learning. Patients with Parkinson disease or other basal ganglia disorders such as Huntington disease (in which caudate neurons themselves are damaged) have deficits in other procedural learning tasks, such as the acquisition of new motor programs. ... Huntington disease is associated with degenerative changes that are most apparent in the caudate nucleus and putamen.{{cite book}}: CS1 maint: multiple names: authors list (link)
^ Grimaldi G, Argyropoulos GP, Bastian A, Cortes M, Davis NJ, Edwards DJ, Ferrucci R, Fregni F, Galea JM, Hamada M, Manto M, Miall RC, Morales-Quezada L, Pope PA, Priori A, Rothwell J, Tomlinson SP, Celnik P (2014). "Cerebellar Transcranial Direct Current Stimulation (ctDCS): A Novel Approach to Understanding Cerebellar Function in Health and Disease". Neuroscientist. doi:10.1177/1073858414559409. PMID 25406224.
^ Sereno MI, Huang RS (2014). "Multisensory maps in parietal cortex". Curr. Opin. Neurobiol. 24 (1): 39–46. doi:10.1016/j.conb.2013.08.014. PMC 3969294. PMID 24492077.
^ ^a ^b ^c ^d ^e Diamond A (2013). "Executive functions". Annu Rev Psychol. 64: 135–168. doi:10.1146/annurev-psych-113011-143750. PMC 4084861. PMID 23020641. Core EFs are inhibition [response inhibition (self-control—resisting temptations and resisting acting impulsively) and interference control (selective attention and cognitive inhibition)], working memory, and cognitive flexibility (including creatively thinking "outside the box," seeing anything from different perspectives, and quickly and flexibly adapting to changed circumstances). ... EFs and prefrontal cortex are the first to suffer, and suffer disproportionately, if something is not right in your life. They suffer first, and most, if you are stressed (Arnsten 1998, Liston et al. 2009, Oaten & Cheng 2005), sad (Hirt et al. 2008, von Hecker & Meiser 2005), lonely (Baumeister et al. 2002, Cacioppo & Patrick 2008, Campbell et al. 2006, Tun et al. 2012), sleep deprived (Barnes et al. 2012, Huang et al. 2007), or not physically fit (Best 2010, Chaddock et al. 2011, Hillman et al. 2008). Any of these can cause you to appear to have a disorder of EFs, such as ADHD, when you do not. You can see the deleterious effects of stress, sadness, loneliness, and lack of physical health or fitness at the physiological and neuroanatomical level in prefrontal cortex and at the behavioral level in worse EFs (poorer reasoning and problem solving, forgetting things, and impaired ability to exercise discipline and self-control). ...
EFs can be improved (Diamond & Lee 2011, Klingberg 2010). ... At any age across the life cycle EFs can be improved, including in the elderly and in infants. There has been much work with excellent results on improving EFs in the elderly by improving physical fitness (Erickson & Kramer 2009, Voss et al. 2011) ... Inhibitory control (one of the core EFs) involves being able to control one's attention, behavior, thoughts, and/or emotions to override a strong internal predisposition or external lure, and instead do what's more appropriate or needed. Without inhibitory control we would be at the mercy of impulses, old habits of thought or action (conditioned responses), and/or stimuli in the environment that pull us this way or that. Thus, inhibitory control makes it possible for us to change and for us to choose how we react and how we behave rather than being unthinking creatures of habit. It doesn't make it easy. Indeed, we usually are creatures of habit and our behavior is under the control of environmental stimuli far more than we usually realize, but having the ability to exercise inhibitory control creates the possibility of change and choice.
^ ^a ^b ^c Janssen M, Toussaint HM, van Mechelen W, Verhagen EA (2014). "Effects of acute bouts of physical activity on children's attention: a systematic review of the literature". Springerplus. 3: 410. doi:10.1186/2193-1801-3-410. PMC 4132441. PMID 25133092. There is weak evidence for the effect of acute bouts of physical activity on attention. ... Fortunately, the literature-base on the acute effect of PA on the underlying cognitive processes of academic performance is growing. Hillman et al. (2011) found in their review a positive effect of acute PA on brain health and cognition in children, but concluded it was complicated to compare the different studies due to the different outcome measures (e.g. memory, response time and accuracy, attention, and comprehension). Therefore, this review focuses on the sole outcome measure 'attention' as a mediator for cognition and achievement.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ ^a ^b Cite error: The named reference Malenka pathways was invoked but never defined (see the help page).
^ ^a ^b Ilieva IP, Hook CJ, Farah MJ (2015). "Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis". J Cogn Neurosci: 1–21. doi:10.1162/jocn_a_00776. PMID 25591060.
^ ^a ^b "Exercise reduces the symptoms of attention-deficit/hyperactivity disorder and improves social behaviour, motor skills, strength and neuropsychological parameters". Acta Paediatr. 103 (7): 709–14. July 2014. doi:10.1111/apa.12628. PMID 24612421. Retrieved 14 March 2015. The present review summarises the impact of exercise interventions (1–10 weeks in duration with at least two sessions each week) on parameters related to ADHD in 7-to 13-year-old children. We may conclude that all different types of exercise (here yoga, active games with and without the involvement of balls, walking and athletic training) attenuate the characteristic symptoms of ADHD and improve social behaviour, motor skills, strength and neuropsychological parameters without any undesirable side effects. Available reports do not reveal which type, intensity, duration and frequency of exercise is most effective in this respect and future research focusing on this question with randomised and controlled long-term interventions is warranted. {{cite journal}}: Cite uses deprecated parameter |authors= (help)
^ ^a ^b "Protection from genetic diathesis in attention-deficit/hyperactivity disorder: possible complementary roles of exercise". J Am Acad Child Adolesc Psychiatry. 52 (9): 900–10. September 2013. doi:10.1016/j.jaac.2013.05.018. PMID 23972692. As exercise has been found to enhance neural growth and development, and improve cognitive and behavioural functioning in [healthy] individuals and animal studies, we reviewed the literature on the effects of exercise in children and adolescents with ADHD and animal models of ADHD behaviours.
A limited number of undersized non-randomized, retrospective and cross-sectional studies have investigated the impact of exercise on ADHD and the emotional, behavioural and neuropsychological problems associated with the disorder. The findings from these studies provide some support for the notion that exercise has the potential to act as a protective factor for ADHD. ... Although it remains unclear which role, if any, BDNF plays in the pathophysiology of ADHD, enhanced neural functioning has been suggested to be associated with the reduction of remission of ADHD symptoms.^49,50,72 As exercise can elicit gene expression changes mediated by alterations in DNA methylation³⁸, the possibility emerges that some of the positive effects of exercise could be caused by epigenetic mechanisms, which may set off a cascade of processes instigated by altered gene expression that could ultimately link to a change in brain function. {{cite journal}}: Cite uses deprecated parameter |authors= (help)
^ ^a ^b ^c ^d Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 14: Mood and Emotion". In Sydor A, Brown RY (ed.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 350–359. ISBN 9780071481274. The excessive release of stress hormones, such as cortisol, which occurs in many individuals with mood disorders, may result from hyperfunctioning of the PVN of the hypothalamus, hyperfunctioning of the amygdala (which activates the PVN), or hypofunctioning of the hippocampus (which exerts a potent inhibitory influence on the PVN). ... Chronic stress decreases the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus, which in turn may contribute to the atrophy of CA3 neurons and their increased vulnerability to a variety of neuronal insults. Chronic elevation of glucocorticoid levels is also known to decrease the survival of these neurons. Such activity may increase the dendritic arborizations and survival of the neurons, or help repair or protect the neurons from further damage. ... Stress and glucocorticoids inhibit, and a wide variety of antidepressant drugs, exercise, and enriched environments activate hippocampal neurogenesis.{{cite book}}: CS1 maint: multiple names: authors list (link)
^ ^a ^b ^c ^d ^e Fuqua JS, Rogol AD (July 2013). "Neuroendocrine alterations in the exercising human: implications for energy homeostasis". Metab. Clin. Exp. 62 (7): 911–921. doi:10.1016/j.metabol.2013.01.016. PMID 23415825. Cortisol has wide-ranging effects, including alterations of carbohydrate, protein, and lipid metabolism; catabolic effects on skin, muscle, connective tissue, and bone; immunomodulatory effects; blood pressure and circulatory system regulation; and effects on mood and central nervous system function. In the short term, activation of the HPA axis in response to stress is adaptive. However, long-term stress promoting chronic exposure of tissues to high cortisol concentrations becomes maladaptive. ... Exercise, particularly sustained aerobic activity, is a potent stimulus of cortisol secretion. The circulating concentrations of cortisol are directly proportional to the intensity of exercise as measured by oxygen uptake. As is the case for the GH/IGF-1 and HPG axes, the HPA axis also receives many other inputs, including the light/dark cycle, feeding schedules, immune regulation, and many neurotransmitters that mediate the effects of exercise and physical and psychic stress [52]. ... The HPA is activated by stress, whether physical (exercise) or psychological. ... Thus, a negative net energy balance leads to activation of the HPA axis and the circulating concomitants of the catabolic state in an attempt to keep core processes functional, realizing that the stress of exercise has no effect on cortisol and circulating metabolic substrates beyond the impact of the exercise energy expenditure on energy availability [60]. Thuma et al. [61] had already made the important observation that the reported differences in cortisol levels pre- and post-exercise depended on whether this difference was measured from a single pre-test level or from the physiologic circadian baseline as determined in an independent session in the resting state. By this analytical technique, these investigators showed that increasing energy expenditure led to significant cortisol release. This release was apparent if they subtracted the physiologic circadian baseline from the post-exercise value.
^ ^a ^b ^c ^d Ebner NC, Kamin H, Diaz V, Cohen RA, MacDonald K (January 2015). "Hormones as "difference makers" in cognitive and socioemotional aging processes". Front Psychol. 5: 1595. doi:10.3389/fpsyg.2014.01595. PMC 4302708. PMID 25657633. It is known that chronically elevated levels of the stress hormone cortisol exert neurotoxic effects on the aging brain with negative impacts on cognition and socioemotional functioning. ... Cortisol is a steroid hormone released by the HPA axis in response to challenging situations. As the primary effector of the biological stress response in humans, it is implicated in a diverse array of physiologic, metabolic, immunologic, and psychological processes directed toward successful coping (Sapolsky et al., 2000; Kassel and Herrlich, 2007). Cortisol receptors are well-represented in limbic structures involved in affective response (i.e., hippocampus, hypothalamus, amygdala) and in regions central to executive function such as the prefrontal cortex and anterior cingulate cortex (Dedovic et al., 2009; Joëls and Baram, 2009). As a result, the effects of cortisol extend beyond the stress and threat response system to impact mood, attention, and memory (Lupien and McEwen, 1997; Sapolsky et al., 2000; de Kloet et al., 2005). ... In contrast, evidence indicated positive associations between cortisol levels that were acutely elevated by stress or hydrocortisone administration and inhibitory control (Schlosser et al., 2013) as well as spatial learning (Meyer et al., 2013). Regarding cortisol's effect on memory, the evidence is currently mixed (Schwabe et al., 2012; van Ast et al., 2013). ... There also is evidence that effects of cortisol on cognition vary in a dose-dependent fashion. In particular, there is evidence of cognitive improvements under conditions of moderate, time-limited cortisol elevation but evidence of cognitive impairments when cortisol concentrations are persistent or excessively high (Lupien et al., 1999; Abercrombie et al., 2003; Hupbach and Fieman, 2012; Schilling et al., 2013; Moriarty et al., 2014).{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ ^a ^b ^c ^d ^e ^f Silverman MN, Deuster PA (October 2014). "Biological mechanisms underlying the role of physical fitness in health and resilience". Interface Focus. 4 (5): 20140040. doi:10.1098/rsfs.2014.0040. PMID 25285199. Physical fitness, achieved through regular exercise and/or spontaneous physical activity, can protect against the development of chronic stress- and inflammatory-related disease by optimizing physiological and neuroendocrine stress responsivity, promoting an anti-inflammatory state, and enhancing neuroplasticity and growth factor expression. stress responsive systems are adaptive when activated and terminated in a timely manner, prolonged (or insufficient) activation of these systems can cause a variety of maladaptive responses. ... For example, Rimelle et al. [123] documented significantly lower cortisol and heart rate responses to psychosocial stress (Trier social stress test) in trained men compared with untrained men. Moreover, significantly greater calmness and better mood, and a trend towards lower state anxiety, were noted in these trained men during the stress protocol. ... Whereas hippocampal and/or serum/plasma BDNF levels are downregulated by chronic psychosocial stress and inflammation [138,180,201], central and peripheral BDNF levels can be upregulated by acute exercise [33,198,202,203]. ... Exercise-induced increases in brain monoamines (norepinephrine and serotonin) may also contribute to increased expression of hippocampal BDNF [194]. In addition, other growth factors—insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor—have been shown to play an important role in BDNF-induced effects on neuroplasticity [33,172,190,192], as well as exerting neuroprotective effects of their own [33,214,215], thereby contributing to the beneficial effects of exercise on brain health. Like BDNF, increases in circulating IGF-1 levels in response to acute exercise are only transient and possibly time-dependent as it relates to chronic training (i.e. increases seen after 12 weeks of training) [216]. ... Whereas reduced HPA axis reactivity to a given stressor has repeatedly been reported in physically fit individuals, the finding of reduced sympathetic reactivity is less consistent.
^ Cite error: The named reference epigenome was invoked but never defined (see the help page).
^ Cite error: The named reference sports epigenetics was invoked but never defined (see the help page).
^ ^a ^b Zschucke E, Gaudlitz K, Ströhle A (January 2013). "Exercise and physical activity in mental disorders: clinical and experimental evidence". J Prev Med Public Health. 46 Suppl 1: S12–521. doi:10.3961/jpmph.2013.46.S.S12. PMC 3567313. PMID 23412549. In psychiatric patients, different mechanisms of action for PA and EX have been discussed: On a neurochemical and physiological level, a number of acute changes occur during and following bouts of EX, and several long-term adaptations are related to regular EX training. For instance, EX has been found to normalize reduced levels of brain-derived neurotrophic factor (BDNF) and therefore has neuroprotective or even neurotrophic effects [7–9]. Animal studies found EX-induced changes in different neurotransmitters such as serotonin and endorphins [10,11], which relate to mood, and positive effects of EX on stress reactivity (e.g., the hypothalamus-pituitary-adrenal axis [12,13]). Finally, anxiolytic effects of EX mediated by atrial natriuretic peptide have been reported [14]. Potential psychological mechanisms of action include learning and extinction, changes in body scheme and health attitudes/behaviors, social reinforcement, experience of mastery, shift of external to more internal locus of control, improved coping strategies, or simple distraction [15,16].{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ ^a ^b Raichlen DA, Foster AD, Gerdeman GL, Seillier A, Giuffrida A (2012). "Wired to run: exercise-induced endocannabinoid signaling in humans and cursorial mammals with implications for the 'runner's high'". J. Exp. Biol. 215 (Pt 8): 1331–6. doi:10.1242/jeb.063677. PMID 22442371. Humans report a wide range of neurobiological rewards following moderate and intense aerobic activity, popularly referred to as the 'runner's high', which may function to encourage habitual aerobic exercise. ... Thus, a neurobiological reward for endurance exercise may explain why humans and other cursorial mammals habitually engage in aerobic exercise despite the higher associated energy costs and injury risks
^ Cohen EE, Ejsmond-Frey R, Knight N, Dunbar RI (2010). "Rowers' high: behavioural synchrony is correlated with elevated pain thresholds". Biol. Lett. 6 (1): 106–8. doi:10.1098/rsbl.2009.0670. PMC 2817271. PMID 19755532.
^ ^a ^b ^c ^d ^e Szabo A, Billett E, Turner J (2001). "Phenylethylamine, a possible link to the antidepressant effects of exercise?". Br J Sports Med. 35 (5): 342–343. doi:10.1136/bjsm.35.5.342. PMC 1724404. PMID 11579070. The 24 hour mean urinary concentration of phenylacetic acid was increased by 77% after exercise. ... These results show substantial increases in urinary phenylacetic acid levels 24 hours after moderate to high intensity aerobic exercise. As phenylacetic acid reflects phenylethylamine levels³ , and the latter has antidepressant effects, the antidepressant effects of exercise appear to be linked to increased phenylethylamine concentrations. Furthermore, considering the structural and pharmacological analogy between amphetamines and phenylethylamine, it is conceivable that phenylethylamine plays a role in the commonly reported "runners high" thought to be linked to cerebral β-endorphin activity. The substantial increase in phenylacetic acid excretion in this study implies that phenylethylamine levels are affected by exercise. ... A 30 minute bout of moderate to high intensity aerobic exercise increases phenylacetic acid levels in healthy regularly exercising men. The findings may be linked to the antidepressant effects of exercise.
^ ^a ^b ^c ^d ^e Lindemann L, Hoener MC (2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends Pharmacol. Sci. 26 (5): 274–281. doi:10.1016/j.tips.2005.03.007. PMID 15860375. The pharmacology of TAs might also contribute to a molecular understanding of the well-recognized antidepressant effect of physical exercise [51]. In addition to the various beneficial effects for brain function mainly attributed to an upregulation of peptide growth factors [52,53], exercise induces a rapidly enhanced excretion of the main β-PEA metabolite β-phenylacetic acid (b-PAA) by on average 77%, compared with resting control subjects [54], which mirrors increased β-PEA synthesis in view of its limited endogenous pool half-life of ~30 s [18,55].
^ ^a ^b ^c ^d ^e Berry MD (2007). "The potential of trace amines and their receptors for treating neurological and psychiatric diseases". Rev Recent Clin Trials. 2 (1): 3–19. doi:10.2174/157488707779318107. PMID 18473983. It has also been suggested that the antidepressant effects of exercise are due to an exercise-induced elevation of PE [151].
^ ^a ^b ^c ^d ^e ^f Dinas PC, Koutedakis Y, Flouris AD (2011). "Effects of exercise and physical activity on depression". Ir J Med Sci. 180 (2): 319–325. doi:10.1007/s11845-010-0633-9. PMID 21076975. According to the 'endorphins hypothesis', exercise augments the secretion of endogenous opioid peptides in the brain, reducing pain and causing general euphoria. ... Based upon a large effect size, the results confirmed the endorphins hypothesis demonstrating that exercise leads to an increased secretion of endorphins which, in turn, improved mood states.
β-Endorphin, an endogenous μ-opioid receptor selective ligand, has received much attention in the literature linking endorphins and depression or mood states. ... exercise of sufficient intensity and duration can increase circulating β-endorphin levels. ... Moreover, a recent study demonstrated that exercise and physical activity increased β-endorphin levels in plasma with positive effects on mood. Interestingly, the researchers reported that, independently of sex and age, dynamic anaerobic exercises increased β-endorphin, while resistance and aerobic exercises seem to only have small effects on β-endorphins. ... The results showed that mood tends to be higher in a day an individual exercises as well as that daily activity and exercise overall are strongly linked with mood states. In line with these findings, a recent study showed that exercise significantly improved mood states in non-exercises, recreational exercisers, as well as marathon runners. More importantly, the effects of exercise on mood were twofold in recreational exercisers and marathon runners.
^ ^a ^b ^c ^d ^e Tantimonaco M, Ceci R, Sabatini S, Catani MV, Rossi A, Gasperi V, Maccarrone M (2014). "Physical activity and the endocannabinoid system: an overview". Cell. Mol. Life Sci. 71 (14): 2681–2698. doi:10.1007/s00018-014-1575-6. PMID 24526057. The traditional view that PA engages the monoaminergic and endorphinergic systems has been challenged by the discovery of the endocannabinoid system (ECS), composed of endogenous lipids, their target receptors, and metabolic enzymes. Indeed, direct and indirect evidence suggests that the ECS might mediate some of the PA-triggered effects throughout the body. ... the evidence that PA induces some of the psychotropic effects elicited by the Cannabis sativa active ingredient Δ9-tetrahydrocannabinol (Δ9-THC, Fig. 1), like bliss, euphoria, and peacefulness, strengthened the hypothesis that endocannabinoids (eCBs) might mediate, at least in part, the central and peripheral effects of exercise [14]. ... To our knowledge, the first experimental study aimed at investigating the influence of PA on ECS in humans was carried out in 2003 by Sparling and coworkers [63], who showed increased plasma AEA content after 45 min of moderate intensity exercise on a treadmill or cycle ergometer. Since then, other human studies have shown increased blood concentrations of AEA ... A dependence of the increase of AEA concentration on exercise intensity has also been documented. Plasma levels of AEA significantly increased upon 30 min of moderate exercise (heart rate of 72 and 83 %), but not at lower and significantly higher exercise intensities, where the age-adjusted maximal heart rate was 44 and 92 %, respectively ... Several experimental data support the hypothesis that ECS might, at least in part, explain PA effects on brain functions, because: (1) CB1 is the most abundant GPCR in the brain participating in neuronal plasticity [18]; (2) eCBs are involved in several brain responses that greatly overlap with the positive effects of exercise; (3) eCBs are able to cross the blood–brain barrier [95]; and (4) exercise increases eCB plasma levels [64–67].
^ "β-phenylethylamine: Biological activity". Guide to Pharmacology. The International Union of Basic and Clinical Pharmacology. Retrieved 10 February 2015.
^ "Dexamfetamine: Biological activity". Guide to Pharmacology. The International Union of Basic and Clinical Pharmacology. Retrieved 10 February 2015.
^ ^a ^b Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacol. Ther. 125 (3): 363–375. doi:10.1016/j.pharmthera.2009.11.005. PMID 19948186. Trace amines are metabolized in the mammalian body via monoamine oxidase (MAO; EC 1.4.3.4) (Berry, 2004) (Fig. 2) ... It deaminates primary and secondary amines that are free in the neuronal cytoplasm but not those bound in storage vesicles of the sympathetic neurone ... Similarly, β-PEA would not be deaminated in the gut as it is a selective substrate for MAO-B which is not found in the gut ...
Brain levels of endogenous trace amines are several hundred-fold below those for the classical neurotransmitters noradrenaline, dopamine and serotonin but their rates of synthesis are equivalent to those of noradrenaline and dopamine and they have a very rapid turnover rate (Berry, 2004). Endogenous extracellular tissue levels of trace amines measured in the brain are in the low nanomolar range. These low concentrations arise because of their very short half-life ...
^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 5: Excitatory and Inhibitory Amino Acids". In Sydor A, Brown RY (ed.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 117–130. ISBN 9780071481274. • The major excitatory neurotransmitter in the brain is glutamate; the major inhibitory neurotransmitter is GABA. ...
• The most extensively studied form of synaptic plasticity is long-term potentiation (LTP) in the hippocampus, which is triggered by strong activation of NMDA receptors and the consequent large rise in postsynaptic calcium concentration.
• Long-term depression (LTD), a long-lasting decrease in synaptic strength, also occurs at most excitatory and some inhibitory synapses in the brain. ... The bidirectional control of synaptic strength by LTP and LTD is believed to underlie some forms of learning and memory in the mammalian brain.{{cite book}}: CS1 maint: multiple names: authors list (link)
^ Broussard JI (2012). "Co-transmission of dopamine and glutamate". J. Gen. Physiol. 139 (1): 93–6. doi:10.1085/jgp.201110659. PMC 3250102. PMID 22200950. Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.
^ Descarries L, Bérubé-Carrière N, Riad M, Bo GD, Mendez JA, Trudeau LE (2008). "Glutamate in dopamine neurons: synaptic versus diffuse transmission". Brain Res Rev. 58 (2): 290–302. doi:10.1016/j.brainresrev.2007.10.005. PMID 18042492. Moreover, all TH varicosities which co-localize VGluT2 are synaptic, as if there was a link between the potential of DA axon terminals to release glutamate and their establishment of synaptic junctions. Together with the RT-PCR and in situ hybridization data demonstrating the co-localization of TH and VGluT2 mRNA in mesencephalic neurons of the VTA, these observations raise a number of fundamental questions regarding the functioning of the meso-telencephalic DA system in healthy or diseased brain.
^ Cite error: The named reference Running vs addiction was invoked but never defined (see the help page).
^ ^a ^b ^c ^d Hillman, C.H., Erickson, K.I., and Kramer, A.F. 2008. Be smart, exercise your heart: exercise effects on brain and cognition. Nature Reviews Neuroscience. 9:58–65.
^ ^a ^b ^c Sibley, B. A. and Etnier, J. L. 2003. The Relationship Between Physical Activity and Cognition in Children: A Meta-Analysis. Pediatric Exercise Science. 15(3):243–256.
^ ^a ^b Chaddock, L., Hillman, C. H., Buck, S. M. and Cohen, N. J. 2011. Aerobic Fitness and Executive Control of Relational Memory in Preadolescent Children. Medicine & Science in Sports & Exercise. 43(2):344–349.
^ ^a ^b ^c Chaddock, I., Erickson, K. I., Prakash, R. S., Kim, J. S., Voss, M. A., VanPatter, M. et al.. 2010. A neuroimaging investigation of the association between aerobic fitness, hippocampal volume, and memory performance in preadolescent children. Brain Research. 1358:172–183.
^ ^a ^b ^c Best, J. R. 2010. Effects of physical activity on children’s executive function: Contributions of experimental research on aerobic exercise. Developmental Review. 30(4):331–351. doi: 10.1016/j.brainres.2010.08.049
^ Dik, M. G., Deeg, D. J. H., Visser, M. and Jonker, C. 2003. Early Life Physical Activity and Cognition at Old Age. Journal of Clinical and Experimental Neuropsychology. 25(5):643–653.
^ Swardfager W, Herrmann N, Marzolini S, Saleem M, Kiss A, Shammi P, Oh PI and Lanctôt KL, 2010. Cardiopulmonary fitness is associated with cognitive performance in patients with coronary artery disease. J. Amer. Geriatrics. Soc. 58(8):1519–25.
^ ^a ^b ^c ^d Farina N, Rusted J, Tabet N (January 2014). "The effect of exercise interventions on cognitive outcome in Alzheimer's disease: a systematic review". Int Psychogeriatr. 26 (1): 9–18. doi:10.1017/S1041610213001385. PMID 23962667. Six RCTs were identified that exclusively considered the effect of exercise in AD patients. Exercise generally had a positive effect on rate of cognitive decline in AD. A meta-analysis found that exercise interventions have a positive effect on global cognitive function, 0.75 (95% CI = 0.32–1.17). ... The most prevalent subtype of dementia is Alzheimer's disease (AD), accounting for up to 65.0% of all dementia cases ... Cognitive decline in AD is attributable at least in part to the buildup of amyloid and tau proteins, which promote neuronal dysfunction and death (Hardy and Selkoe, 2002; Karran et al., 2011). Evidence in transgenic mouse models of AD, in which the mice have artificially elevated amyloid load, suggests that exercise programs are able to improve cognitive function (Adlard et al., 2005; Nichol et al., 2007). Adlard and colleagues also determined that the improvement in cognitive performance occurred in conjunction with a reduced amyloid load. Research that includes direct indices of change in such biomarkers will help to determine the mechanisms by which exercise may act on cognition in AD.
^ ^a ^b ^c Rao AK, Chou A, Bursley B, Smulofsky J, Jezequel J (January 2014). "Systematic review of the effects of exercise on activities of daily living in people with Alzheimer's disease". Am J Occup Ther. 68 (1): 50–56. doi:10.5014/ajot.2014.009035. PMID 24367955. Alzheimer's disease (AD) is a progressive neurological disorder characterized by loss in cognitive function, abnormal behavior, and decreased ability to perform basic activities of daily living [(ADLs)] ... All studies included people with AD who completed an exercise program consisting of aerobic, strength, or balance training or any combination of the three. The length of the exercise programs varied from 12 weeks to 12 months. ... Six studies involving 446 participants tested the effect of exercise on ADL performance ... exercise had a large and significant effect on ADL performance (z = 4.07, p < .0001; average effect size = 0.80). ... These positive effects were apparent with programs ranging in length from 12 wk (Santana-Sosa et al., 2008; Teri et al., 2003) and intermediate length of 16 wk (Roach et al., 2011; Vreugdenhil et al., 2012) to 6 mo (Venturelli et al., 2011) and 12 mo (Rolland et al., 2007). Furthermore, the positive effects of a 3-mo intervention lasted 24 mo (Teri et al., 2003). ... No adverse effects of exercise on ADL performance were noted. ... The study with the largest effect size implemented a walking and aerobic program of only 30 min four times a week (Venturelli et al., 2011).
^ Adlard PA, Perreau VM, Pop V, Cotman CW (2005). "Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer's disease". J. Neurosci. 25 (17): 4217–21. doi:10.1523/JNEUROSCI.0496-05.2005. PMID 15858047.
^ ^a ^b Elwood P, Galante J, Pickering J, Palmer S, Bayer A, Ben-Shlomo Y, Longley M, Gallacher J (December 2013). "Healthy lifestyles reduce the incidence of chronic diseases and dementia: evidence from the Caerphilly cohort study". PLoS ONE. 8 (12): e81877. doi:10.1371/journal.pone.0081877. PMC 3857242. PMID 24349147.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ Morgan GS, Gallacher J, Bayer A, Fish M, Ebrahim S, Ben-Shlomo Y (2012). "Physical activity in middle-age and dementia in later life: findings from a prospective cohort of men in Caerphilly, South Wales and a meta-analysis". J. Alzheimers Dis. 31 (3): 569–80. doi:10.3233/JAD-2012-112171. PMID 22647258.
^ ^a ^b Blondell SJ, Hammersley-Mather R, Veerman JL (May 2014). "Does physical activity prevent cognitive decline and dementia?: A systematic review and meta-analysis of longitudinal studies". BMC Public Health. 14: 510. doi:10.1186/1471-2458-14-510. PMC 4064273. PMID 24885250. Longitudinal observational studies show an association between higher levels of physical activity and a reduced risk of cognitive decline and dementia. A case can be made for a causal interpretation. Future research should use objective measures of physical activity, adjust for the full range of confounders and have adequate follow-up length. Ideally, randomised controlled trials will be conducted. ... On the whole the results do, however, lend support to the notion of a causal relationship between physical activity, cognitive decline and dementia, according to the established criteria for causal inference.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ ^a ^b Pang, T.Y.C., Stam, N. C., Nithianantharajah, J., Howard, M. L., and Hannan, A. J. 2006. Differential effects of voluntary physical exercise on behavioral and brain-derived neurotrophic factor expression deficits in Huntington's disease transgenic mice. Neuroscience. 141:569–584.
^ ^a ^b ^c Kohl, Z., Kandasamy, M., Winner, B., Aigner, R., Gross, C., Couillard-Despres et al.. 2007. Physical activity fails to rescue hippocampal neurogenesis deficits in the R6/2 mouse model of Huntington's disease. Trends in Cognitive Sciences. 11(8):342–348.
^ Baatile, J., Langbein, W.E., Weaver, F., Maloney, C., and Jost, M.B. 2000. Effect of exercise on perceived quality of life of individuals with Parkinson's Disease. Journal of Rehabilitation Research and Development. 37(5):529–534.
^ ^a ^b Kramer, A. F., Erickson, K. I. And Colcombe, S. J. 2006. Exercise, cognition, and the aging brain. Journal of Applied Physiology. 101(4):1237–1242.
^ Kramer, A. F., Hahn, S., Cohen, N. J., Banich, M. T., McAuley, Harrison, C. R. et al. 1999. Ageing, fitness and neurocognitive function. Nature. 400:418–419.
^ ^a ^b Nocera, J. R., Altman, L. J. P., Sapienza, C., Okun, M. S. and Hass, C. J. 2010. Can exercise improve language and cognition in Parkinson's disease? A case report. Neurocase: The Neural Basis of Cognition. 16(4):301–306.

[63] In simplest terms, this means that when either amphetamine or sex is perceived as "more alluring or desirable" through reward sensitization, this effect occurs with the other as well.

[68] Inhibitors of class I histone deacetylase (HDAC) enzymes are drugs that inhibit four specific histone-modifying enzymes: HDAC1, HDAC2, HDAC3, and HDAC8. Most of the animal research with HDAC inhibitors has been conducted with four drugs: butyrate salts (mainly sodium butyrate), trichostatin A, valproic acid, and SAHA;^[64]^[65] butyric acid is a naturally occurring short-chain fatty acid in humans, while the latter two compounds are FDA-approved drugs with medical indications unrelated to addiction.

[70] Specifically, prolonged administration of a class I HDAC inhibitor appears to reduce an animal's motivation to acquire and use an addictive drug without affecting an animals motivation to attain other rewards (i.e., it does not appear to cause motivational anhedonia) and reduce the amount of the drug that is self-administered when it is readily available.^[61]^[65]^[66]

[73] Among the few clinical trials that employed a class I HDAC inhibitor, one utilized valproate for methamphetamine addiction.^[68]

[77] In other words, c-Fos repression allows ΔFosB to accumulate within nucleus accumbens medium spiny neurons more rapidly because it is selectively induced in this state.^[38]

[78] ΔFosB has been implicated in causing both increases and decreases in dynorphin expression in different studies;^[37]^[43] this table entry reflects only a decrease.

[52] 
Ion channel
G proteins & linked receptors
(Text color) Transcription factors

[NHM-Plasticity-1] Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY (ed.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 5, 351. ISBN 9780071481274. The clinical actions of fluoxetine, like those of many neuropharmacologic agents, reflect drug-induced neural plasticity, which is the process by which neurons adapt over time in response to chronic disturbance. ... For example, evidence indicates that prolonged increases in cortisol may be damaging to hippocampal neurons and can suppress hippocampal neurogenesis (the generation of new neurons postnatally).{{cite book}}: CS1 maint: multiple names: authors list (link)

[Cerebral_hemodynamics_and_AD-2] Tarumi T, Zhang R (January 2014). "Cerebral hemodynamics of the aging brain: risk of Alzheimer disease and benefit of aerobic exercise". Front Physiol. 5: 6. doi:10.3389/fphys.2014.00006. PMC 3896879. PMID 24478719. Exercise-related improvements in brain function and structure may be conferred by the concurrent adaptations in vascular function and structure. Aerobic exercise increases the peripheral levels of growth factors (e.g., BDNF, IFG-1, and VEGF) which cross the blood-brain barrier (BBB) and stimulate neurogenesis and angiogenesis (Trejo et al., 2001; Lee et al., 2002; Fabel et al., 2003; Lopez-Lopez et al., 2004).{{cite journal}}: CS1 maint: unflagged free DOI (link)

[BDNF_meta_analysis-3] Szuhany KL, Bugatti M, Otto MW (October 2014). "A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor". J Psychiatr Res. 60C: 56–64. doi:10.1016/j.jpsychires.2014.10.003. PMC 4314337. PMID 25455510. Consistent evidence indicates that exercise improves cognition and mood, with preliminary evidence suggesting that brain-derived neurotrophic factor (BDNF) may mediate these effects. The aim of the current meta-analysis was to provide an estimate of the strength of the association between exercise and increased BDNF levels in humans across multiple exercise paradigms. We conducted a meta-analysis of 29 studies (N = 1111 participants) examining the effect of exercise on BDNF levels in three exercise paradigms: (1) a single session of exercise, (2) a session of exercise following a program of regular exercise, and (3) resting BDNF levels following a program of regular exercise. Moderators of this effect were also examined. Results demonstrated a moderate effect size for increases in BDNF following a single session of exercise (Hedges' g = 0.46, p < 0.001). Further, regular exercise intensified the effect of a session of exercise on BDNF levels (Hedges' g = 0.59, p = 0.02). Finally, results indicated a small effect of regular exercise on resting BDNF levels (Hedges' g = 0.27, p = 0.005). ... Effect size analysis supports the role of exercise as a strategy for enhancing BDNF activity in humans{{cite journal}}: CS1 maint: multiple names: authors list (link)

[Comprehensive_review-4] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ Gomez-Pinilla F, Hillman C (January 2013). "The influence of exercise on cognitive abilities". Compr Physiol. 3 (1): 403–428. doi:10.1002/cphy.c110063. PMC 3951958. PMID 23720292. A second recent meta-analysis (162) corroborated Colcombe and Kramer's (30) findings, in that aerobic exercise was related to attention, processing speed, memory, and cognitive control. ... Normal aging results in the loss of brain tissue (31), with markedly larger tissue loss evidenced in the frontal, temporal, and parietal cortices (16, 58, 149). As such, cognitive functions subserved by these brain regions (such as those involved in cognitive control and memory) are expected to decay more dramatically than other aspects of cognition. Specifically, age-related decreases in gray matter volume have been associated with decrements in a variety of cognitive control processes. ... Decreases in gray matter volume may result from several factors including loss in the number of neurons, neuronal shrinkage, reduction in dendritic arborization, and alterations in glia (158). Further, decreases in white matter (brain tissue composed primarily of myelinated nerve fibers) volume, which represent changes in connectivity between neurons, also occur as a result of aging. Loss of white matter volume further relates to performance decrements on a host of cognitive tasks ... aerobic fitness relates to larger hippocampal volume (23) and better relational memory performance (24), during preadolescent childhood. ... Specifically, those assigned to the aerobic training group demonstrated increases in gray matter in the frontal lobes, including the dorsal anterior cingulate cortex (ACC), supplementary motor area, middle frontal gyrus, dorsolateral region of the right inferior frontal gyrus, and the left superior temporal lobe (32). White matter volume changes were also evidenced for the aerobic fitness group with increases in white matter tracts within the anterior third of the corpus callosum (32). ... In addition, aerobic fitness has been shown to promote better functioning of brain, especially in neural networks involved in cognitive control of inhibition and attention (33). ... In addition to BDNF, the actions of IGF-1 and vascular endothelial growth factor (VEGF) (54) are considered essential for the angiogenic and neurogenic effects of exercise in the brain. ... Randomized and crossover clinical trials demonstrate the efficacy of aerobic or resistance training exercise (2–4 months) as a treatment for depression in both young and older individuals. ... exercise seems to have both preventative and therapeutic effects on the course of depression

[gray_matter-5] ^ ^a ^b ^c ^d ^e ^f Erickson KI, Leckie RL, Weinstein AM (September 2014). "Physical activity, fitness, and gray matter volume". Neurobiol. Aging. 35 Suppl 2: S20–528. doi:10.1016/j.neurobiolaging.2014.03.034. PMC 4094356. PMID 24952993. Retrieved 9 December 2014. We conclude that higher cardiorespiratory fitness levels are routinely associated with greater gray matter volume in the prefrontal cortex and hippocampus and less consistently in other regions. We also conclude that physical activity is associated with greater gray matter volume in the same regions that are associated with cardiorespiratory fitness including the prefrontal cortex and hippocampus. ... Meta-analyses (Colcombe and Kramer, 2003; Smith et al., 2010) suggest that the effects of exercise on the brain might not be uniform across all regions and that some brain areas, specifically those areas supporting executive functions, might be more influenced by participation in exercise than areas not as critically involved in executive functions. ... The effects appear to be general in the sense that many different cognitive domains are improved after several months of aerobic exercise, but specific in the sense that executive functions are improved more than other cognitive domains. ... physical activity and exercise may reduce the risk for AD (Barnes and Yaffe, 2011; Podewils et al., 2005; Sofi et al., 2011) ... Erickson et al. (2010) reported that greater amounts of physical activity were associated with greater gray matter volume 9-years later in the prefrontal cortex, anterior cingulate, parietal cortex, cerebellum, and hippocampus. ... higher fitness levels (VO2max) were associated with larger hippocampal volumes, better executive function, and faster processing speed. ... Verstynen et al. (2012) examined the association between cardiorespiratory fitness levels (VO2max) and the size of the basal ganglia ... Verstynen et al. (2012) found that higher fitness levels were associated with greater volume of the caudate nucleus and nucleus accumbens, and in turn, greater volumes were associated with better performance on a task-switching paradigm. ... That is, higher physical activity levels mitigated the detrimental effects of lifetime stress on the size of the hippocampus. ... The few randomized interventions published thus far have found results highly overlapping with the cross-sectional studies and suggest that the prefrontal cortex and hippocampus remain pliable in late life and that moderate intensity exercise for 6 months–1 year is sufficient for changing the size of these areas.{{cite journal}}: CS1 maint: multiple names: authors list (link)

[exercise_benefits-6] Cite error: The named reference exercise benefits was invoked but never defined (see the help page).

[cognitive_control_of_exercise-7] Cite error: The named reference cognitive control of exercise was invoked but never defined (see the help page).

[BDNF_depression-8] Cite error: The named reference BDNF depression was invoked but never defined (see the help page).

[Malenka_pathways-9] Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY (ed.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 147–148, 154–157. ISBN 9780071481274. Neurons from the SNc densely innervate the dorsal striatum where they play a critical role in the learning and execution of motor programs. Neurons from the VTA innervate the ventral striatum (nucleus accumbens), olfactory bulb, amygdala, hippocampus, orbital and medial prefrontal cortex, and cingulate cortex. VTA DA neurons play a critical role in motivation, reward-related behavior, attention, and multiple forms of memory. ... Thus, acting in diverse terminal fields, dopamine confers motivational salience ("wanting") on the reward itself or associated cues (nucleus accumbens shell region), updates the value placed on different goals in light of this new experience (orbital prefrontal cortex), helps consolidate multiple forms of memory (amygdala and hippocampus), and encodes new motor programs that will facilitate obtaining this reward in the future (nucleus accumbens core region and dorsal striatum). ... DA has multiple actions in the prefrontal cortex. It promotes the "cognitive control" of behavior: the selection and successful monitoring of behavior to facilitate attainment of chosen goals. Aspects of cognitive control in which DA plays a role include working memory, the ability to hold information "on line" in order to guide actions, suppression of prepotent behaviors that compete with goal-directed actions, and control of attention and thus the ability to overcome distractions. ... Noradrenergic projections from the LC thus interact with dopaminergic projections from the VTA to regulate cognitive control. ...{{cite book}}: CS1 maint: multiple names: authors list (link)

[Exercise_children-10] Lees C, Hopkins J (2013). "Effect of aerobic exercise on cognition, academic achievement, and psychosocial function in children: a systematic review of randomized control trials". Prev Chronic Dis. 10: E174. doi:10.5888/pcd10.130010. PMC 3809922. PMID 24157077. This omission is relevant, given the evidence that aerobic-based physical activity generates structural changes in the brain, such as neurogenesis, angiogenesis, increased hippocampal volume, and connectivity (12,13). In children, a positive relationship between aerobic fitness, hippocampal volume, and memory has been found (12,13). ... Mental health outcomes included reduced depression and increased self-esteem, although no change was found in anxiety levels (18). ... This systematic review of the literature found that APA is positively associated with cognition, academic achievement, behavior, and psychosocial functioning outcomes. Importantly, Shephard also showed that curriculum time reassigned to APA still results in a measurable, albeit small, improvement in academic performance (24). ... The actual aerobic-based activity does not appear to be a major factor; interventions used many different types of APA and found similar associations. In positive association studies, intensity of the aerobic activity was moderate to vigorous. The amount of time spent in APA varied significantly between studies; however, even as little as 45 minutes per week appeared to have a benefit.

[Associated_review-11] Carvalho A, Rea IM, Parimon T, Cusack BJ (2014). "Physical activity and cognitive function in individuals over 60 years of age: a systematic review". Clin Interv Aging. 9: 661–682. doi:10.2147/CIA.S55520. PMC 3990369. PMID 24748784.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[epigenome-12] ^ ^a ^b ^c ^d ^e ^f Denham J, Marques FZ, O'Brien BJ, Charchar FJ (February 2014). "Exercise: putting action into our epigenome". Sports Med. 44 (2): 189–209. doi:10.1007/s40279-013-0114-1. PMID 24163284. Aerobic physical exercise produces numerous health benefits in the brain. Regular engagement in physical exercise enhances cognitive functioning, increases brain neurotrophic proteins, such as brain-derived neurotrophic factor (BDNF), and prevents cognitive diseases [76–78]. Recent findings highlight a role for aerobic exercise in modulating chromatin remodelers [21, 79–82]. ... These results were the first to demonstrate that acute and relatively short aerobic exercise modulates epigenetic modifications. The transient epigenetic modifications observed due to chronic running training have also been associated with improved learning and stress-coping strategies, epigenetic changes and increased c-Fos-positive neurons ... Nonetheless, these studies demonstrate the existence of epigenetic changes after acute and chronic exercise and show they are associated with improved cognitive function and elevated markers of neurotrophic factors and neuronal activity (BDNF and c-Fos). ... The aerobic exercise training-induced changes to miRNA profile in the brain seem to be intensity-dependent [164]. These few studies provide a basis for further exploration into potential miRNAs involved in brain and neuronal development and recovery via aerobic exercise.{{cite journal}}: CS1 maint: multiple names: authors list (link)

[sports_epigenetics-13] Ehlert T, Simon P, Moser DA (February 2013). "Epigenetics in sports". Sports Med. 43 (2): 93–110. doi:10.1007/s40279-012-0012-y. PMID 23329609. Alterations in epigenetic modification patterns have been demonstrated to be dependent on exercise and growth hormone (GH), insulin-like growth factor 1 (IGF-1), and steroid administration. ... the authors observed improved stress coping in exercised subjects. Investigating the dentate gyrus, a brain region which is involved in learning and coping with stressful and traumatic events, they could show that this effect is mediated by increased phosphorylation of serine 10 combined with H3K14 acetylation, which is associated with local opening of condensed chromatin. Consequently, they found increased immediate early gene expression as shown for c-FOS (FBJ murine osteosarcoma viral oncogene homologue).{{cite journal}}: CS1 maint: multiple names: authors list (link)

[trophic_factor_signaling-14] ^ ^a ^b ^c ^d ^e ^f ^g Phillips C, Baktir MA, Srivatsan M, Salehi A (2014). "Neuroprotective effects of physical activity on the brain: a closer look at trophic factor signaling". Front Cell Neurosci. 8: 170. doi:10.3389/fncel.2014.00170. PMC 4064707. PMID 24999318. Moreover, recent evidence suggests that myokines released by exercising muscles affect the expression of brain-derived neurotrophic factor synthesis in the dentate gyrus of the hippocampus, a finding that could lead to the identification of new and therapeutically important mediating factors. ... Studies have demonstrated the intensity of exercise training is positively correlated with BDNF plasma levels in young, healthy individuals (Ferris et al., 2007). Resistance exercise has also been shown to elevate serum BDNF levels in young individuals (Yarrow et al., 2010). Moreover, it has been shown that moderate levels of physical activity in people with AD significantly increased plasma levels of BDNF (Coelho et al., 2014). ... In humans, it has been shown that 4 h of rowing activity leads to increased levels of plasma BDNF from the internal jugular (an indicator of central release from the brain) and radial artery (an indicator of peripheral release; Rasmussen et al., 2009). Seifert et al. (2010) reported that basal release of BDNF increases following 3 months endurance training in young and healthy individuals, as measured from the jugular vein. These trends are augmented by rodent studies showing that endurance training leads to increased synthesis of BDNF in the hippocampal formation (Neeper et al., 1995, 1996). ... Both BDNF and IGF-1 play a significant role in cognition and motor function in humans. ... Multiple large-scale studies in humans have shown that serum levels of IGF-1 are correlated with fitness and as well as body mass indices (Poehlman and Copeland, 1990). Furthermore, animal studies have shown that exercise in rats is associated with increased amounts of IGF-1 in the CSF.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)

[Organ_response-15] Heinonen I, Kalliokoski KK, Hannukainen JC, Duncker DJ, Nuutila P, Knuuti J (November 2014). "Organ-Specific Physiological Responses to Acute Physical Exercise and Long-Term Training in Humans". Physiology (Bethesda). 29 (6): 421–436. doi:10.1152/physiol.00067.2013. PMID 25362636. The Effects of Acute Exercise
Studies in humans and animals have shown that brain blood flow remains largely unchanged in response to acute exercise[,] ... does not increase with increasing exercise intensity[, and] ... increased metabolic demands of active brain parts are mostly met by redistributing oxygen supply, although changes in oxygen extraction may also contribute. During exercise, blood flow is directed to the areas controlling locomotor, vestibular, cardiorespiratory, and visual functions (8, 91), facilitated by direct communication of neurons and vascular cells (94, 134). ... with increasing exercise intensity, brain glucose uptake decreases (75) as the uptake and utilization of lactate is enhanced (65, 139, 182). Regional differences in brain glucose uptake are also evident, which is furthermore influenced by the level of physical fitness. Thus the decrease in glucose uptake in the dorsal part of the anterior cingulate cortex during exercise is significantly more pronounced in subjects with higher exercise capacity (75) ...
The Effects of Long-Term Exercise Training
[A] physically active lifestyle has been shown to lead to higher cognitive performance and delayed or prevented neurological conditions in humans (71, 101, 143, 191). ... The production of brain-derived neurotrophic factor (BDNF), a key protein regulating maintenance and growth of neurons, is known to be stimulated by acute exercise (145), which may contribute to learning and memory. BDNF is released from brain already at rest but increases two- to threefold during exercise, which contributes 70–80% of circulating BDNF (145).{{cite journal}}: CS1 maint: multiple names: authors list (link)

[Cochrane_exercise_depression-16] Cooney GM, Dwan K, Greig CA, Lawlor DA, Rimer J, Waugh FR, McMurdo M, Mead GE (2013). "Exercise for depression". Cochrane Database Syst Rev. 9: CD004366. doi:10.1002/14651858.CD004366.pub6. PMID 24026850. Exercise is moderately more effective than a control intervention for reducing symptoms of depression, but analysis of methodologically robust trials only shows a smaller effect in favour of exercise. When compared to psychological or pharmacological therapies, exercise appears to be no more effective, though this conclusion is based on a few small trials.

[Exercise_MDD_antidepressant-17] Mura G, Moro MF, Patten SB, Carta MG (2014). "Exercise as an add-on strategy for the treatment of major depressive disorder: a systematic review". CNS Spectr. 19 (6): 496–508. doi:10.1017/S1092852913000953. PMID 24589012. Considered overall, the studies included in the present review showed a strong effectiveness of exercise combined with antidepressants. ... Conclusions
This is the first review to have focused on exercise as an add-on strategy in the treatment of MDD. Our findings corroborate some previous observations that were based on few studies and which were difficult to generalize.^{41,51,73,92,93} Given the results of the present article, it seems that exercise might be an effective strategy to enhance the antidepressant effect of medication treatments. Moreover, we hypothesize that the main role of exercise on treatment-resistant depression is in inducing neurogenesis by increasing BDNF expression, as was demonstrated by several recent studies.

[Exercise_depression_intervention-18] Josefsson T, Lindwall M, Archer T (2014). "Physical exercise intervention in depressive disorders: meta-analysis and systematic review". Scand J Med Sci Sports. 24 (2): 259–272. doi:10.1111/sms.12050. PMID 23362828. Physical activity has also become increasingly and firmly associated with improvements in mental health and psychological well-being (Mutrie, 2000; Landers & Arent, 2007). In particular, exercise is believed to be effective in preventing depression and also to significantly reduce depressive symptoms in clinical as well as in nonclinical populations (O'Neal et al., 2000; Landers & Arent, 2007). Several correlational studies show that exercise is negatively related to depressive symptoms (e.g., Galper et al., 2006; Hassmén et al., 2000). Moreover, a considerably large number of intervention studies have by now investigated the effect of various exercise programs on depression and the vast majority of them indicate that exercise significantly reduces depression (e.g., Blumenthal et al., 2007; Martinsen et al., 1985; Singh et al., 1997). ... To date, it is not possible to determine exactly how effective exercise is in reducing depression symptoms in clinical and nonclinical depressed populations, respectively. However, the results from the present meta-analysis as well as from seven earlier meta-analyses (North et al., 1990; Craft & Landers, 1998; Lawlor & Hopker, 2001; Stathopoulou et al., 2006; Mead et al., 2009; Rethorst et al., 2009; Krogh et al., 2011) indicate that exercise has a moderate to large antidepressant effect. Some meta-analytic results (e.g., Rethorst et al., 2009) suggest that exercise may be even more efficacious for clinically depressed people. ... In short, our final conclusion is that exercise may well be recommended for people with mild and moderate depression who are willing, motivated, and physically healthy enough to engage in such a program.

[Physical_activity_intervention-19] Rosenbaum S, Tiedemann A, Sherrington C, Curtis J, Ward PB (2014). "Physical activity interventions for people with mental illness: a systematic review and meta-analysis". J Clin Psychiatry. 75 (9): 964–974. doi:10.4088/JCP.13r08765. PMID 24813261. This systematic review and meta-analysis found that physical activity reduced depressive symptoms among people with a psychiatric illness. The current meta-analysis differs from previous studies, as it included participants with depressive symptoms with a variety of psychiatric diagnoses (except dysthymia and eating disorders). ... This review provides strong evidence for the antidepressant effect of physical activity; however, the optimal exercise modality, volume, and intensity remain to be determined. ... Conclusion
Few interventions exist whereby patients can hope to achieve improvements in both psychiatric symptoms and physical health simultaneously without significant risks of adverse effects. Physical activity offers substantial promise for improving outcomes for people living with mental illness, and the inclusion of physical activity and exercise programs within treatment facilities is warranted given the results of this review.

[Running_antidepressant-20] Brené S, Bjørnebekk A, Aberg E, Mathé AA, Olson L, Werme M (2007). "Running is rewarding and antidepressive". Physiol. Behav. 92 (1–2): 136–140. doi:10.1016/j.physbeh.2007.05.015. PMC 2040025. PMID 17561174.

[Serum-brain_IGF-1-21] Torres-Aleman I (2010). "Toward a comprehensive neurobiology of IGF-I". Dev Neurobiol. 70 (5): 384–96. doi:10.1002/dneu.20778. PMID 20186710. However, the adult brain appears to have an external input from serum IGF-I, where this anabolic peptide is abundant. Thus, serum IGF-I has been proven to be an important modulator of brain activity, including higher functions such as cognition. Many of these functions can be ascribed to its tissue-remodeling activity as IGF-I modulates adult neurogenesis and angiogenesis. Other activities are cytoprotective; indeed, IGF-I can be considered a key neuroprotective peptide. Still others pertain to the functional characteristics of brain cells, such as cell excitability. Through modulation of membrane channels and neurotransmission, IGF-I impinges directly on neuronal plasticity, the cellular substrate of cognition. However, to fully understand the role of IGF-I in the brain, we have to sum the actions of locally produced IGF-I to those of serum IGF-I ... An operational approach to overcome this limitation would be to consider IGF-I as a signal coupling environmental influences on body metabolism with brain function. Or in a more colloquial way, we may say that IGF-I links body "fitness" with brain fitness

[IGF-1_neuroplasticity-22] Aberg D (2010). "Role of the growth hormone/insulin-like growth factor 1 axis in neurogenesis". Endocr Dev. 17: 63–76. doi:10.1159/000262529. PMID 19955757. The growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis is not only involved in brain growth, development and myelination, but also in brain plasticity as indexed by neurogenesis. This may have links to various cognitive effects of GH and IGF-1. GH and IGF-1 affect the genesis of neurons, astrocytes, endothelial cells and oligodendrocytes. Specifically, IGF-1 increases progenitor cell proliferation and numbers of new neurons, oligodendrocytes, and blood vessels in the dentate gyrus of the hippocampus. In the adult cerebral cortex IGF-1 only affects oligodendrogenesis. ... Altogether, data suggest that both exogenous and endogenous GH and/or IGF-1 may be used as agents to enhance cell genesis and neurogenesis in the adult brain. ... GH and IGF-1 have been shown to affect a multitude of mechanisms, including neurogenesis, oligodendrogenesis, angiogenesis, glutamate receptor activation, cholinergic system, dopaminergic reward system, monoamine abundance, dendritic arborization, astrocyte communication via connexin 43, and opioid receptor abundance ... IGF-1 also reaches the brain via both the capillary bed BBB and via the blood-CSF barrier. It appears that IGF-1 uptake is mediated by a specific carrier both in the capillary bed BBB [40] and in the blood-CSF barrier [41, 42]. Moreover, IGF-1 transport across the BBB can be either increased, such as by exercise [43] ... Thus, although not fully characterized, there appear to be mechanisms for transport of both GH and IGF-1 across the BBB. ... Interestingly, exercise is a factor known to enhance cell genesis in the brain, and it appears that IGF-1 is a key mediator of the effect of exercise in terms of cell genesis in the adult brain [52, 53]. ... IGF-1 treatment enhances neurogenesis [52, 53, 55], oligodendrogenesis [56, 58] and angiogenesis [59]. ... As physical exercise has positive effects in many diseases as well as in normal health, it is of interest that circulating IGF-1 as been shown to be one of the mediators of enhanced neurogenesis in the hippocampus.

[NHM_IGF-1_VEGF-23] Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY (ed.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 221, 412. ISBN 9780071481274. BDNF, CNTF, insulin-like growth factor-1 (IGF-1), and VEGF have been proven to support motor neuron survival in vitro and in vivo. ... VEGF exerts its effects through two receptor tyrosine kinases, VEGFR1 (also known as flt-1) and VEGFR2 (or flk-1). VEGF and its receptors are expressed in neurons and glia, and this expression is highly up-regulated by hypoxia. The neurotrophic properties of VEGF were first identified when mutations in the VEGF promoter of mice resulted in ALS-like symptoms. Subsequently, VEGF was found to rescue hypoxia-induced motor neuron death both in vivo and in vitro. Recently, a polymorphism in the VEGF promoter sequence was identified in a subset of ALS patients. It is thought that low VEGF levels may underlie motor neuron degeneration in at least one group of patients, but measurement of VEGF in ALS patients has proven difficult. VEGF may also be important for response to stroke and other forms of neural injury. ... One of the prototypical triggers for apoptosis, at least in vitro, is the withdrawal of neurotrophic factors. Neurotrophic factor receptors, such as the TrkA receptor for NGF or the IGF-I receptor for insulin-like growth factor, activate prosurvival signaling cascades{{cite book}}: CS1 maint: multiple names: authors list (link)

[pmid22714057-24] Gatti R, De Palo EF, Antonelli G, Spinella P (2012). "IGF-I/IGFBP system: metabolism outline and physical exercise". J. Endocrinol. Invest. 35 (7): 699–707. doi:10.3275/8456. PMID 22714057.

[Fitness_mechanism-25] Cite error: The named reference Fitness mechanism was invoked but never defined (see the help page).

[VEGF_aging_brain-26] Bouchard J, Villeda SA (2015). "Aging and brain rejuvenation as systemic events". J. Neurochem. 132 (1): 5–19. doi:10.1111/jnc.12969. PMC 4301186. PMID 25327899. The beneficial effects of exercise extend beyond peripheral tissues to also include the brain. ... Because of the blood–brain barrier, it was traditionally thought that the beneficial effects of exercise on the CNS were not orchestrated through systemic changes in the periphery. However, recent studies suggest that the effects of exercise are, in part, mediated by changes in the systemic environment. Investigations looking at magnetic resonance imaging (MRI) measurements of cerebral blood volume in the hippocampus have demonstrated that exercise selectively increased the cerebral blood volume of the dentate gyrus, correlating with post-mortem increase in neurogenesis (Pereira et al. 2007). From a molecular perspective, elevated systemic levels of circulating growth factors such as vascular endothelial growth factor and insulin-like growth factor 1 (IGF-1) in blood elicited by increased exercise have been shown to mediate, in part, enhancements in neurogenesis (Trejo et al. 2001; Fabel et al. 2003). Coincidently, circulating levels of IGF-1 decrease with age and the restoration to levels resembling a younger systemic environment up-regulate neurogenesis and improve learning and memory (Lichtenwalner et al. 2001; Darnaudery et al. 2006).

[Nestler-27] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure^14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption^14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. Cite error: The named reference "Nestler" was defined multiple times with different content (see the help page).

[Natural_and_drug_addictions-28] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t ^u ^v ^w Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–1122. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader, 2008). Cite error: The named reference "Natural and drug addictions" was defined multiple times with different content (see the help page).

[c-Fos_NAcc_exercise-29] Zlebnik NE, Hedges VL, Carroll ME, Meisel RL (2014). "Chronic wheel running affects cocaine-induced c-Fos expression in brain reward areas in rats". Behav. Brain Res. 261: 71–78. doi:10.1016/j.bbr.2013.12.012. PMID 24342748.

[c-Fos_repression-30] Nestler EJ (October 2008). "Review. Transcriptional mechanisms of addiction: role of DeltaFosB". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 363 (1507): 3245–3255. doi:10.1098/rstb.2008.0067. PMC 2607320. PMID 18640924. Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure—cited earlier (Renthal et al. in press). The mechanism responsible for ΔFosB repression of c-fos expression is complex and is covered below. ...
Examples of validated targets for ΔFosB in nucleus accumbens ... GluR2 ... dynorphin ... Cdk5 ... NFκB ... c-Fos
Table 3 Cite error: The named reference "c-Fos repression" was defined multiple times with different content (see the help page).

[Running_vs_addiction-31] Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA (September 2013). "Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis". Neurosci Biobehav Rev. 37 (8): 1622–44. doi:10.1016/j.neubiorev.2013.06.011. PMC 3788047. PMID 23806439. [exercise] efficacy may be related to its ability to normalize glutamatergic and dopaminergic signaling and reverse drug-induced changes in chromatin via epigenetic interactions with brain-derived neurotrophic factor (BDNF) in the reward pathway. ... these data show that exercise can affect dopaminergic signaling at many different levels, which may underlie its ability to modify vulnerability during drug use initiation. Exercise also produces neuroadaptations that may influence an individual's vulnerability to initiate drug use. Consistent with this idea, chronic moderate levels of forced treadmill running blocks not only subsequent methamphetamine-induced conditioned place preference, but also stimulant-induced increases in dopamine release in the NAc (Chen et al., 2008) and striatum (Marques et al., 2008). ... [These] findings indicate the efficacy of exercise at reducing drug intake in drug-dependent individuals ... wheel running [reduces] methamphetamine self-administration under extended access conditions (Engelmann et al., 2013) ... These findings suggest that exercise may "magnitude"-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuro-adaptive changes that develop during and following extended access to the drug. ... Exercise has been proposed as a treatment for drug addiction that may reduce drug craving and risk of relapse. Although few clinical studies have investigated the efficacy of exercise for preventing relapse, the few studies that have been conducted generally report a reduction in drug craving and better treatment outcomes (see Table 4). ... Taken together, these data suggest that the potential benefits of exercise during relapse, particularly for relapse to psychostimulants, may be mediated via chromatin remodeling and possibly lead to greater treatment outcomes.{{cite journal}}: CS1 maint: multiple names: authors list (link)

[Exercise_Rev_3-32] Linke SE, Ussher M (2015). "Exercise-based treatments for substance use disorders: evidence, theory, and practicality". Am J Drug Alcohol Abuse. 41 (1): 7–15. doi:10.3109/00952990.2014.976708. PMID 25397661. The limited research conducted suggests that exercise may be an effective adjunctive treatment for SUDs. In contrast to the scarce intervention trials to date, a relative abundance of literature on the theoretical and practical reasons supporting the investigation of this topic has been published. ... numerous theoretical and practical reasons support exercise-based treatments for SUDs, including psychological, behavioral, neurobiological, nearly universal safety profile, and overall positive health effects.

[entrez-33] "Entrez Gene: FOSB FBJ murine osteosarcoma viral oncogene homolog B".

[pmid1702972-34] Siderovski DP, Blum S, Forsdyke RE, Forsdyke DR (October 1990). "A set of human putative lymphocyte G0/G1 switch genes includes genes homologous to rodent cytokine and zinc finger protein-encoding genes". DNA and Cell Biology. 9 (8): 579–87. doi:10.1089/dna.1990.9.579. PMID 1702972.

[pmid1301997-35] Martin-Gallardo A, McCombie WR, Gocayne JD, FitzGerald MG, Wallace S, Lee BM, Lamerdin J, Trapp S, Kelley JM, Liu LI (April 1992). "Automated DNA sequencing and analysis of 106 kilobases from human chromosome 19q13.3". Nature Genetics. 1 (1): 34–9. doi:10.1038/ng0492-34. PMID 1301997. S2CID 1986255.

[Δ2ΔFosB_transactivation_osteoclast-36] Sabatakos G, Rowe GC, Kveiborg M, Wu M, Neff L, Chiusaroli R, Philbrick WM, Baron R (May 2008). "Doubly truncated FosB isoform (Delta2DeltaFosB) induces osteosclerosis in transgenic mice and modulates expression and phosphorylation of Smads in osteoblasts independent of intrinsic AP-1 activity". Journal of Bone and Mineral Research. 23 (5): 584–95. doi:10.1359/jbmr.080110. PMC 2674536. PMID 18433296.

[What_the_ΔFosB?-37] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". The American Journal of Drug and Alcohol Abuse. 40 (6): 428–37. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711.
ΔFosB as a therapeutic biomarker
The strong correlation between chronic drug exposure and ΔFosB provides novel opportunities for targeted therapies in addiction (118), and suggests methods to analyze their efficacy (119). Over the past two decades, research has progressed from identifying ΔFosB induction to investigating its subsequent action (38). It is likely that ΔFosB research will now progress into a new era – the use of ΔFosB as a biomarker. If ΔFosB detection is indicative of chronic drug exposure (and is at least partly responsible for dependence of the substance), then its monitoring for therapeutic efficacy in interventional studies is a suitable biomarker (Figure 2). Examples of therapeutic avenues are discussed herein. ...

Conclusions
ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades, involving effectors such as GluR2 (87,88), Cdk5 (93) and NFkB (100). Moreover, many of these molecular changes identified are now directly linked to the structural, physiological and behavioral changes observed following chronic drug exposure (60,95,97,102). New frontiers of research investigating the molecular roles of ΔFosB have been opened by epigenetic studies, and recent advances have illustrated the role of ΔFosB acting on DNA and histones, truly as a molecular switch (34). As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much needed in addiction.

[Cellular_basis-38] ^ ^a ^b ^c ^d ^e ^f ^g Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.⁴¹ ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.

[G9a_reverses_ΔFosB_plasticity-39] Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T (2012). "Epigenetic regulation in drug addiction". Annals of Agricultural and Environmental Medicine. 19 (3): 491–6. PMID 23020045. For these reasons, ΔFosB is considered a primary and causative transcription factor in creating new neural connections in the reward centre, prefrontal cortex, and other regions of the limbic system. This is reflected in the increased, stable and long-lasting level of sensitivity to cocaine and other drugs, and tendency to relapse even after long periods of abstinence. These newly constructed networks function very efficiently via new pathways as soon as drugs of abuse are further taken ... In this way, the induction of CDK5 gene expression occurs together with suppression of the G9A gene coding for dimethyltransferase acting on the histone H3. A feedback mechanism can be observed in the regulation of these 2 crucial factors that determine the adaptive epigenetic response to cocaine. This depends on ΔFosB inhibiting G9a gene expression, i.e. H3K9me2 synthesis which in turn inhibits transcription factors for ΔFosB. For this reason, the observed hyper-expression of G9a, which ensures high levels of the dimethylated form of histone H3, eliminates the neuronal structural and plasticity effects caused by cocaine by means of this feedback which blocks ΔFosB transcription

[FosB_ΔFosB_Δ2ΔFosB_drugs-40] Ohnishi YN, Ohnishi YH, Vialou V, Mouzon E, LaPlant Q, Nishi A, Nestler EJ (January 2015). "Functional role of the N-terminal domain of ΔFosB in response to stress and drugs of abuse". Neuroscience. 284: 165–70. doi:10.1016/j.neuroscience.2014.10.002. PMC 4268105. PMID 25313003.

[pmid1900040-41] Nakabeppu Y, Nathans D (February 1991). "A naturally occurring truncated form of FosB that inhibits Fos/Jun transcriptional activity". Cell. 64 (4): 751–9. doi:10.1016/0092-8674(91)90504-R. PMID 1900040. S2CID 23904956.

[ΔFosB_reward-42] Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M (2012). "Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms". Journal of Psychoactive Drugs. 44 (1): 38–55. doi:10.1080/02791072.2012.662112. PMC 4040958. PMID 22641964.

[pmid18640924-43] Nestler EJ (October 2008). "Review. Transcriptional mechanisms of addiction: role of DeltaFosB". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 363 (1507): 3245–55. doi:10.1098/rstb.2008.0067. PMC 2607320. PMID 18640924. Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure—cited earlier (Renthal et al. in press). The mechanism responsible for ΔFosB repression of c-fos expression is complex and is covered below. ...
Examples of validated targets for ΔFosB in nucleus accumbens ... GluR2 ... dynorphin ... Cdk5 ... NFκB ... c-Fos
Table 3

[pmid18635399-44] Renthal W, Nestler EJ (August 2008). "Epigenetic mechanisms in drug addiction". Trends in Molecular Medicine. 14 (8): 341–50. doi:10.1016/j.molmed.2008.06.004. PMC 2753378. PMID 18635399.

[pmid19447090-45] Renthal W, Kumar A, Xiao G, Wilkinson M, Covington HE, Maze I, Sikder D, Robison AJ, LaPlant Q, Dietz DM, Russo SJ, Vialou V, Chakravarty S, Kodadek TJ, Stack A, Kabbaj M, Nestler EJ (May 2009). "Genome-wide analysis of chromatin regulation by cocaine reveals a role for sirtuins". Neuron. 62 (3): 335–48. doi:10.1016/j.neuron.2009.03.026. PMC 2779727. PMID 19447090.

[pmid10973317-46] Sabatakos G, Sims NA, Chen J, Aoki K, Kelz MB, Amling M, Bouali Y, Mukhopadhyay K, Ford K, Nestler EJ, Baron R (September 2000). "Overexpression of DeltaFosB transcription factor(s) increases bone formation and inhibits adipogenesis". Nature Medicine. 6 (9): 985–90. doi:10.1038/79683. PMID 10973317. S2CID 20302360.

[Nestler1-47] Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nature Reviews Neuroscience. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB serves as one of the master control proteins governing this structural plasticity. ... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. ... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net result is c-fos gene repression.
Figure 4: Epigenetic basis of drug regulation of gene expression

[pmid11572966-48] Nestler EJ, Barrot M, Self DW (September 2001). "DeltaFosB: a sustained molecular switch for addiction". Proceedings of the National Academy of Sciences of the United States of America. 98 (20): 11042–6. Bibcode:2001PNAS...9811042N. doi:10.1073/pnas.191352698. PMC 58680. PMID 11572966.

[49] Salaya-Velazquez NF, López-Muciño LA, Mejía-Chávez S, Sánchez-Aparicio P, Domínguez-Guadarrama AA, Venebra-Muñoz A (February 2020). "Anandamide and sucralose change ΔFosB expression in the reward system". NeuroReport. 31 (3): 240–244. doi:10.1097/WNR.0000000000001400. PMID 31923023. S2CID 210149592.

[Addiction_glossary-50] Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. ISBN 978-0-07-148127-4.

[Brain_disease-51] Volkow ND, Koob GF, McLellan AT (January 2016). "Neurobiologic Advances from the Brain Disease Model of Addiction". New England Journal of Medicine. 374 (4): 363–371. doi:10.1056/NEJMra1511480. PMC 6135257. PMID 26816013. Substance-use disorder: A diagnostic term in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other drugs that causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home. Depending on the level of severity, this disorder is classified as mild, moderate, or severe.
Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder.

[Nestler-Renthal_Figure_2-53] Renthal W, Nestler EJ (September 2009). "Chromatin regulation in drug addiction and depression". Dialogues in Clinical Neuroscience. 11 (3): 257–268. doi:10.31887/DCNS.2009.11.3/wrenthal. PMC 2834246. PMID 19877494. [Psychostimulants] increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein (CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes including fosB and c-fos in response to psychostimulant exposure. ΔFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg, c-fos) where it recruits HDAC1 as a corepressor. ... Chronic exposure to psychostimulants increases glutamatergic [signaling] from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5.
Figure 2: Psychostimulant-induced signaling events

[Glutamate-dopamine_cotransmission_review-54] Broussard JI (January 2012). "Co-transmission of dopamine and glutamate". The Journal of General Physiology. 139 (1): 93–96. doi:10.1085/jgp.201110659. PMC 3250102. PMID 22200950. Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.

[Amphetamine_KEGG_ΔFosB-55] Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014. Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the "brain reward circuit". Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. ... Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain.

[Meth_cAMP/calcium-dependent_cascade-56] Cadet JL, Brannock C, Jayanthi S, Krasnova IN (2015). "Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat". Molecular Neurobiology. 51 (2): 696–717 (Figure 1). doi:10.1007/s12035-014-8776-8. PMC 4359351. PMID 24939695.

[Nestler2-57] Nestler EJ (December 2012). "Transcriptional mechanisms of drug addiction". Clinical Psychopharmacology and Neuroscience. 10 (3): 136–143. doi:10.9758/cpn.2012.10.3.136. PMC 3569166. PMID 23430970. The 35-37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. ... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. ... ΔFosB overexpression in nucleus accumbens induces NFκB ... In contrast, the ability of ΔFosB to repress the c-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase

[Nestler,_Hyman,_and_Malenka_2-58] Hyman SE, Malenka RC, Nestler EJ (2006). "Neural mechanisms of addiction: the role of reward-related learning and memory". Annual Review of Neuroscience. 29: 565–98. doi:10.1146/annurev.neuro.29.051605.113009. PMID 16776597.

[Addiction_genetics-59] Steiner H, Van Waes V (January 2013). "Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants". Progress in Neurobiology. 100: 60–80. doi:10.1016/j.pneurobio.2012.10.001. PMC 3525776. PMID 23085425.

[Alcoholism_ΔFosB-60] Kanehisa Laboratories (29 October 2014). "Alcoholism – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014.

[MPH_ΔFosB-61] Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P (February 2009). "Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens". Proceedings of the National Academy of Sciences of the United States of America. 106 (8): 2915–20. Bibcode:2009PNAS..106.2915K. doi:10.1073/pnas.0813179106. PMC 2650365. PMID 19202072.

[Nestler_2014_epigenetics-62] Nestler EJ (January 2014). "Epigenetic mechanisms of drug addiction". Neuropharmacology. 76 Pt B: 259–268. doi:10.1016/j.neuropharm.2013.04.004. PMC 3766384. PMID 23643695. Short-term increases in histone acetylation generally promote behavioral responses to the drugs, while sustained increases oppose cocaine's effects, based on the actions of systemic or intra-NAc administration of HDAC inhibitors. ... Genetic or pharmacological blockade of G9a in the NAc potentiates behavioral responses to cocaine and opiates, whereas increasing G9a function exerts the opposite effect (Maze et al., 2010; Sun et al., 2012a). Such drug-induced downregulation of G9a and H3K9me2 also sensitizes animals to the deleterious effects of subsequent chronic stress (Covington et al., 2011). Downregulation of G9a increases the dendritic arborization of NAc neurons, and is associated with increased expression of numerous proteins implicated in synaptic function, which directly connects altered G9a/H3K9me2 in the synaptic plasticity associated with addiction (Maze et al., 2010).
G9a appears to be a critical control point for epigenetic regulation in NAc, as we know it functions in two negative feedback loops. It opposes the induction of ΔFosB, a long-lasting transcription factor important for drug addiction (Robison and Nestler, 2011), while ΔFosB in turn suppresses G9a expression (Maze et al., 2010; Sun et al., 2012a). ... Also, G9a is induced in NAc upon prolonged HDAC inhibition, which explains the paradoxical attenuation of cocaine's behavioral effects seen under these conditions, as noted above (Kennedy et al., 2013). GABAA receptor subunit genes are among those that are controlled by this feedback loop. Thus, chronic cocaine, or prolonged HDAC inhibition, induces several GABAA receptor subunits in NAc, which is associated with increased frequency of inhibitory postsynaptic currents (IPSCs). In striking contrast, combined exposure to cocaine and HDAC inhibition, which triggers the induction of G9a and increased global levels of H3K9me2, leads to blockade of GABAA receptor and IPSC regulation.

[Amph_and_sex_addiction-64] Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (February 2013). "Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator". The Journal of Neuroscience. 33 (8): 3434–42. doi:10.1523/JNEUROSCI.4881-12.2013. PMC 3865508. PMID 23426671.

[Malenka_2009_04-65] Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and addictive disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 384–385. ISBN 9780071481274.

[Amphetamine_epigenetics-66] McCowan TJ, Dhasarathy A, Carvelli L (February 2015). "The Epigenetic Mechanisms of Amphetamine". J. Addict. Prev. 2015 (Suppl 1). PMC 4955852. PMID 27453897. Epigenetic modifications caused by addictive drugs play an important role in neuronal plasticity and in drug-induced behavioral responses. Although few studies have investigated the effects of AMPH on gene regulation (Table 1), current data suggest that AMPH acts at multiple levels to alter histone/DNA interaction and to recruit transcription factors which ultimately cause repression of some genes and activation of other genes. Importantly, some studies have also correlated the epigenetic regulation induced by AMPH with the behavioral outcomes caused by this drug, suggesting therefore that epigenetics remodeling underlies the behavioral changes induced by AMPH. If this proves to be true, the use of specific drugs that inhibit histone acetylation, methylation or DNA methylation might be an important therapeutic alternative to prevent and/or reverse AMPH addiction and mitigate the side effects generate by AMPH when used to treat ADHD.

[Chromatin_states-67] Walker DM, Cates HM, Heller EA, Nestler EJ (February 2015). "Regulation of chromatin states by drugs of abuse". Curr. Opin. Neurobiol. 30: 112–121. doi:10.1016/j.conb.2014.11.002. PMC 4293340. PMID 25486626. Studies investigating general HDAC inhibition on behavioral outcomes have produced varying results but it seems that the effects are specific to the timing of exposure (either before, during or after exposure to drugs of abuse) as well as the length of exposure

[HDACi_primaries-69] Primary references involving sodium butyrate:

• Kennedy PJ, Feng J, Robison AJ, Maze I, Badimon A, Mouzon E, Chaudhury D, Damez-Werno DM, Haggarty SJ, Han MH, Bassel-Duby R, Olson EN, Nestler EJ (April 2013). "Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation". Nat. Neurosci. 16 (4): 434–440. doi:10.1038/nn.3354. PMC 3609040. PMID 23475113. While acute HDAC inhibition enhances the behavioral effects of cocaine or amphetamine^1,3,4,13,14, studies suggest that more chronic regimens block psychostimulant-induced plasticity^3,5,11,12. ... The effects of pharmacological inhibition of HDACs on psychostimulant-induced plasticity appear to depend on the timecourse of HDAC inhibition. Studies employing co-administration procedures in which inhibitors are given acutely, just prior to psychostimulant administration, report heightened behavioral responses to the drug^1,3,4,13,14. In contrast, experimental paradigms like the one employed here, in which HDAC inhibitors are administered more chronically, for several days prior to psychostimulant exposure, show inhibited expression³ or decreased acquisition of behavioral adaptations to drug^5,11,12. The clustering of seemingly discrepant results based on experimental methodologies is interesting in light of our present findings. Both HDAC inhibitors and psychostimulants increase global levels of histone acetylation in NAc. Thus, when co-administered acutely, these drugs may have synergistic effects, leading to heightened transcriptional activation of psychostimulant-regulated target genes. In contrast, when a psychostimulant is given in the context of prolonged, HDAC inhibitor-induced hyperacetylation, homeostatic processes may direct AcH3 binding to the promoters of genes (e.g., G9a) responsible for inducing chromatin condensation and gene repression (e.g., via H3K9me2) in order to dampen already heightened transcriptional activation. Our present findings thus demonstrate clear cross talk among histone PTMs and suggest that decreased behavioral sensitivity to psychostimulants following prolonged HDAC inhibition might be mediated through decreased activity of HDAC1 at H3K9 KMT promoters and subsequent increases in H3K9me2 and gene repression.

• Simon-O'Brien E, Alaux-Cantin S, Warnault V, Buttolo R, Naassila M, Vilpoux C (July 2015). "The histone deacetylase inhibitor sodium butyrate decreases excessive ethanol intake in dependent animals". Addict Biol. 20 (4): 676–689. doi:10.1111/adb.12161. PMID 25041570. S2CID 28667144. Altogether, our results clearly demonstrated the efficacy of NaB in preventing excessive ethanol intake and relapse and support the hypothesis that HDACi may have a potential use in alcohol addiction treatment.

• Castino MR, Cornish JL, Clemens KJ (April 2015). "Inhibition of histone deacetylases facilitates extinction and attenuates reinstatement of nicotine self-administration in rats". PLOS ONE. 10 (4): e0124796. Bibcode:2015PLoSO..1024796C. doi:10.1371/journal.pone.0124796. PMC 4399837. PMID 25880762. treatment with NaB significantly attenuated nicotine and nicotine + cue reinstatement when administered immediately ... These results provide the first demonstration that HDAC inhibition facilitates the extinction of responding for an intravenously self-administered drug of abuse and further highlight the potential of HDAC inhibitors in the treatment of drug addiction.

[HDAC_alcoholism_review-71] Kyzar EJ, Pandey SC (August 2015). "Molecular mechanisms of synaptic remodeling in alcoholism". Neurosci. Lett. 601: 11–9. doi:10.1016/j.neulet.2015.01.051. PMC 4506731. PMID 25623036. Increased HDAC2 expression decreases the expression of genes important for the maintenance of dendritic spine density such as BDNF, Arc, and NPY, leading to increased anxiety and alcohol-seeking behavior. Decreasing HDAC2 reverses both the molecular and behavioral consequences of alcohol addiction, thus implicating this enzyme as a potential treatment target (Fig. 3). HDAC2 is also crucial for the induction and maintenance of structural synaptic plasticity in other neurological domains such as memory formation [115]. Taken together, these findings underscore the potential usefulness of HDAC inhibition in treating alcohol use disorders ... Given the ability of HDAC inhibitors to potently modulate the synaptic plasticity of learning and memory [118], these drugs hold potential as treatment for substance abuse-related disorders. ... Our lab and others have published extensively on the ability of HDAC inhibitors to reverse the gene expression deficits caused by multiple models of alcoholism and alcohol abuse, the results of which were discussed above [25,112,113]. This data supports further examination of histone modifying agents as potential therapeutic drugs in the treatment of alcohol addiction ... Future studies should continue to elucidate the specific epigenetic mechanisms underlying compulsive alcohol use and alcoholism, as this is likely to provide new molecular targets for clinical intervention.

[Valproate_for_methamphetamine_addiction_primary_source-72] Kheirabadi GR, Ghavami M, Maracy MR, Salehi M, Sharbafchi MR (2016). "Effect of add-on valproate on craving in methamphetamine depended patients: A randomized trial". Advanced Biomedical Research. 5: 149. doi:10.4103/2277-9175.187404. PMC 5025910. PMID 27656618.

[pmid9668659-74] Hope BT (May 1998). "Cocaine and the AP-1 transcription factor complex". Annals of the New York Academy of Sciences. 844 (1): 1–6. Bibcode:1998NYASA.844....1H. doi:10.1111/j.1749-6632.1998.tb08216.x. PMID 9668659. S2CID 11683570.

[pmid10499584-75] Kelz MB, Chen J, Carlezon WA, Whisler K, Gilden L, Beckmann AM, Steffen C, Zhang YJ, Marotti L, Self DW, Tkatch T, Baranauskas G, Surmeier DJ, Neve RL, Duman RS, Picciotto MR, Nestler EJ (September 1999). "Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine". Nature. 401 (6750): 272–6. Bibcode:1999Natur.401..272K. doi:10.1038/45790. PMID 10499584. S2CID 4390717.

[pmid12657709-76] Colby CR, Whisler K, Steffen C, Nestler EJ, Self DW (March 2003). "Striatal cell type-specific overexpression of DeltaFosB enhances incentive for cocaine". The Journal of Neuroscience. 23 (6): 2488–93. doi:10.1523/JNEUROSCI.23-06-02488.2003. PMC 6742034. PMID 12657709.

[pmid20505100-79] Cao X, Yasuda T, Uthayathas S, Watts RL, Mouradian MM, Mochizuki H, Papa SM (May 2010). "Striatal overexpression of DeltaFosB reproduces chronic levodopa-induced involuntary movements". The Journal of Neuroscience. 30 (21): 7335–43. doi:10.1523/JNEUROSCI.0252-10.2010. PMC 2888489. PMID 20505100.

[Levetiracetam-80] Du H, Nie S, Chen G, Ma K, Xu Y, Zhang Z, Papa SM, Cao X (2015). "Levetiracetam Ameliorates L-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats Inducing Critical Molecular Changes in the Striatum". Parkinson's Disease. 2015: 253878. doi:10.1155/2015/253878. PMC 4322303. PMID 25692070. Furthermore, the transgenic overexpression of ΔFosB reproduces AIMs in hemiparkinsonian rats without chronic exposure to L-DOPA [13]. ... FosB/ΔFosB immunoreactive neurons increased in the dorsolateral part of the striatum on the lesion side with the used antibody that recognizes all members of the FosB family. All doses of levetiracetam decreased the number of FosB/ΔFosB positive cells (from 88.7 ± 1.7/section in the control group to 65.7 ± 0.87, 42.3 ± 1.88, and 25.7 ± 1.2/section in the 15, 30, and 60 mg groups, resp.; Figure 2). These results indicate dose-dependent effects of levetiracetam on FosB/ΔFosB expression. ... In addition, transcription factors expressed with chronic events such as ΔFosB (a truncated splice variant of FosB) are overexpressed in the striatum of rodents and primates with dyskinesias [9, 10]. ... Furthermore, ΔFosB overexpression has been observed in postmortem striatal studies of Parkinsonian patients chronically treated with L-DOPA [26]. ... Of note, the most prominent effect of levetiracetam was the reduction of ΔFosB expression, which cannot be explained by any of its known actions on vesicular protein or ion channels. Therefore, the exact mechanism(s) underlying the antiepileptic effects of levetiracetam remains uncertain.

[Nestler's_lab-81] "ROLE OF ΔFOSB IN THE NUCLEUS ACCUMBENS". Mount Sinai School of Medicine. NESTLER LAB: LABORATORY OF MOLECULAR PSYCHIATRY. Archived from the original on 28 June 2017. Retrieved 6 September 2014.

[Stress_and_NAcc_shell-82] Furuyashiki T, Deguchi Y (August 2012). "[Roles of altered striatal function in major depression]". Brain and Nerve = Shinkei Kenkyū No Shinpo (in Japanese). 64 (8): 919–26. PMID 22868883.

[NAcc_∆FosB_depression-83] Nestler EJ (April 2015). "∆FosB: a transcriptional regulator of stress and antidepressant responses". European Journal of Pharmacology. 753: 66–72. doi:10.1016/j.ejphar.2014.10.034. PMC 4380559. PMID 25446562. In more recent years, prolonged induction of ∆FosB has also been observed within NAc in response to chronic administration of certain forms of stress. Increasing evidence indicates that this induction represents a positive, homeostatic adaptation to chronic stress, since overexpression of ∆FosB in this brain region promotes resilience to stress, whereas blockade of its activity promotes stress susceptibility. Chronic administration of several antidepressant medications also induces ∆FosB in the NAc, and this induction is required for the therapeutic-like actions of these drugs in mouse models. Validation of these rodent findings is the demonstration that depressed humans, examined at autopsy, display reduced levels of ∆FosB within the NAc. As a transcription factor, ΔFosB produces this behavioral phenotype by regulating the expression of specific target genes, which are under current investigation. These studies of ΔFosB are providing new insight into the molecular basis of depression and antidepressant action, which is defining a host of new targets for possible therapeutic development.

[pmid24067299-84] Dietz DM, Kennedy PJ, Sun H, Maze I, Gancarz AM, Vialou V, Koo JW, Mouzon E, Ghose S, Tamminga CA, Nestler EJ (February 2014). "ΔFosB induction in prefrontal cortex by antipsychotic drugs is associated with negative behavioral outcomes". Neuropsychopharmacology. 39 (3): 538–44. doi:10.1038/npp.2013.255. PMC 3895248. PMID 24067299.

[102] Attentional control allows an individual to focus their attention on a specific source and ignore other stimuli that compete for one's attention,^[17] such as in the cocktail party effect.

[104] Inhibitory control is the process of altering one's learned behavioral responses, sometimes called "prepotent responses", in a way that makes it easier to complete a particular goal.^[9]^[18] Inhibitory control allows individuals to control their impulses and habits when necessary or desired,^[9]^[15]^[18] e.g., to overcome procrastination.

[105] Working memory is the form of memory used by an individual at any given moment for active information processing,^[17] such as when reading or writing an encyclopedia article. Working memory has a limited capacity and functions as an information buffer, analogous to a computer's data buffer, that permits the manipulation of information for comprehension, decision-making, and guidance of behavior.^[9]

[106] Declarative memory, also known as explicit memory, is the form of memory that pertains to facts and events.^[12]

[113] In healthy individuals, this energy deficit resolves simply from eating and drinking a sufficient amount of food and beverage after exercising.

[Comprehensive_review-85] ^ ^a ^b ^c ^d ^e ^f ^g Cite error: The named reference Comprehensive review was invoked but never defined (see the help page).

[gray_matter-86] ^ ^a ^b ^c ^d ^e ^f ^g Cite error: The named reference gray matter was invoked but never defined (see the help page).

[BDNF_depression-87] ^ ^a ^b ^c ^d ^e ^f ^g ^h Erickson KI, Miller DL, Roecklein KA (2012). "The aging hippocampus: interactions between exercise, depression, and BDNF". Neuroscientist. 18 (1): 82–97. doi:10.1177/1073858410397054. PMC 3575139. PMID 21531985. Late adulthood is associated with increased hippocampal atrophy and dysfunction. ... However, there is strong evidence that decreased BDNF is associated with age-related hippocampal dysfunction, memory impairment, and increased risk for depression, whereas increasing BDNF by aerobic exercise appears to ameliorate hippocampal atrophy, improve memory function, and reduce depression. ... For example, longitudinal studies have reported between 1% and 2% annual hippocampal atrophy in adults older than 55 years without dementia ... Over a nine-year period, greater amounts of physical activity in the form of walking are associated with greater gray matter volume in several regions including prefrontal, temporal, and hippocampal areas. ... The prefrontal cortex and hippocampus deteriorate in late adulthood, preceding and leading to deficits in executive and memory function. We examined in this review the evidence that age-related changes in BDNF might at least partially explain hippocampal atrophy and increased risk for memory impairment. We can conclude that 1) decreases in BDNF protein expression are associated with poorer hippocampal function and increased rates of geriatric depression and AD. ... 3) Aerobic exercise enhances executive and memory function and reduces hippocampal atrophy in late adulthood, and this may be partially mediated through a BDNF pathway.

[cognitive_control_of_exercise-88] Buckley J, Cohen JD, Kramer AF, McAuley E, Mullen SP (2014). "Cognitive control in the self-regulation of physical activity and sedentary behavior". Front Hum Neurosci. 8: 747. doi:10.3389/fnhum.2014.00747. PMC 4179677. PMID 25324754. Recent theory (e.g., Temporal Self-Regulation Theory; Hall and Fong, 2007, 2010, 2013) and evidence suggest that the relation between physical activity and cognitive control is reciprocal (Daly et al., 2013). Most research has focused on the beneficial effects of regular physical activity on executive functions-the set of neural processes that define cognitive control. Considerable evidence shows that regular physical activity is associated with enhanced cognitive functions, including attention, processing speed, task switching, inhibition of prepotent responses and declarative memory (for reviews see Colcombe and Kramer, 2003; Smith et al., 2010; Guiney and Machado, 2013; McAuley et al., 2013). Recent research demonstrates a dose-response relationship between fitness and spatial memory (Erickson et al., 2011) ... The effects of physical activity on cognitive control appear to be underpinned by a variety of brain processes including: increased hippocampal volume, increased gray matter density in the prefrontal cortex (PFC), upregulation of neurotrophins and greater microvascular density ... Together, this research suggests that an improvement in control processes, such as attention and inhibition or interference control, is associated with an improvement in self-regulation of physical activity. ... Hoang et al. (2013) found that young adults who initially exhibited low levels of physical activity and remained relatively inactive for 25 years had nearly twofold greater odds of impaired executive function compared with those who exhibited higher activity levels; very-low physical activity patterns were associated with even more pronounced declines in executive functioning. … sedentary behavior indirectly led to poor executive function through depressive symptoms (Vance et al., 2005). … sedentary individuals display less capacity to quickly and accurately switch between tasks.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)

[exercise_benefits-89] Guiney H, Machado L (February 2013). "Benefits of regular aerobic exercise for executive functioning in healthy populations". Psychon Bull Rev. 20 (1): 73–86. doi:10.3758/s13423-012-0345-4. PMID 23229442. Executive functions are strategic in nature and depend on higher-order cognitive processes that underpin planning, sustained attention, selective attention, resistance to interference, volitional inhibition, working memory, and mental flexibility ... Data to date from studies of aging provide strong evidence of exercise-linked benefits related to task switching, selective attention, inhibition of prepotent responses, and working memory capacity; furthermore, cross-sectional fitness data suggest that working memory updating could potentially benefit as well. In young adults, working memory updating is the main executive function shown to benefit from regular exercise, but cross-sectional data further suggest that task-switching and post-error performance may also benefit. In children, working memory capacity has been shown to benefit, and cross-sectional data suggest potential benefits for selective attention and inhibitory control. ... Support for the idea that higher levels of aerobic activity may be associated with superior brain structure has been gained through cross-sectional studies in older adults and children (for a recent review, see Voss, Nagamatsu, et al., 2011). ... only those in the aerobic exercise group exhibited improved connectivity between the left and right prefrontal cortices, two areas that are crucial to the effective functioning of the fronto-executive network. ... Together, these studies provide evidence that regular aerobic exercise benefits control over responses during selective attention in older adults. ... aerobic fitness is a good predictor of performance on tasks that rely relatively heavily on inhibitory control over prepotent responses (e.g., Colcombe et al., 2004, Study 1; Prakash et al., 2011) and also that regular aerobic exercise improves performance on such tasks ... Overall, the results from the span and Sternberg tasks suggest that regular exercise can also confer benefits for the volume of information that children and older adults can hold in mind at one time.

[Mind_over_matter-90] Valkanova V, Eguia Rodriguez R, Ebmeier KP (June 2014). "Mind over matter—what do we know about neuroplasticity in adults?". Int Psychogeriatr. 26 (6): 891–909. doi:10.1017/S1041610213002482. PMID 24382194. Control group: Active
Intervention: Aerobic exercise
[Increased GMV in:] Lobes (dorsal anterior cingulate cortex, supplementary motor area, middle frontal gyrus bilaterally); R inferior frontal gyrus, middle frontal gyrus and L superior temporal lobe; increase in the volume of anterior white matter tracts ... ↑GMV anterior hippocampus

[Ruscheweyh-91] Ruscheweyh R, Willemer C, Krüger K, Duning T, Warnecke T, Sommer J, Völker K, Ho HV, Mooren F, Knecht S, Flöel A (July 2011). "Physical activity and memory functions: an interventional study". Neurobiol. Aging. 32 (7): 1304–19. doi:10.1016/j.neurobiolaging.2009.08.001. PMID 19716631.{{cite journal}}: CS1 maint: multiple names: authors list (link)

[Hippocampus-92] Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, Kim JS, Heo S, Alves H, White SM, Wojcicki TR, Mailey E, Vieira VJ, Martin SA, Pence BD, Woods JA, McAuley E, Kramer AF (February 2011). "Exercise training increases size of hippocampus and improves memory". Proc. Natl. Acad. Sci. U.S.A. 108 (7): 3017–22. doi:10.1073/pnas.1015950108. PMC 3041121. PMID 21282661.{{cite journal}}: CS1 maint: multiple names: authors list (link)

[NHM-Cognitive_Control-93] ^ ^a ^b ^c ^d ^e ^f ^g ^h Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY (ed.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 313–321. ISBN 9780071481274. • Executive function, the cognitive control of behavior, depends on the prefrontal cortex, which is highly developed in higher primates and especially humans.
• Working memory is a short-term, capacity-limited cognitive buffer that stores information and permits its manipulation to guide decision-making and behavior. ...
These diverse inputs and back projections to both cortical and subcortical structures put the prefrontal cortex in a position to exert what is often called "top-down" control or cognitive control of behavior. ... The prefrontal cortex receives inputs not only from other cortical regions, including association cortex, but also, via the thalamus, inputs from subcortical structures subserving emotion and motivation, such as the amygdala (Chapter 14) and ventral striatum (or nucleus accumbens; Chapter 15). ...
In conditions in which prepotent responses tend to dominate behavior, such as in drug addiction, where drug cues can elicit drug seeking (Chapter 15), or in attention deficit hyperactivity disorder (ADHD; described below), significant negative consequences can result. ... ADHD can be conceptualized as a disorder of executive function; specifically, ADHD is characterized by reduced ability to exert and maintain cognitive control of behavior. Compared with healthy individuals, those with ADHD have diminished ability to suppress inappropriate prepotent responses to stimuli (impaired response inhibition) and diminished ability to inhibit responses to irrelevant stimuli (impaired interference suppression). ... Functional neuroimaging in humans demonstrates activation of the prefrontal cortex and caudate nucleus (part of the striatum) in tasks that demand inhibitory control of behavior. ... Early results with structural MRI show thinning of the cerebral cortex in ADHD subjects compared with age-matched controls in prefrontal cortex and posterior parietal cortex, areas involved in working memory and attention.{{cite book}}: CS1 maint: multiple names: authors list (link)

[NHM-PFC_cognitive_processes-94] Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY (ed.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 315. ISBN 9780071481274. However, damage to the prefrontal cortex has a significant deleterious effect on social behavior, decision making, and adaptive responding to the changing circumstances of life. ... Several subregions of the prefrontal cortex have been implicated in partly distinct aspects of cognitive control, although these distinctions remain somewhat vaguely defined. The anterior cingulate cortex is involved in processes that require correct decision-making, as seen in conflict resolution (eg, the Stroop test, see in Chapter 16), or cortical inhibition (eg, stopping one task and switching to another). The medial prefrontal cortex is involved in supervisory attentional functions (eg, action-outcome rules) and behavioral flexibility (the ability to switch strategies). The dorsolateral prefrontal cortex, the last brain area to undergo myelination during development in late adolescence, is implicated in matching sensory inputs with planned motor responses. The ventromedial prefrontal cortex seems to regulate social cognition, including empathy. The orbitofrontal cortex is involved in social decision making and in representing the valuations assigned to different experiences.{{cite book}}: CS1 maint: multiple names: authors list (link)

[NAcc_function-95] Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY (ed.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 147, 266, 376. ISBN 9780071481274. VTA DA neurons play a critical role in motivation, reward-related behavior (Chapter 15), attention, and multiple forms of memory. This organization of the DA system, wide projection from a limited number of cell bodies, permits coordinated responses to potent new rewards. Thus, acting in diverse terminal fields, dopamine confers motivational salience ("wanting") on the reward itself or associated cues (nucleus accumbens shell region) ... Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward. ... The NAc and VTA are central components of the circuitry underlying reward and memory of reward. As previously mentioned, the activity of dopaminergic neurons in the VTA appears to be linked to reward prediction. The NAc is involved in learning associated with reinforcement ... The shell of the NAc appears to be particularly important to initial drug actions within reward circuitry; addictive drugs appear to have a greater effect on dopamine release in the shell than in the core of the NAc.{{cite book}}: CS1 maint: multiple names: authors list (link)

[NHM-Caudate_Hippocampus-96] Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY (ed.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 148, 324–328, 438. ISBN 9780071481274. [dopamine] helps consolidate multiple forms of memory (amygdala and hippocampus) ... the specific crucial structures underlying the ability to store declarative memories are the hippocampus, the subicular complex, and the entorhinal cortex ... These findings strongly suggest that LTP in the hippocampus is required for at least some forms of learning and memory known to be dependent on this brain region. ... Evidence that the caudate nucleus and putamen influence stimulus-response learning comes from lesion studies in rodents and primates and from neuroimaging studies in humans and from studies of human disease. In Parkinson disease, the dopaminergic innervation of the caudate and putamen is severely compromised by the death of dopamine neurons in the substantia nigra pars compacta (Chapter 17). Patients with Parkinson disease have normal declarative memory ... However, they have marked impairments of stimulus-response learning. Patients with Parkinson disease or other basal ganglia disorders such as Huntington disease (in which caudate neurons themselves are damaged) have deficits in other procedural learning tasks, such as the acquisition of new motor programs. ... Huntington disease is associated with degenerative changes that are most apparent in the caudate nucleus and putamen.{{cite book}}: CS1 maint: multiple names: authors list (link)

[Cerebellum-97] Grimaldi G, Argyropoulos GP, Bastian A, Cortes M, Davis NJ, Edwards DJ, Ferrucci R, Fregni F, Galea JM, Hamada M, Manto M, Miall RC, Morales-Quezada L, Pope PA, Priori A, Rothwell J, Tomlinson SP, Celnik P (2014). "Cerebellar Transcranial Direct Current Stimulation (ctDCS): A Novel Approach to Understanding Cerebellar Function in Health and Disease". Neuroscientist. doi:10.1177/1073858414559409. PMID 25406224.

[parietal-98] Sereno MI, Huang RS (2014). "Multisensory maps in parietal cortex". Curr. Opin. Neurobiol. 24 (1): 39–46. doi:10.1016/j.conb.2013.08.014. PMC 3969294. PMID 24492077.

[Executive_functions-99] Diamond A (2013). "Executive functions". Annu Rev Psychol. 64: 135–168. doi:10.1146/annurev-psych-113011-143750. PMC 4084861. PMID 23020641. Core EFs are inhibition [response inhibition (self-control—resisting temptations and resisting acting impulsively) and interference control (selective attention and cognitive inhibition)], working memory, and cognitive flexibility (including creatively thinking "outside the box," seeing anything from different perspectives, and quickly and flexibly adapting to changed circumstances). ... EFs and prefrontal cortex are the first to suffer, and suffer disproportionately, if something is not right in your life. They suffer first, and most, if you are stressed (Arnsten 1998, Liston et al. 2009, Oaten & Cheng 2005), sad (Hirt et al. 2008, von Hecker & Meiser 2005), lonely (Baumeister et al. 2002, Cacioppo & Patrick 2008, Campbell et al. 2006, Tun et al. 2012), sleep deprived (Barnes et al. 2012, Huang et al. 2007), or not physically fit (Best 2010, Chaddock et al. 2011, Hillman et al. 2008). Any of these can cause you to appear to have a disorder of EFs, such as ADHD, when you do not. You can see the deleterious effects of stress, sadness, loneliness, and lack of physical health or fitness at the physiological and neuroanatomical level in prefrontal cortex and at the behavioral level in worse EFs (poorer reasoning and problem solving, forgetting things, and impaired ability to exercise discipline and self-control). ...
EFs can be improved (Diamond & Lee 2011, Klingberg 2010). ... At any age across the life cycle EFs can be improved, including in the elderly and in infants. There has been much work with excellent results on improving EFs in the elderly by improving physical fitness (Erickson & Kramer 2009, Voss et al. 2011) ... Inhibitory control (one of the core EFs) involves being able to control one's attention, behavior, thoughts, and/or emotions to override a strong internal predisposition or external lure, and instead do what's more appropriate or needed. Without inhibitory control we would be at the mercy of impulses, old habits of thought or action (conditioned responses), and/or stimuli in the environment that pull us this way or that. Thus, inhibitory control makes it possible for us to change and for us to choose how we react and how we behave rather than being unthinking creatures of habit. It doesn't make it easy. Indeed, we usually are creatures of habit and our behavior is under the control of environmental stimuli far more than we usually realize, but having the ability to exercise inhibitory control creates the possibility of change and choice.

[Attention-acute_exercise-100] Janssen M, Toussaint HM, van Mechelen W, Verhagen EA (2014). "Effects of acute bouts of physical activity on children's attention: a systematic review of the literature". Springerplus. 3: 410. doi:10.1186/2193-1801-3-410. PMC 4132441. PMID 25133092. There is weak evidence for the effect of acute bouts of physical activity on attention. ... Fortunately, the literature-base on the acute effect of PA on the underlying cognitive processes of academic performance is growing. Hillman et al. (2011) found in their review a positive effect of acute PA on brain health and cognition in children, but concluded it was complicated to compare the different studies due to the different outcome measures (e.g. memory, response time and accuracy, attention, and comprehension). Therefore, this review focuses on the sole outcome measure 'attention' as a mediator for cognition and achievement.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[Malenka_pathways-101] Cite error: The named reference Malenka pathways was invoked but never defined (see the help page).

[Cognitive_and_motivational_effects-103] Ilieva IP, Hook CJ, Farah MJ (2015). "Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis". J Cogn Neurosci: 1–21. doi:10.1162/jocn_a_00776. PMID 25591060.

[ADHD_Exercise_2014-107] "Exercise reduces the symptoms of attention-deficit/hyperactivity disorder and improves social behaviour, motor skills, strength and neuropsychological parameters". Acta Paediatr. 103 (7): 709–14. July 2014. doi:10.1111/apa.12628. PMID 24612421. Retrieved 14 March 2015. The present review summarises the impact of exercise interventions (1–10 weeks in duration with at least two sessions each week) on parameters related to ADHD in 7-to 13-year-old children. We may conclude that all different types of exercise (here yoga, active games with and without the involvement of balls, walking and athletic training) attenuate the characteristic symptoms of ADHD and improve social behaviour, motor skills, strength and neuropsychological parameters without any undesirable side effects. Available reports do not reveal which type, intensity, duration and frequency of exercise is most effective in this respect and future research focusing on this question with randomised and controlled long-term interventions is warranted. {{cite journal}}: Cite uses deprecated parameter |authors= (help)

[ADHD_Exercise_2013-108] "Protection from genetic diathesis in attention-deficit/hyperactivity disorder: possible complementary roles of exercise". J Am Acad Child Adolesc Psychiatry. 52 (9): 900–10. September 2013. doi:10.1016/j.jaac.2013.05.018. PMID 23972692. As exercise has been found to enhance neural growth and development, and improve cognitive and behavioural functioning in [healthy] individuals and animal studies, we reviewed the literature on the effects of exercise in children and adolescents with ADHD and animal models of ADHD behaviours.
A limited number of undersized non-randomized, retrospective and cross-sectional studies have investigated the impact of exercise on ADHD and the emotional, behavioural and neuropsychological problems associated with the disorder. The findings from these studies provide some support for the notion that exercise has the potential to act as a protective factor for ADHD. ... Although it remains unclear which role, if any, BDNF plays in the pathophysiology of ADHD, enhanced neural functioning has been suggested to be associated with the reduction of remission of ADHD symptoms.^49,50,72 As exercise can elicit gene expression changes mediated by alterations in DNA methylation³⁸, the possibility emerges that some of the positive effects of exercise could be caused by epigenetic mechanisms, which may set off a cascade of processes instigated by altered gene expression that could ultimately link to a change in brain function. {{cite journal}}: Cite uses deprecated parameter |authors= (help)

[NHM-Stress-109] Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 14: Mood and Emotion". In Sydor A, Brown RY (ed.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 350–359. ISBN 9780071481274. The excessive release of stress hormones, such as cortisol, which occurs in many individuals with mood disorders, may result from hyperfunctioning of the PVN of the hypothalamus, hyperfunctioning of the amygdala (which activates the PVN), or hypofunctioning of the hippocampus (which exerts a potent inhibitory influence on the PVN). ... Chronic stress decreases the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus, which in turn may contribute to the atrophy of CA3 neurons and their increased vulnerability to a variety of neuronal insults. Chronic elevation of glucocorticoid levels is also known to decrease the survival of these neurons. Such activity may increase the dendritic arborizations and survival of the neurons, or help repair or protect the neurons from further damage. ... Stress and glucocorticoids inhibit, and a wide variety of antidepressant drugs, exercise, and enriched environments activate hippocampal neurogenesis.{{cite book}}: CS1 maint: multiple names: authors list (link)

[Exercise_neuroendocrine_effects-110] Fuqua JS, Rogol AD (July 2013). "Neuroendocrine alterations in the exercising human: implications for energy homeostasis". Metab. Clin. Exp. 62 (7): 911–921. doi:10.1016/j.metabol.2013.01.016. PMID 23415825. Cortisol has wide-ranging effects, including alterations of carbohydrate, protein, and lipid metabolism; catabolic effects on skin, muscle, connective tissue, and bone; immunomodulatory effects; blood pressure and circulatory system regulation; and effects on mood and central nervous system function. In the short term, activation of the HPA axis in response to stress is adaptive. However, long-term stress promoting chronic exposure of tissues to high cortisol concentrations becomes maladaptive. ... Exercise, particularly sustained aerobic activity, is a potent stimulus of cortisol secretion. The circulating concentrations of cortisol are directly proportional to the intensity of exercise as measured by oxygen uptake. As is the case for the GH/IGF-1 and HPG axes, the HPA axis also receives many other inputs, including the light/dark cycle, feeding schedules, immune regulation, and many neurotransmitters that mediate the effects of exercise and physical and psychic stress [52]. ... The HPA is activated by stress, whether physical (exercise) or psychological. ... Thus, a negative net energy balance leads to activation of the HPA axis and the circulating concomitants of the catabolic state in an attempt to keep core processes functional, realizing that the stress of exercise has no effect on cortisol and circulating metabolic substrates beyond the impact of the exercise energy expenditure on energy availability [60]. Thuma et al. [61] had already made the important observation that the reported differences in cortisol levels pre- and post-exercise depended on whether this difference was measured from a single pre-test level or from the physiologic circadian baseline as determined in an independent session in the resting state. By this analytical technique, these investigators showed that increasing energy expenditure led to significant cortisol release. This release was apparent if they subtracted the physiologic circadian baseline from the post-exercise value.

[Endocrine_cognition-111] Ebner NC, Kamin H, Diaz V, Cohen RA, MacDonald K (January 2015). "Hormones as "difference makers" in cognitive and socioemotional aging processes". Front Psychol. 5: 1595. doi:10.3389/fpsyg.2014.01595. PMC 4302708. PMID 25657633. It is known that chronically elevated levels of the stress hormone cortisol exert neurotoxic effects on the aging brain with negative impacts on cognition and socioemotional functioning. ... Cortisol is a steroid hormone released by the HPA axis in response to challenging situations. As the primary effector of the biological stress response in humans, it is implicated in a diverse array of physiologic, metabolic, immunologic, and psychological processes directed toward successful coping (Sapolsky et al., 2000; Kassel and Herrlich, 2007). Cortisol receptors are well-represented in limbic structures involved in affective response (i.e., hippocampus, hypothalamus, amygdala) and in regions central to executive function such as the prefrontal cortex and anterior cingulate cortex (Dedovic et al., 2009; Joëls and Baram, 2009). As a result, the effects of cortisol extend beyond the stress and threat response system to impact mood, attention, and memory (Lupien and McEwen, 1997; Sapolsky et al., 2000; de Kloet et al., 2005). ... In contrast, evidence indicated positive associations between cortisol levels that were acutely elevated by stress or hydrocortisone administration and inhibitory control (Schlosser et al., 2013) as well as spatial learning (Meyer et al., 2013). Regarding cortisol's effect on memory, the evidence is currently mixed (Schwabe et al., 2012; van Ast et al., 2013). ... There also is evidence that effects of cortisol on cognition vary in a dose-dependent fashion. In particular, there is evidence of cognitive improvements under conditions of moderate, time-limited cortisol elevation but evidence of cognitive impairments when cortisol concentrations are persistent or excessively high (Lupien et al., 1999; Abercrombie et al., 2003; Hupbach and Fieman, 2012; Schilling et al., 2013; Moriarty et al., 2014).{{cite journal}}: CS1 maint: unflagged free DOI (link)

[Fitness_mechanism-112] ^ ^a ^b ^c ^d ^e ^f Silverman MN, Deuster PA (October 2014). "Biological mechanisms underlying the role of physical fitness in health and resilience". Interface Focus. 4 (5): 20140040. doi:10.1098/rsfs.2014.0040. PMID 25285199. Physical fitness, achieved through regular exercise and/or spontaneous physical activity, can protect against the development of chronic stress- and inflammatory-related disease by optimizing physiological and neuroendocrine stress responsivity, promoting an anti-inflammatory state, and enhancing neuroplasticity and growth factor expression. stress responsive systems are adaptive when activated and terminated in a timely manner, prolonged (or insufficient) activation of these systems can cause a variety of maladaptive responses. ... For example, Rimelle et al. [123] documented significantly lower cortisol and heart rate responses to psychosocial stress (Trier social stress test) in trained men compared with untrained men. Moreover, significantly greater calmness and better mood, and a trend towards lower state anxiety, were noted in these trained men during the stress protocol. ... Whereas hippocampal and/or serum/plasma BDNF levels are downregulated by chronic psychosocial stress and inflammation [138,180,201], central and peripheral BDNF levels can be upregulated by acute exercise [33,198,202,203]. ... Exercise-induced increases in brain monoamines (norepinephrine and serotonin) may also contribute to increased expression of hippocampal BDNF [194]. In addition, other growth factors—insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor—have been shown to play an important role in BDNF-induced effects on neuroplasticity [33,172,190,192], as well as exerting neuroprotective effects of their own [33,214,215], thereby contributing to the beneficial effects of exercise on brain health. Like BDNF, increases in circulating IGF-1 levels in response to acute exercise are only transient and possibly time-dependent as it relates to chronic training (i.e. increases seen after 12 weeks of training) [216]. ... Whereas reduced HPA axis reactivity to a given stressor has repeatedly been reported in physically fit individuals, the finding of reduced sympathetic reactivity is less consistent.

[epigenome-114] Cite error: The named reference epigenome was invoked but never defined (see the help page).

[sports_epigenetics-115] Cite error: The named reference sports epigenetics was invoked but never defined (see the help page).

[Exercise_mental_disorders-116] Zschucke E, Gaudlitz K, Ströhle A (January 2013). "Exercise and physical activity in mental disorders: clinical and experimental evidence". J Prev Med Public Health. 46 Suppl 1: S12–521. doi:10.3961/jpmph.2013.46.S.S12. PMC 3567313. PMID 23412549. In psychiatric patients, different mechanisms of action for PA and EX have been discussed: On a neurochemical and physiological level, a number of acute changes occur during and following bouts of EX, and several long-term adaptations are related to regular EX training. For instance, EX has been found to normalize reduced levels of brain-derived neurotrophic factor (BDNF) and therefore has neuroprotective or even neurotrophic effects [7–9]. Animal studies found EX-induced changes in different neurotransmitters such as serotonin and endorphins [10,11], which relate to mood, and positive effects of EX on stress reactivity (e.g., the hypothalamus-pituitary-adrenal axis [12,13]). Finally, anxiolytic effects of EX mediated by atrial natriuretic peptide have been reported [14]. Potential psychological mechanisms of action include learning and extinction, changes in body scheme and health attitudes/behaviors, social reinforcement, experience of mastery, shift of external to more internal locus of control, improved coping strategies, or simple distraction [15,16].{{cite journal}}: CS1 maint: multiple names: authors list (link)

[Primary-Runner's_high_definition-117] Raichlen DA, Foster AD, Gerdeman GL, Seillier A, Giuffrida A (2012). "Wired to run: exercise-induced endocannabinoid signaling in humans and cursorial mammals with implications for the 'runner's high'". J. Exp. Biol. 215 (Pt 8): 1331–6. doi:10.1242/jeb.063677. PMID 22442371. Humans report a wide range of neurobiological rewards following moderate and intense aerobic activity, popularly referred to as the 'runner's high', which may function to encourage habitual aerobic exercise. ... Thus, a neurobiological reward for endurance exercise may explain why humans and other cursorial mammals habitually engage in aerobic exercise despite the higher associated energy costs and injury risks

[Primary-Rower's_high_definition-118] Cohen EE, Ejsmond-Frey R, Knight N, Dunbar RI (2010). "Rowers' high: behavioural synchrony is correlated with elevated pain thresholds". Biol. Lett. 6 (1): 106–8. doi:10.1098/rsbl.2009.0670. PMC 2817271. PMID 19755532.

[PEA_exercise_primary-119] Szabo A, Billett E, Turner J (2001). "Phenylethylamine, a possible link to the antidepressant effects of exercise?". Br J Sports Med. 35 (5): 342–343. doi:10.1136/bjsm.35.5.342. PMC 1724404. PMID 11579070. The 24 hour mean urinary concentration of phenylacetic acid was increased by 77% after exercise. ... These results show substantial increases in urinary phenylacetic acid levels 24 hours after moderate to high intensity aerobic exercise. As phenylacetic acid reflects phenylethylamine levels³ , and the latter has antidepressant effects, the antidepressant effects of exercise appear to be linked to increased phenylethylamine concentrations. Furthermore, considering the structural and pharmacological analogy between amphetamines and phenylethylamine, it is conceivable that phenylethylamine plays a role in the commonly reported "runners high" thought to be linked to cerebral β-endorphin activity. The substantial increase in phenylacetic acid excretion in this study implies that phenylethylamine levels are affected by exercise. ... A 30 minute bout of moderate to high intensity aerobic exercise increases phenylacetic acid levels in healthy regularly exercising men. The findings may be linked to the antidepressant effects of exercise.

[Renaissance-120] Lindemann L, Hoener MC (2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends Pharmacol. Sci. 26 (5): 274–281. doi:10.1016/j.tips.2005.03.007. PMID 15860375. The pharmacology of TAs might also contribute to a molecular understanding of the well-recognized antidepressant effect of physical exercise [51]. In addition to the various beneficial effects for brain function mainly attributed to an upregulation of peptide growth factors [52,53], exercise induces a rapidly enhanced excretion of the main β-PEA metabolite β-phenylacetic acid (b-PAA) by on average 77%, compared with resting control subjects [54], which mirrors increased β-PEA synthesis in view of its limited endogenous pool half-life of ~30 s [18,55].

[Neuropsychiatric-121] Berry MD (2007). "The potential of trace amines and their receptors for treating neurological and psychiatric diseases". Rev Recent Clin Trials. 2 (1): 3–19. doi:10.2174/157488707779318107. PMID 18473983. It has also been suggested that the antidepressant effects of exercise are due to an exercise-induced elevation of PE [151].

[Endorphin-122] ^ ^a ^b ^c ^d ^e ^f Dinas PC, Koutedakis Y, Flouris AD (2011). "Effects of exercise and physical activity on depression". Ir J Med Sci. 180 (2): 319–325. doi:10.1007/s11845-010-0633-9. PMID 21076975. According to the 'endorphins hypothesis', exercise augments the secretion of endogenous opioid peptides in the brain, reducing pain and causing general euphoria. ... Based upon a large effect size, the results confirmed the endorphins hypothesis demonstrating that exercise leads to an increased secretion of endorphins which, in turn, improved mood states.
β-Endorphin, an endogenous μ-opioid receptor selective ligand, has received much attention in the literature linking endorphins and depression or mood states. ... exercise of sufficient intensity and duration can increase circulating β-endorphin levels. ... Moreover, a recent study demonstrated that exercise and physical activity increased β-endorphin levels in plasma with positive effects on mood. Interestingly, the researchers reported that, independently of sex and age, dynamic anaerobic exercises increased β-endorphin, while resistance and aerobic exercises seem to only have small effects on β-endorphins. ... The results showed that mood tends to be higher in a day an individual exercises as well as that daily activity and exercise overall are strongly linked with mood states. In line with these findings, a recent study showed that exercise significantly improved mood states in non-exercises, recreational exercisers, as well as marathon runners. More importantly, the effects of exercise on mood were twofold in recreational exercisers and marathon runners.

[endocannabinoids-123] Tantimonaco M, Ceci R, Sabatini S, Catani MV, Rossi A, Gasperi V, Maccarrone M (2014). "Physical activity and the endocannabinoid system: an overview". Cell. Mol. Life Sci. 71 (14): 2681–2698. doi:10.1007/s00018-014-1575-6. PMID 24526057. The traditional view that PA engages the monoaminergic and endorphinergic systems has been challenged by the discovery of the endocannabinoid system (ECS), composed of endogenous lipids, their target receptors, and metabolic enzymes. Indeed, direct and indirect evidence suggests that the ECS might mediate some of the PA-triggered effects throughout the body. ... the evidence that PA induces some of the psychotropic effects elicited by the Cannabis sativa active ingredient Δ9-tetrahydrocannabinol (Δ9-THC, Fig. 1), like bliss, euphoria, and peacefulness, strengthened the hypothesis that endocannabinoids (eCBs) might mediate, at least in part, the central and peripheral effects of exercise [14]. ... To our knowledge, the first experimental study aimed at investigating the influence of PA on ECS in humans was carried out in 2003 by Sparling and coworkers [63], who showed increased plasma AEA content after 45 min of moderate intensity exercise on a treadmill or cycle ergometer. Since then, other human studies have shown increased blood concentrations of AEA ... A dependence of the increase of AEA concentration on exercise intensity has also been documented. Plasma levels of AEA significantly increased upon 30 min of moderate exercise (heart rate of 72 and 83 %), but not at lower and significantly higher exercise intensities, where the age-adjusted maximal heart rate was 44 and 92 %, respectively ... Several experimental data support the hypothesis that ECS might, at least in part, explain PA effects on brain functions, because: (1) CB1 is the most abundant GPCR in the brain participating in neuronal plasticity [18]; (2) eCBs are involved in several brain responses that greatly overlap with the positive effects of exercise; (3) eCBs are able to cross the blood–brain barrier [95]; and (4) exercise increases eCB plasma levels [64–67].

[PEA-124] "β-phenylethylamine: Biological activity". Guide to Pharmacology. The International Union of Basic and Clinical Pharmacology. Retrieved 10 February 2015.

[Amph-125] "Dexamfetamine: Biological activity". Guide to Pharmacology. The International Union of Basic and Clinical Pharmacology. Retrieved 10 February 2015.

[Vascular-126] Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacol. Ther. 125 (3): 363–375. doi:10.1016/j.pharmthera.2009.11.005. PMID 19948186. Trace amines are metabolized in the mammalian body via monoamine oxidase (MAO; EC 1.4.3.4) (Berry, 2004) (Fig. 2) ... It deaminates primary and secondary amines that are free in the neuronal cytoplasm but not those bound in storage vesicles of the sympathetic neurone ... Similarly, β-PEA would not be deaminated in the gut as it is a selective substrate for MAO-B which is not found in the gut ...
Brain levels of endogenous trace amines are several hundred-fold below those for the classical neurotransmitters noradrenaline, dopamine and serotonin but their rates of synthesis are equivalent to those of noradrenaline and dopamine and they have a very rapid turnover rate (Berry, 2004). Endogenous extracellular tissue levels of trace amines measured in the brain are in the low nanomolar range. These low concentrations arise because of their very short half-life ...

[NHM-glutamate-127] Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 5: Excitatory and Inhibitory Amino Acids". In Sydor A, Brown RY (ed.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 117–130. ISBN 9780071481274. • The major excitatory neurotransmitter in the brain is glutamate; the major inhibitory neurotransmitter is GABA. ...
• The most extensively studied form of synaptic plasticity is long-term potentiation (LTP) in the hippocampus, which is triggered by strong activation of NMDA receptors and the consequent large rise in postsynaptic calcium concentration.
• Long-term depression (LTD), a long-lasting decrease in synaptic strength, also occurs at most excitatory and some inhibitory synapses in the brain. ... The bidirectional control of synaptic strength by LTP and LTD is believed to underlie some forms of learning and memory in the mammalian brain.{{cite book}}: CS1 maint: multiple names: authors list (link)

[Glutamate-dopamine_cotransmission_review-128] Broussard JI (2012). "Co-transmission of dopamine and glutamate". J. Gen. Physiol. 139 (1): 93–6. doi:10.1085/jgp.201110659. PMC 3250102. PMID 22200950. Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.

[Glutamate-dopamine_cotransmission_review_2-129] Descarries L, Bérubé-Carrière N, Riad M, Bo GD, Mendez JA, Trudeau LE (2008). "Glutamate in dopamine neurons: synaptic versus diffuse transmission". Brain Res Rev. 58 (2): 290–302. doi:10.1016/j.brainresrev.2007.10.005. PMID 18042492. Moreover, all TH varicosities which co-localize VGluT2 are synaptic, as if there was a link between the potential of DA axon terminals to release glutamate and their establishment of synaptic junctions. Together with the RT-PCR and in situ hybridization data demonstrating the co-localization of TH and VGluT2 mRNA in mesencephalic neurons of the VTA, these observations raise a number of fundamental questions regarding the functioning of the meso-telencephalic DA system in healthy or diseased brain.

[Running_vs_addiction-130] Cite error: The named reference Running vs addiction was invoked but never defined (see the help page).

[hillman-131] Hillman, C.H., Erickson, K.I., and Kramer, A.F. 2008. Be smart, exercise your heart: exercise effects on brain and cognition. Nature Reviews Neuroscience. 9:58–65.

[sibley-132] Sibley, B. A. and Etnier, J. L. 2003. The Relationship Between Physical Activity and Cognition in Children: A Meta-Analysis. Pediatric Exercise Science. 15(3):243–256.

[chaddock-133] Chaddock, L., Hillman, C. H., Buck, S. M. and Cohen, N. J. 2011. Aerobic Fitness and Executive Control of Relational Memory in Preadolescent Children. Medicine & Science in Sports & Exercise. 43(2):344–349.

[chaddocke-134] Chaddock, I., Erickson, K. I., Prakash, R. S., Kim, J. S., Voss, M. A., VanPatter, M. et al.. 2010. A neuroimaging investigation of the association between aerobic fitness, hippocampal volume, and memory performance in preadolescent children. Brain Research. 1358:172–183.

[best-135] Best, J. R. 2010. Effects of physical activity on children’s executive function: Contributions of experimental research on aerobic exercise. Developmental Review. 30(4):331–351. doi: 10.1016/j.brainres.2010.08.049

[dik-136] Dik, M. G., Deeg, D. J. H., Visser, M. and Jonker, C. 2003. Early Life Physical Activity and Cognition at Old Age. Journal of Clinical and Experimental Neuropsychology. 25(5):643–653.

[Swardfager2010-137] Swardfager W, Herrmann N, Marzolini S, Saleem M, Kiss A, Shammi P, Oh PI and Lanctôt KL, 2010. Cardiopulmonary fitness is associated with cognitive performance in patients with coronary artery disease. J. Amer. Geriatrics. Soc. 58(8):1519–25.

[Alz_1-138] Farina N, Rusted J, Tabet N (January 2014). "The effect of exercise interventions on cognitive outcome in Alzheimer's disease: a systematic review". Int Psychogeriatr. 26 (1): 9–18. doi:10.1017/S1041610213001385. PMID 23962667. Six RCTs were identified that exclusively considered the effect of exercise in AD patients. Exercise generally had a positive effect on rate of cognitive decline in AD. A meta-analysis found that exercise interventions have a positive effect on global cognitive function, 0.75 (95% CI = 0.32–1.17). ... The most prevalent subtype of dementia is Alzheimer's disease (AD), accounting for up to 65.0% of all dementia cases ... Cognitive decline in AD is attributable at least in part to the buildup of amyloid and tau proteins, which promote neuronal dysfunction and death (Hardy and Selkoe, 2002; Karran et al., 2011). Evidence in transgenic mouse models of AD, in which the mice have artificially elevated amyloid load, suggests that exercise programs are able to improve cognitive function (Adlard et al., 2005; Nichol et al., 2007). Adlard and colleagues also determined that the improvement in cognitive performance occurred in conjunction with a reduced amyloid load. Research that includes direct indices of change in such biomarkers will help to determine the mechanisms by which exercise may act on cognition in AD.

[Alz_2-139] Rao AK, Chou A, Bursley B, Smulofsky J, Jezequel J (January 2014). "Systematic review of the effects of exercise on activities of daily living in people with Alzheimer's disease". Am J Occup Ther. 68 (1): 50–56. doi:10.5014/ajot.2014.009035. PMID 24367955. Alzheimer's disease (AD) is a progressive neurological disorder characterized by loss in cognitive function, abnormal behavior, and decreased ability to perform basic activities of daily living [(ADLs)] ... All studies included people with AD who completed an exercise program consisting of aerobic, strength, or balance training or any combination of the three. The length of the exercise programs varied from 12 weeks to 12 months. ... Six studies involving 446 participants tested the effect of exercise on ADL performance ... exercise had a large and significant effect on ADL performance (z = 4.07, p < .0001; average effect size = 0.80). ... These positive effects were apparent with programs ranging in length from 12 wk (Santana-Sosa et al., 2008; Teri et al., 2003) and intermediate length of 16 wk (Roach et al., 2011; Vreugdenhil et al., 2012) to 6 mo (Venturelli et al., 2011) and 12 mo (Rolland et al., 2007). Furthermore, the positive effects of a 3-mo intervention lasted 24 mo (Teri et al., 2003). ... No adverse effects of exercise on ADL performance were noted. ... The study with the largest effect size implemented a walking and aerobic program of only 30 min four times a week (Venturelli et al., 2011).

[adlard-140] Adlard PA, Perreau VM, Pop V, Cotman CW (2005). "Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer's disease". J. Neurosci. 25 (17): 4217–21. doi:10.1523/JNEUROSCI.0496-05.2005. PMID 15858047.

[Caerphilly_primary-141] Elwood P, Galante J, Pickering J, Palmer S, Bayer A, Ben-Shlomo Y, Longley M, Gallacher J (December 2013). "Healthy lifestyles reduce the incidence of chronic diseases and dementia: evidence from the Caerphilly cohort study". PLoS ONE. 8 (12): e81877. doi:10.1371/journal.pone.0081877. PMC 3857242. PMID 24349147.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[Caerphilly_meta-analysis-142] Morgan GS, Gallacher J, Bayer A, Fish M, Ebrahim S, Ben-Shlomo Y (2012). "Physical activity in middle-age and dementia in later life: findings from a prospective cohort of men in Caerphilly, South Wales and a meta-analysis". J. Alzheimers Dis. 31 (3): 569–80. doi:10.3233/JAD-2012-112171. PMID 22647258.

[Longitudinal_SystRev_dementia-143] Blondell SJ, Hammersley-Mather R, Veerman JL (May 2014). "Does physical activity prevent cognitive decline and dementia?: A systematic review and meta-analysis of longitudinal studies". BMC Public Health. 14: 510. doi:10.1186/1471-2458-14-510. PMC 4064273. PMID 24885250. Longitudinal observational studies show an association between higher levels of physical activity and a reduced risk of cognitive decline and dementia. A case can be made for a causal interpretation. Future research should use objective measures of physical activity, adjust for the full range of confounders and have adequate follow-up length. Ideally, randomised controlled trials will be conducted. ... On the whole the results do, however, lend support to the notion of a causal relationship between physical activity, cognitive decline and dementia, according to the established criteria for causal inference.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[pang-144] Pang, T.Y.C., Stam, N. C., Nithianantharajah, J., Howard, M. L., and Hannan, A. J. 2006. Differential effects of voluntary physical exercise on behavioral and brain-derived neurotrophic factor expression deficits in Huntington's disease transgenic mice. Neuroscience. 141:569–584.

[kohl-145] Kohl, Z., Kandasamy, M., Winner, B., Aigner, R., Gross, C., Couillard-Despres et al.. 2007. Physical activity fails to rescue hippocampal neurogenesis deficits in the R6/2 mouse model of Huntington's disease. Trends in Cognitive Sciences. 11(8):342–348.

[baatile-146] Baatile, J., Langbein, W.E., Weaver, F., Maloney, C., and Jost, M.B. 2000. Effect of exercise on perceived quality of life of individuals with Parkinson's Disease. Journal of Rehabilitation Research and Development. 37(5):529–534.

[kramer-147] Kramer, A. F., Erickson, K. I. And Colcombe, S. J. 2006. Exercise, cognition, and the aging brain. Journal of Applied Physiology. 101(4):1237–1242.

[148] Kramer, A. F., Hahn, S., Cohen, N. J., Banich, M. T., McAuley, Harrison, C. R. et al. 1999. Ageing, fitness and neurocognitive function. Nature. 400:418–419.

[nocera-149] Nocera, J. R., Altman, L. J. P., Sapienza, C., Okun, M. S. and Hass, C. J. 2010. Can exercise improve language and cognition in Parkinson's disease? A case report. Neurocase: The Neural Basis of Cognition. 16(4):301–306.

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 ===Neuroplasticity and neurogenesis===
-[[Neuroplasticity]] is essentially the ability of neurons in the brain to adapt over time, and most often occurs in response to repeated exposure to stimuli;<ref name="NHM-Plasticity">{{cite book | author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 5, 351 | edition = 2nd | quote= The clinical actions of fluoxetine, like those of many neuropharmacologic agents, reflect drug-induced neural plasticity, which is the process by which neurons adapt over time in response to chronic disturbance.&nbsp;... For example, evidence indicates that prolonged increases in cortisol may be damaging to hippocampal neurons and can suppress hippocampal neurogenesis (the generation of new neurons postnatally).}}</ref> whereas [[neurogenesis]] is the postnatal (after-birth) growth of new neurons, a beneficial form of neuroplasticity.<ref name="NHM-Plasticity" /> Aerobic exercise promotes neurogenesis by increasing the production of [[neurotrophic factors]] (compounds which promote the growth or survival of neurons), such as [[brain-derived neurotrophic factor]] (BDNF), [[insulin-like growth factor 1]] (IGF-1), and [[vascular endothelial growth factor]] (VEGF).<ref name="Cerebral hemodynamics and AD" /><ref name="BDNF meta analysis">{{cite journal | author = Szuhany KL, Bugatti M, Otto MW | title = A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor | journal = J Psychiatr Res | volume = 60C | issue = | pages = 56–64 | date = October 2014 | pmid = 25455510 | pmc = 4314337 | doi = 10.1016/j.jpsychires.2014.10.003 | quote = Consistent evidence indicates that exercise improves cognition and mood, with preliminary evidence suggesting that brain-derived neurotrophic factor (BDNF) may mediate these effects. The aim of the current meta-analysis was to provide an estimate of the strength of the association between exercise and increased BDNF levels in humans across multiple exercise paradigms. We conducted a meta-analysis of 29 studies (N = 1111 participants) examining the effect of exercise on BDNF levels in three exercise paradigms: (1) a single session of exercise, (2) a session of exercise following a program of regular exercise, and (3) resting BDNF levels following a program of regular exercise. Moderators of this effect were also examined. Results demonstrated a moderate effect size for increases in BDNF following a single session of exercise (Hedges' g = 0.46, p < 0.001). Further, regular exercise intensified the effect of a session of exercise on BDNF levels (Hedges' g = 0.59, p = 0.02). Finally, results indicated a small effect of regular exercise on resting BDNF levels (Hedges' g = 0.27, p = 0.005).&nbsp;... Effect size analysis supports the role of exercise as a strategy for enhancing BDNF activity in humans}}</ref><ref name="Comprehensive review" />  Consistent aerobic exercise over a period of several months induces marked [[clinically significant]] improvements in [[executive function]] (i.e., the "[[cognitive control]]" of behavior) and increased [[gray matter]] volume in multiple brain regions, particularly those which give rise to cognitive control.<ref name="Comprehensive review">{{cite journal | author = Gomez-Pinilla F, Hillman C | title = The influence of exercise on cognitive abilities | journal = Compr Physiol | volume = 3 | issue = 1 | pages = 403–428 | date = January 2013 | pmid = 23720292 | pmc = 3951958 | doi = 10.1002/cphy.c110063 | quote = A second recent meta-analysis (162) corroborated Colcombe and Kramer’s (30) findings, in that aerobic exercise was related to attention, processing speed, memory, and cognitive control.&nbsp;... Normal aging results in the loss of brain tissue (31), with markedly larger tissue loss evidenced in the frontal, temporal, and parietal cortices (16, 58, 149). As such, cognitive functions subserved by these brain regions (such as those involved in cognitive control and memory) are expected to decay more dramatically than other aspects of cognition. Specifically, age-related decreases in gray matter volume have been associated with decrements in a variety of cognitive control processes.&nbsp;... Decreases in gray matter volume may result from several factors including loss in the number of neurons, neuronal shrinkage, reduction in dendritic arborization, and alterations in glia (158). Further, decreases in white matter (brain tissue composed primarily of myelinated nerve fibers) volume, which represent changes in connectivity between neurons, also occur as a result of aging. Loss of white matter volume further relates to performance decrements on a host of cognitive tasks&nbsp;... aerobic fitness relates to larger hippocampal volume (23) and better relational memory performance (24), during preadolescent childhood.&nbsp;... Specifically, those assigned to the aerobic training group demonstrated increases in gray matter in the frontal lobes, including the dorsal anterior cingulate cortex (ACC), supplementary motor area, middle frontal gyrus, dorsolateral region of the right inferior frontal gyrus, and the left superior temporal lobe (32). White matter volume changes were also evidenced for the aerobic fitness group with increases in white matter tracts within the anterior third of the corpus callosum (32).&nbsp;...  In addition, aerobic fitness has been shown to promote better functioning of brain, especially in neural networks involved in cognitive control of inhibition and attention (33).&nbsp;... In addition to BDNF, the actions of IGF-1 and vascular endothelial growth factor (VEGF) (54) are considered essential for the angiogenic and neurogenic effects of exercise in the brain.&nbsp;... Randomized and crossover clinical trials demonstrate the efficacy of aerobic or resistance training exercise (2–4 months) as a treatment for depression in both young and older individuals.&nbsp;... exercise seems to have both preventative and therapeutic effects on the course of depression}}</ref><ref name="gray matter">{{cite journal | author = Erickson KI, Leckie RL, Weinstein AM | title = Physical activity, fitness, and gray matter volume | journal = Neurobiol. Aging | volume = 35 Suppl 2 | issue = | pages = S20–528 | date = September 2014 | pmid = 24952993 | pmc = 4094356 | doi = 10.1016/j.neurobiolaging.2014.03.034 |url=http://www.neurobiologyofaging.org/article/S0197-4580(14)00349-2/fulltext | accessdate = 9 December 2014 | quote = We conclude that higher cardiorespiratory fitness levels are routinely associated with greater gray matter volume in the prefrontal cortex and hippocampus and less consistently in other regions. We also conclude that physical activity is associated with greater gray matter volume in the same regions that are associated with cardiorespiratory fitness including the prefrontal cortex and hippocampus.&nbsp;... Meta-analyses (Colcombe and Kramer, 2003; Smith et al., 2010) suggest that the effects of exercise on the brain might not be uniform across all regions and that some brain areas, specifically those areas supporting executive functions, might be more influenced by participation in exercise than areas not as critically involved in executive functions.&nbsp;... The effects appear to be general in the sense that many different cognitive domains are improved after several months of aerobic exercise, but specific in the sense that executive functions are improved more than other cognitive domains.&nbsp;... physical activity and exercise may reduce the risk for {{abbr|AD|Alzheimer’s disease}} (Barnes and Yaffe, 2011; Podewils et al., 2005; Sofi et al., 2011)&nbsp;... Erickson et al. (2010) reported that greater amounts of physical activity were associated with greater gray matter volume 9-years later in the prefrontal cortex, anterior cingulate, parietal cortex, cerebellum, and hippocampus.&nbsp;... higher fitness levels (VO2max) were associated with larger hippocampal volumes, better executive function, and faster processing speed.&nbsp;...  Verstynen et al. (2012) examined the association between cardiorespiratory fitness levels (VO2max) and the size of the basal ganglia&nbsp;... Verstynen et al. (2012) found that higher fitness levels were associated with greater volume of the caudate nucleus and nucleus accumbens, and in turn, greater volumes were associated with better performance on a task-switching paradigm.&nbsp;... That is, higher physical activity levels mitigated the detrimental effects of lifetime stress on the size of the hippocampus.&nbsp;... The few randomized interventions published thus far have found results highly overlapping with the cross-sectional studies and suggest that the prefrontal cortex and hippocampus remain pliable in late life and that moderate intensity exercise for 6 months–1 year is sufficient for changing the size of these areas.}}</ref><ref name="exercise benefits" /><ref name="cognitive control of exercise" /> The brain structures that show the greatest improvements in gray matter volume in response to aerobic exercise are the [[prefrontal cortex]] and [[hippocampus]];<ref name="Comprehensive review" /><ref name="gray matter" /><ref name="BDNF depression" /> moderate improvements seen in the [[anterior cingulate cortex]], [[parietal cortex]], [[cerebellum]], [[caudate nucleus]], and [[nucleus accumbens]].<ref name="Comprehensive review" /><ref name="gray matter" /><ref name="BDNF depression" /> The prefrontal cortex, caudate nucleus, and anterior cingulate cortex are among the most significant brain structures in the [[Neurotransmitter#Brain neurotransmitter systems|dopamine and norepinephrine systems]] that give rise to cognitive control.<ref name="gray matter" /><ref name="Malenka pathways">{{cite book | author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 147–148, 154–157 | edition = 2nd | chapter = Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin | quote=Neurons from the {{abbr|SNc|Substantia nigra pars compacta}} densely innervate the dorsal striatum where they play a critical role in the learning and execution of motor programs.  Neurons from the {{abbr|VTA|Ventral tegmental area}} innervate the ventral striatum (nucleus accumbens), olfactory bulb, amygdala, hippocampus, orbital and medial prefrontal cortex, and cingulate cortex. VTA {{abbr|DA|Dopamine}} neurons play a critical role in motivation, reward-related behavior, attention, and multiple forms of memory.&nbsp;... Thus, acting in diverse terminal fields, dopamine confers motivational salience ("wanting") on the reward itself or associated cues (nucleus accumbens shell region), updates the value placed on different goals in light of this new experience (orbital prefrontal cortex), helps consolidate multiple forms of memory (amygdala and hippocampus), and encodes new motor programs that will facilitate obtaining this reward in the future (nucleus accumbens core region and dorsal striatum).&nbsp;... {{Abbr|DA|Dopamine}} has multiple actions in the prefrontal cortex.  It promotes the "cognitive control" of behavior: the selection and successful monitoring of behavior to facilitate attainment of chosen goals.  Aspects of cognitive control in which DA plays a role include working memory, the ability to hold information "on line" in order to guide actions, suppression of prepotent behaviors that compete with goal-directed actions, and control of attention and thus the ability to overcome distractions.&nbsp;... Noradrenergic projections from the {{abbr|LC|locus coeruleus}} thus interact with dopaminergic projections from the VTA to regulate cognitive control.&nbsp;...}}</ref> Exercise-induced neurogenesis (i.e., the increases in gray matter volume) in the hippocampus is associated with measurable improvements in [[spatial memory]].<ref name="gray matter" /><ref name="BDNF depression" /><ref name="Exercise children">{{cite journal | author = Lees C, Hopkins J | title = Effect of aerobic exercise on cognition, academic achievement, and psychosocial function in children: a systematic review of randomized control trials | journal = Prev Chronic Dis | volume = 10 | issue = | pages = E174 | year = 2013 | pmid = 24157077 | pmc = 3809922 | doi = 10.5888/pcd10.130010 | quote = This omission is relevant, given the evidence that aerobic-based physical activity generates structural changes in the brain, such as neurogenesis, angiogenesis, increased hippocampal volume, and connectivity (12,13). In children, a positive relationship between aerobic fitness, hippocampal volume, and memory has been found (12,13).&nbsp;... Mental health outcomes included reduced depression and increased self-esteem, although no change was found in anxiety levels (18).&nbsp;... This systematic review of the literature found that APA is positively associated with cognition, academic achievement, behavior, and psychosocial functioning outcomes. Importantly, Shephard also showed that curriculum time reassigned to APA still results in a measurable, albeit small, improvement in academic performance (24). &nbsp;... The actual aerobic-based activity does not appear to be a major factor; interventions used many different types of APA and found similar associations. In positive association studies, intensity of the aerobic activity was moderate to vigorous. The amount of time spent in APA varied significantly between studies; however, even as little as 45 minutes per week appeared to have a benefit.}}</ref><ref name="Associated review">{{vcite2 journal | vauthors = Carvalho A, Rea IM, Parimon T, Cusack BJ | title = Physical activity and cognitive function in individuals over 60 years of age: a systematic review | journal = Clin Interv Aging | volume = 9 | issue = | pages = 661–682 | year = 2014 | pmid = 24748784 | pmc = 3990369 | doi = 10.2147/CIA.S55520 | quote = }}</ref> Higher [[physical fitness]] scores (measured by [[VO2 max|VO<sub>2</sub> max]]) are associated with better executive function, faster processing speed, and greater volume of the hippocampus, caudate nucleus, and nucleus accumbens.<ref name="gray matter" /> Long-term aerobic exercise is also associated with persistent beneficial [[behavioral epigenetics|epigenetic]] changes that result in improved stress coping, improved cognitive function, and increased neuronal activity ({{nowrap|[[c-Fos]]}} and [[BDNF]] signaling).<ref name="epigenome" /><ref name="sports epigenetics">{{cite journal | author = Ehlert T, Simon P, Moser DA | title = Epigenetics in sports | journal = Sports Med | volume = 43 | issue = 2 | pages = 93–110 | date = February 2013 | pmid = 23329609 | doi = 10.1007/s40279-012-0012-y | quote = Alterations in epigenetic modification patterns have been demonstrated to be dependent on exercise and growth hormone (GH), insulin-like growth factor 1 (IGF-1), and steroid administration.&nbsp;... the authors observed improved stress coping in exercised subjects. Investigating the dentate gyrus, a brain region which is involved in learning and coping with stressful and traumatic events, they could show that this effect is mediated by increased phosphorylation of serine 10 combined with H3K14 acetylation, which is associated with local opening of condensed chromatin. Consequently, they found increased immediate early gene expression as shown for c-FOS (FBJ murine osteosarcoma viral oncogene homologue).}}</ref>
+[[Neuroplasticity]] is essentially the ability of neurons in the brain to adapt over time, and most often occurs in response to repeated exposure to stimuli;<ref name="NHM-Plasticity">{{cite book | author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 5, 351 | edition = 2nd | quote= The clinical actions of fluoxetine, like those of many neuropharmacologic agents, reflect drug-induced neural plasticity, which is the process by which neurons adapt over time in response to chronic disturbance.&nbsp;... For example, evidence indicates that prolonged increases in cortisol may be damaging to hippocampal neurons and can suppress hippocampal neurogenesis (the generation of new neurons postnatally).}}</ref> whereas [[neurogenesis]] is the postnatal (after-birth) growth of new neurons, a beneficial form of neuroplasticity.<ref name="NHM-Plasticity" /> Aerobic exercise promotes neurogenesis by increasing the production of [[neurotrophic factors]] (compounds which promote the growth or survival of neurons), such as [[brain-derived neurotrophic factor]] (BDNF), [[insulin-like growth factor 1]] (IGF-1), and [[vascular endothelial growth factor]] (VEGF).<ref name="Cerebral hemodynamics and AD" /><ref name="BDNF meta analysis">{{cite journal | author = Szuhany KL, Bugatti M, Otto MW | title = A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor | journal = J Psychiatr Res | volume = 60C | issue = | pages = 56–64 | date = October 2014 | pmid = 25455510 | pmc = 4314337 | doi = 10.1016/j.jpsychires.2014.10.003 | quote = Consistent evidence indicates that exercise improves cognition and mood, with preliminary evidence suggesting that brain-derived neurotrophic factor (BDNF) may mediate these effects. The aim of the current meta-analysis was to provide an estimate of the strength of the association between exercise and increased BDNF levels in humans across multiple exercise paradigms. We conducted a meta-analysis of 29 studies (N = 1111 participants) examining the effect of exercise on BDNF levels in three exercise paradigms: (1) a single session of exercise, (2) a session of exercise following a program of regular exercise, and (3) resting BDNF levels following a program of regular exercise. Moderators of this effect were also examined. Results demonstrated a moderate effect size for increases in BDNF following a single session of exercise (Hedges' g = 0.46, p < 0.001). Further, regular exercise intensified the effect of a session of exercise on BDNF levels (Hedges' g = 0.59, p = 0.02). Finally, results indicated a small effect of regular exercise on resting BDNF levels (Hedges' g = 0.27, p = 0.005).&nbsp;... Effect size analysis supports the role of exercise as a strategy for enhancing BDNF activity in humans}}</ref><ref name="Comprehensive review" />  Consistent aerobic exercise over a period of several months induces marked [[clinically significant]] improvements in [[executive function]] (i.e., the "[[cognitive control]]" of behavior) and increased [[gray matter]] volume in multiple brain regions, particularly those which give rise to cognitive control.<ref name="Comprehensive review">{{cite journal | author = Gomez-Pinilla F, Hillman C | title = The influence of exercise on cognitive abilities | journal = Compr Physiol | volume = 3 | issue = 1 | pages = 403–428 | date = January 2013 | pmid = 23720292 | pmc = 3951958 | doi = 10.1002/cphy.c110063 | quote = A second recent meta-analysis (162) corroborated Colcombe and Kramer’s (30) findings, in that aerobic exercise was related to attention, processing speed, memory, and cognitive control.&nbsp;... Normal aging results in the loss of brain tissue (31), with markedly larger tissue loss evidenced in the frontal, temporal, and parietal cortices (16, 58, 149). As such, cognitive functions subserved by these brain regions (such as those involved in cognitive control and memory) are expected to decay more dramatically than other aspects of cognition. Specifically, age-related decreases in gray matter volume have been associated with decrements in a variety of cognitive control processes.&nbsp;... Decreases in gray matter volume may result from several factors including loss in the number of neurons, neuronal shrinkage, reduction in dendritic arborization, and alterations in glia (158). Further, decreases in white matter (brain tissue composed primarily of myelinated nerve fibers) volume, which represent changes in connectivity between neurons, also occur as a result of aging. Loss of white matter volume further relates to performance decrements on a host of cognitive tasks&nbsp;... aerobic fitness relates to larger hippocampal volume (23) and better relational memory performance (24), during preadolescent childhood.&nbsp;... Specifically, those assigned to the aerobic training group demonstrated increases in gray matter in the frontal lobes, including the dorsal anterior cingulate cortex (ACC), supplementary motor area, middle frontal gyrus, dorsolateral region of the right inferior frontal gyrus, and the left superior temporal lobe (32). White matter volume changes were also evidenced for the aerobic fitness group with increases in white matter tracts within the anterior third of the corpus callosum (32).&nbsp;...  In addition, aerobic fitness has been shown to promote better functioning of brain, especially in neural networks involved in cognitive control of inhibition and attention (33).&nbsp;... In addition to BDNF, the actions of IGF-1 and vascular endothelial growth factor (VEGF) (54) are considered essential for the angiogenic and neurogenic effects of exercise in the brain.&nbsp;... Randomized and crossover clinical trials demonstrate the efficacy of aerobic or resistance training exercise (2–4 months) as a treatment for depression in both young and older individuals.&nbsp;... exercise seems to have both preventative and therapeutic effects on the course of depression}}</ref><ref name="gray matter">{{cite journal | author = Erickson KI, Leckie RL, Weinstein AM | title = Physical activity, fitness, and gray matter volume | journal = Neurobiol. Aging | volume = 35 Suppl 2 | issue = | pages = S20–528 | date = September 2014 | pmid = 24952993 | pmc = 4094356 | doi = 10.1016/j.neurobiolaging.2014.03.034 |url=http://www.neurobiologyofaging.org/article/S0197-4580(14)00349-2/fulltext | accessdate = 9 December 2014 | quote = We conclude that higher cardiorespiratory fitness levels are routinely associated with greater gray matter volume in the prefrontal cortex and hippocampus and less consistently in other regions. We also conclude that physical activity is associated with greater gray matter volume in the same regions that are associated with cardiorespiratory fitness including the prefrontal cortex and hippocampus.&nbsp;... Meta-analyses (Colcombe and Kramer, 2003; Smith et al., 2010) suggest that the effects of exercise on the brain might not be uniform across all regions and that some brain areas, specifically those areas supporting executive functions, might be more influenced by participation in exercise than areas not as critically involved in executive functions.&nbsp;... The effects appear to be general in the sense that many different cognitive domains are improved after several months of aerobic exercise, but specific in the sense that executive functions are improved more than other cognitive domains.&nbsp;... physical activity and exercise may reduce the risk for {{abbr|AD|Alzheimer’s disease}} (Barnes and Yaffe, 2011; Podewils et al., 2005; Sofi et al., 2011)&nbsp;... Erickson et al. (2010) reported that greater amounts of physical activity were associated with greater gray matter volume 9-years later in the prefrontal cortex, anterior cingulate, parietal cortex, cerebellum, and hippocampus.&nbsp;... higher fitness levels (VO2max) were associated with larger hippocampal volumes, better executive function, and faster processing speed.&nbsp;...  Verstynen et al. (2012) examined the association between cardiorespiratory fitness levels (VO2max) and the size of the basal ganglia&nbsp;... Verstynen et al. (2012) found that higher fitness levels were associated with greater volume of the caudate nucleus and nucleus accumbens, and in turn, greater volumes were associated with better performance on a task-switching paradigm.&nbsp;... That is, higher physical activity levels mitigated the detrimental effects of lifetime stress on the size of the hippocampus.&nbsp;... The few randomized interventions published thus far have found results highly overlapping with the cross-sectional studies and suggest that the prefrontal cortex and hippocampus remain pliable in late life and that moderate intensity exercise for 6 months–1 year is sufficient for changing the size of these areas.}}</ref><ref name="exercise benefits" /><ref name="cognitive control of exercise" /> The brain structures that show the greatest improvements in gray matter volume in response to aerobic exercise are the [[prefrontal cortex]] and [[hippocampus]];<ref name="Comprehensive review" /><ref name="gray matter" /><ref name="BDNF depression" /> moderate improvements seen in the [[anterior cingulate cortex]], [[parietal cortex]], [[cerebellum]], [[caudate nucleus]], and [[nucleus accumbens]].<ref name="Comprehensive review" /><ref name="gray matter" /><ref name="BDNF depression" /> The prefrontal cortex, caudate nucleus, and anterior cingulate cortex are among the most significant brain structures in the [[Neurotransmitter#Brain neurotransmitter systems|dopamine and norepinephrine systems]] that give rise to cognitive control.<ref name="gray matter" /><ref name="Malenka pathways">{{cite book | author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 147–148, 154–157 | edition = 2nd | chapter = Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin | quote=Neurons from the {{abbr|SNc|Substantia nigra pars compacta}} densely innervate the dorsal striatum where they play a critical role in the learning and execution of motor programs.  Neurons from the {{abbr|VTA|Ventral tegmental area}} innervate the ventral striatum (nucleus accumbens), olfactory bulb, amygdala, hippocampus, orbital and medial prefrontal cortex, and cingulate cortex. VTA {{abbr|DA|Dopamine}} neurons play a critical role in motivation, reward-related behavior, attention, and multiple forms of memory.&nbsp;... Thus, acting in diverse terminal fields, dopamine confers motivational salience ("wanting") on the reward itself or associated cues (nucleus accumbens shell region), updates the value placed on different goals in light of this new experience (orbital prefrontal cortex), helps consolidate multiple forms of memory (amygdala and hippocampus), and encodes new motor programs that will facilitate obtaining this reward in the future (nucleus accumbens core region and dorsal striatum).&nbsp;... {{Abbr|DA|Dopamine}} has multiple actions in the prefrontal cortex.  It promotes the "cognitive control" of behavior: the selection and successful monitoring of behavior to facilitate attainment of chosen goals.  Aspects of cognitive control in which DA plays a role include working memory, the ability to hold information "on line" in order to guide actions, suppression of prepotent behaviors that compete with goal-directed actions, and control of attention and thus the ability to overcome distractions.&nbsp;... Noradrenergic projections from the {{abbr|LC|locus coeruleus}} thus interact with dopaminergic projections from the VTA to regulate cognitive control.&nbsp;...}}</ref> Exercise-induced neurogenesis (i.e., the increases in gray matter volume) in the hippocampus is associated with measurable improvements in [[spatial memory]].<ref name="gray matter" /><ref name="BDNF depression" /><ref name="Exercise children">{{cite journal | author = Lees C, Hopkins J | title = Effect of aerobic exercise on cognition, academic achievement, and psychosocial function in children: a systematic review of randomized control trials | journal = Prev Chronic Dis | volume = 10 | issue = | pages = E174 | year = 2013 | pmid = 24157077 | pmc = 3809922 | doi = 10.5888/pcd10.130010 | quote = This omission is relevant, given the evidence that aerobic-based physical activity generates structural changes in the brain, such as neurogenesis, angiogenesis, increased hippocampal volume, and connectivity (12,13). In children, a positive relationship between aerobic fitness, hippocampal volume, and memory has been found (12,13).&nbsp;... Mental health outcomes included reduced depression and increased self-esteem, although no change was found in anxiety levels (18).&nbsp;... This systematic review of the literature found that APA is positively associated with cognition, academic achievement, behavior, and psychosocial functioning outcomes. Importantly, Shephard also showed that curriculum time reassigned to APA still results in a measurable, albeit small, improvement in academic performance (24). &nbsp;... The actual aerobic-based activity does not appear to be a major factor; interventions used many different types of APA and found similar associations. In positive association studies, intensity of the aerobic activity was moderate to vigorous. The amount of time spent in APA varied significantly between studies; however, even as little as 45 minutes per week appeared to have a benefit.}}</ref><ref name="Associated review">{{cite journal | vauthors = Carvalho A, Rea IM, Parimon T, Cusack BJ | title = Physical activity and cognitive function in individuals over 60 years of age: a systematic review | journal = Clin Interv Aging | volume = 9 | issue = | pages = 661–682 | year = 2014 | pmid = 24748784 | pmc = 3990369 | doi = 10.2147/CIA.S55520 | quote = }}</ref> Higher [[physical fitness]] scores (measured by [[VO2 max|VO<sub>2</sub> max]]) are associated with better executive function, faster processing speed, and greater volume of the hippocampus, caudate nucleus, and nucleus accumbens.<ref name="gray matter" /> Long-term aerobic exercise is also associated with persistent beneficial [[behavioral epigenetics|epigenetic]] changes that result in improved stress coping, improved cognitive function, and increased neuronal activity ({{nowrap|[[c-Fos]]}} and [[BDNF]] signaling).<ref name="epigenome" /><ref name="sports epigenetics">{{cite journal | author = Ehlert T, Simon P, Moser DA | title = Epigenetics in sports | journal = Sports Med | volume = 43 | issue = 2 | pages = 93–110 | date = February 2013 | pmid = 23329609 | doi = 10.1007/s40279-012-0012-y | quote = Alterations in epigenetic modification patterns have been demonstrated to be dependent on exercise and growth hormone (GH), insulin-like growth factor 1 (IGF-1), and steroid administration.&nbsp;... the authors observed improved stress coping in exercised subjects. Investigating the dentate gyrus, a brain region which is involved in learning and coping with stressful and traumatic events, they could show that this effect is mediated by increased phosphorylation of serine 10 combined with H3K14 acetylation, which is associated with local opening of condensed chromatin. Consequently, they found increased immediate early gene expression as shown for c-FOS (FBJ murine osteosarcoma viral oncogene homologue).}}</ref>
 ====BDNF signaling{{anchor|BDNF<!--|BDNF signaling-->}}====
@@ Line 29: / Line 29: @@
 =====Antidepressant effect=====
-A number of medical reviews have indicated that exercise has a marked and persistent [[antidepressant]] effect in humans,<ref name="Comprehensive review" /><ref name="Cochrane exercise depression" /><ref name="Exercise MDD antidepressant" /><ref name="Exercise depression intervention" /><ref name="Physical activity intervention" /><ref name="Running antidepressant">{{vcite2 journal | vauthors = Brené S, Bjørnebekk A, Aberg E, Mathé AA, Olson L, Werme M | title = Running is rewarding and antidepressive | journal = Physiol. Behav. | volume = 92 | issue = 1–2 | pages = 136–140 | year = 2007 | pmid = 17561174 | pmc = 2040025 | doi = 10.1016/j.physbeh.2007.05.015 }}</ref> an effect believed to be mediated through enhanced {{abbr|BDNF|brain-derived neurotrophic factor}} signaling in the brain.<ref name="BDNF depression" /><ref name="Exercise MDD antidepressant" /> Several systematic reviews have analyzed the potential for physical exercise in the treatment of [[major depressive disorder|depressive disorders]]. The 2013 [[Cochrane Collaboration]] review on [[physical exercise]] for depression noted that, based upon limited evidence, it is more effective than a control intervention and comparable to psychological or antidepressant drug therapies.<ref name="Cochrane exercise depression">{{vcite2 journal | vauthors = Cooney GM, Dwan K, Greig CA, Lawlor DA, Rimer J, Waugh FR, McMurdo M, Mead GE | title = Exercise for depression | journal = Cochrane Database Syst Rev | volume = 9 | issue = | pages = CD004366 | year = 2013 | pmid = 24026850 | doi = 10.1002/14651858.CD004366.pub6 | quote = Exercise is moderately more effective than a control intervention for reducing symptoms of depression, but analysis of methodologically robust trials only shows a smaller effect in favour of exercise. When compared to psychological or pharmacological therapies, exercise appears to be no more effective, though this conclusion is based on a few small trials.}}</ref> Three subsequent 2014 systematic reviews that included the Cochrane review in their analysis concluded with similar findings: one indicated that that physical exercise is effective as an [[wikt:adjunct treatment|adjunct treatment]] (i.e., treatments that are used together) with antidepressant medication;<ref name="Exercise MDD antidepressant">{{vcite2 journal | vauthors = Mura G, Moro MF, Patten SB, Carta MG | title = Exercise as an add-on strategy for the treatment of major depressive disorder: a systematic review | journal = CNS Spectr | volume = 19 | issue = 6 | pages = 496–508 | year = 2014 | pmid = 24589012 | doi = 10.1017/S1092852913000953 | quote = Considered overall, the studies included in the present review showed a strong effectiveness of exercise combined with antidepressants.&nbsp;... Conclusions<br /> This is the first review to have focused on exercise as an add-on strategy in the treatment of MDD. Our findings corroborate some previous observations that were based on few studies and which were difficult to generalize.<sup>41,51,73,92,93</sup> Given the results of the present article, it seems that exercise might be an effective strategy to enhance the antidepressant effect of medication treatments. Moreover, we hypothesize that the main role of exercise on treatment-resistant depression is in inducing neurogenesis by increasing BDNF expression, as was demonstrated by several recent studies.}}</ref> the other two indicated that physical exercise has marked antidepressant effects and recommended the inclusion of physical activity as an adjunct treatment for mild–moderate depression<ref name="Exercise depression intervention">{{vcite2 journal | vauthors = Josefsson T, Lindwall M, Archer T | title = Physical exercise intervention in depressive disorders: meta-analysis and systematic review | journal = Scand J Med Sci Sports | volume = 24 | issue = 2 | pages = 259–272 | year = 2014 | pmid = 23362828 | doi = 10.1111/sms.12050 | quote = Physical activity has also become increasingly and firmly associated with improvements in mental health and psychological well-being (Mutrie, 2000; Landers & Arent, 2007). In particular, exercise is believed to be effective in preventing depression and also to significantly reduce depressive symptoms in clinical as well as in nonclinical populations (O’Neal et al., 2000; Landers & Arent, 2007). Several correlational studies show that exercise is negatively related to depressive symptoms (e.g., Galper et al., 2006; Hassmén et al., 2000). Moreover, a considerably large number of intervention studies have by now investigated the effect of various exercise programs on depression and the vast majority of them indicate that exercise significantly reduces depression (e.g., Blumenthal et al., 2007; Martinsen et al., 1985; Singh et al., 1997).&nbsp;... To date, it is not possible to determine exactly how effective exercise is in reducing depression symptoms in clinical and nonclinical depressed populations, respectively. However, the results from the present meta-analysis as well as from seven earlier meta-analyses (North et al., 1990; Craft & Landers, 1998; Lawlor & Hopker, 2001; Stathopoulou et al., 2006; Mead et al., 2009; Rethorst et al., 2009; Krogh et al., 2011) indicate that exercise has a moderate to large antidepressant effect. Some meta-analytic results (e.g., Rethorst et al., 2009) suggest that exercise may be even more efficacious for clinically depressed people.&nbsp;... In short, our final conclusion is that exercise may well be recommended for people with mild and moderate depression who are willing, motivated, and physically healthy enough to engage in such a program.}}</ref> and mental illness in general.<ref name="Physical activity intervention">{{vcite2 journal | vauthors = Rosenbaum S, Tiedemann A, Sherrington C, Curtis J, Ward PB | title = Physical activity interventions for people with mental illness: a systematic review and meta-analysis | journal = J Clin Psychiatry | volume = 75 | issue = 9 | pages = 964–974 | year = 2014 | pmid = 24813261 | doi = 10.4088/JCP.13r08765 | quote = This systematic review and meta-analysis found that physical activity reduced depressive symptoms among people with a psychiatric illness.  The current meta-analysis differs from previous studies, as it included participants with depressive symptoms with a variety of psychiatric diagnoses (except dysthymia and eating disorders).&nbsp;... This review provides strong evidence for the antidepressant effect of physical activity; however, the optimal exercise modality, volume, and intensity remain to be determined.&nbsp;... Conclusion<br /> Few interventions exist whereby patients can hope to achieve improvements in both psychiatric symptoms and physical health simultaneously without significant risks of adverse effects.  Physical activity offers substantial promise for improving outcomes for people living with mental illness, and the inclusion of physical activity and exercise programs within treatment facilities is warranted given the results of this review.}}</ref> One review asserted that evidence from [[clinical trials]] supports the efficacy of physical exercise as a treatment for depression over 2–4&nbsp;months.<ref name="Comprehensive review" />
+A number of medical reviews have indicated that exercise has a marked and persistent [[antidepressant]] effect in humans,<ref name="Comprehensive review" /><ref name="Cochrane exercise depression" /><ref name="Exercise MDD antidepressant" /><ref name="Exercise depression intervention" /><ref name="Physical activity intervention" /><ref name="Running antidepressant">{{cite journal | vauthors = Brené S, Bjørnebekk A, Aberg E, Mathé AA, Olson L, Werme M | title = Running is rewarding and antidepressive | journal = Physiol. Behav. | volume = 92 | issue = 1–2 | pages = 136–140 | year = 2007 | pmid = 17561174 | pmc = 2040025 | doi = 10.1016/j.physbeh.2007.05.015 }}</ref> an effect believed to be mediated through enhanced {{abbr|BDNF|brain-derived neurotrophic factor}} signaling in the brain.<ref name="BDNF depression" /><ref name="Exercise MDD antidepressant" /> Several systematic reviews have analyzed the potential for physical exercise in the treatment of [[major depressive disorder|depressive disorders]]. The 2013 [[Cochrane Collaboration]] review on [[physical exercise]] for depression noted that, based upon limited evidence, it is more effective than a control intervention and comparable to psychological or antidepressant drug therapies.<ref name="Cochrane exercise depression">{{cite journal | vauthors = Cooney GM, Dwan K, Greig CA, Lawlor DA, Rimer J, Waugh FR, McMurdo M, Mead GE | title = Exercise for depression | journal = Cochrane Database Syst Rev | volume = 9 | issue = | pages = CD004366 | year = 2013 | pmid = 24026850 | doi = 10.1002/14651858.CD004366.pub6 | quote = Exercise is moderately more effective than a control intervention for reducing symptoms of depression, but analysis of methodologically robust trials only shows a smaller effect in favour of exercise. When compared to psychological or pharmacological therapies, exercise appears to be no more effective, though this conclusion is based on a few small trials.}}</ref> Three subsequent 2014 systematic reviews that included the Cochrane review in their analysis concluded with similar findings: one indicated that that physical exercise is effective as an [[wikt:adjunct treatment|adjunct treatment]] (i.e., treatments that are used together) with antidepressant medication;<ref name="Exercise MDD antidepressant">{{cite journal | vauthors = Mura G, Moro MF, Patten SB, Carta MG | title = Exercise as an add-on strategy for the treatment of major depressive disorder: a systematic review | journal = CNS Spectr | volume = 19 | issue = 6 | pages = 496–508 | year = 2014 | pmid = 24589012 | doi = 10.1017/S1092852913000953 | quote = Considered overall, the studies included in the present review showed a strong effectiveness of exercise combined with antidepressants.&nbsp;... Conclusions<br /> This is the first review to have focused on exercise as an add-on strategy in the treatment of MDD. Our findings corroborate some previous observations that were based on few studies and which were difficult to generalize.<sup>41,51,73,92,93</sup> Given the results of the present article, it seems that exercise might be an effective strategy to enhance the antidepressant effect of medication treatments. Moreover, we hypothesize that the main role of exercise on treatment-resistant depression is in inducing neurogenesis by increasing BDNF expression, as was demonstrated by several recent studies.}}</ref> the other two indicated that physical exercise has marked antidepressant effects and recommended the inclusion of physical activity as an adjunct treatment for mild–moderate depression<ref name="Exercise depression intervention">{{cite journal | vauthors = Josefsson T, Lindwall M, Archer T | title = Physical exercise intervention in depressive disorders: meta-analysis and systematic review | journal = Scand J Med Sci Sports | volume = 24 | issue = 2 | pages = 259–272 | year = 2014 | pmid = 23362828 | doi = 10.1111/sms.12050 | quote = Physical activity has also become increasingly and firmly associated with improvements in mental health and psychological well-being (Mutrie, 2000; Landers & Arent, 2007). In particular, exercise is believed to be effective in preventing depression and also to significantly reduce depressive symptoms in clinical as well as in nonclinical populations (O’Neal et al., 2000; Landers & Arent, 2007). Several correlational studies show that exercise is negatively related to depressive symptoms (e.g., Galper et al., 2006; Hassmén et al., 2000). Moreover, a considerably large number of intervention studies have by now investigated the effect of various exercise programs on depression and the vast majority of them indicate that exercise significantly reduces depression (e.g., Blumenthal et al., 2007; Martinsen et al., 1985; Singh et al., 1997).&nbsp;... To date, it is not possible to determine exactly how effective exercise is in reducing depression symptoms in clinical and nonclinical depressed populations, respectively. However, the results from the present meta-analysis as well as from seven earlier meta-analyses (North et al., 1990; Craft & Landers, 1998; Lawlor & Hopker, 2001; Stathopoulou et al., 2006; Mead et al., 2009; Rethorst et al., 2009; Krogh et al., 2011) indicate that exercise has a moderate to large antidepressant effect. Some meta-analytic results (e.g., Rethorst et al., 2009) suggest that exercise may be even more efficacious for clinically depressed people.&nbsp;... In short, our final conclusion is that exercise may well be recommended for people with mild and moderate depression who are willing, motivated, and physically healthy enough to engage in such a program.}}</ref> and mental illness in general.<ref name="Physical activity intervention">{{cite journal | vauthors = Rosenbaum S, Tiedemann A, Sherrington C, Curtis J, Ward PB | title = Physical activity interventions for people with mental illness: a systematic review and meta-analysis | journal = J Clin Psychiatry | volume = 75 | issue = 9 | pages = 964–974 | year = 2014 | pmid = 24813261 | doi = 10.4088/JCP.13r08765 | quote = This systematic review and meta-analysis found that physical activity reduced depressive symptoms among people with a psychiatric illness.  The current meta-analysis differs from previous studies, as it included participants with depressive symptoms with a variety of psychiatric diagnoses (except dysthymia and eating disorders).&nbsp;... This review provides strong evidence for the antidepressant effect of physical activity; however, the optimal exercise modality, volume, and intensity remain to be determined.&nbsp;... Conclusion<br /> Few interventions exist whereby patients can hope to achieve improvements in both psychiatric symptoms and physical health simultaneously without significant risks of adverse effects.  Physical activity offers substantial promise for improving outcomes for people living with mental illness, and the inclusion of physical activity and exercise programs within treatment facilities is warranted given the results of this review.}}</ref> One review asserted that evidence from [[clinical trials]] supports the efficacy of physical exercise as a treatment for depression over 2–4&nbsp;months.<ref name="Comprehensive review" />
 ====IGF-1 signaling====
 {{See also|Insulin-like growth factor 1}}
-{{abbr|IGF-1|Insulin-like growth factor 1}} is a [[peptide]] that mediates some of the effects of [[growth hormone]] and acts through the [[IGF-1 receptor]] to control body growth and tissue remodeling.<ref name="Serum-brain IGF-1" /> In the brain, IGF-1 functions as a neurotrophic factor that, like {{abbr|BDNF|brain-derived neurotrophic factor}}, plays a significant role in cognition, neurogenesis, and neuronal survival.<ref name="trophic factor signaling" /><ref name="IGF-1 neuroplasticity">{{vcite2 journal | vauthors = Aberg D | title = Role of the growth hormone/insulin-like growth factor 1 axis in neurogenesis | journal = Endocr Dev | volume = 17 | issue = | pages = 63–76 | year = 2010 | pmid = 19955757 | doi = 10.1159/000262529 | quote = The growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis is not only involved in brain growth, development and myelination, but also in brain plasticity as indexed by neurogenesis. This may have links to various cognitive effects of GH and IGF-1. GH and IGF-1 affect the genesis of neurons, astrocytes, endothelial cells and oligodendrocytes. Specifically, IGF-1 increases progenitor cell proliferation and numbers of new neurons, oligodendrocytes, and blood vessels in the dentate gyrus of the hippocampus. In the adult cerebral cortex IGF-1 only affects oligodendrogenesis.&nbsp;... Altogether, data suggest that both exogenous and endogenous GH and/or IGF-1 may be used as agents to enhance cell genesis and neurogenesis in the adult brain. &nbsp;... GH and IGF-1 have been shown to affect a multitude of mechanisms, including neurogenesis, oligodendrogenesis, angiogenesis, glutamate receptor activation, cholinergic system, dopaminergic reward system, monoamine abundance, dendritic arborization, astrocyte communication via connexin 43, and opioid receptor abundance&nbsp;... IGF-1 also reaches the brain via both the capillary bed BBB and via the blood-CSF barrier. It appears that IGF-1 uptake is mediated by a specific carrier both in the capillary bed BBB [40] and in the blood-CSF barrier [41, 42]. Moreover, IGF-1 transport across the BBB can be either increased, such as by exercise [43]&nbsp;... Thus, although not fully characterized, there appear to be mechanisms for transport of both GH and IGF-1 across the BBB.&nbsp;...  Interestingly, exercise is a factor known to enhance cell genesis in the brain, and it appears that IGF-1 is a key mediator of the effect of exercise in terms of cell genesis in the adult brain [52, 53].&nbsp;... IGF-1 treatment enhances neurogenesis [52, 53, 55], oligodendrogenesis [56, 58] and angiogenesis [59].&nbsp;... As physical exercise has positive effects in many diseases as well as in normal health, it is of interest that circulating IGF-1 as been shown to be one of the mediators of enhanced neurogenesis in the hippocampus.}}</ref><ref name="NHM IGF-1 VEGF">{{cite book | author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 221, 412 | edition = 2nd | quote= BDNF, CNTF, insulin-like growth factor-1 (IGF-1), and VEGF have been proven to support motor neuron survival in vitro and in vivo.&nbsp;... VEGF exerts its effects through two receptor tyrosine kinases, VEGFR1 (also known as flt-1) and VEGFR2 (or flk-1). VEGF and its receptors are expressed in neurons and glia, and this expression is highly up-regulated by hypoxia. The neurotrophic properties of VEGF were first identified when mutations in the VEGF promoter of mice resulted in ALS-like symptoms. Subsequently, VEGF was found to rescue hypoxia-induced motor neuron death both in vivo and in vitro. Recently, a polymorphism in the VEGF promoter sequence was identified in a subset of ALS patients. It is thought that low VEGF levels may underlie motor neuron degeneration in at least one group of patients, but measurement of VEGF in ALS patients has proven difficult. VEGF may also be important for response to stroke and other forms of neural injury.&nbsp;... One of the prototypical triggers for apoptosis, at least in vitro, is the withdrawal of neurotrophic factors. Neurotrophic factor receptors, such as the TrkA receptor for NGF or the IGF-I receptor for insulin-like growth factor, activate prosurvival signaling cascades}}</ref> Physical activity is associated with increased levels of serum IGF-1, which is known to contribute to neuroplasticity along with locally produced IGF-1 in the brain due to its capacity to cross the [[blood–brain barrier]] in the [[capillary bed]] and [[blood–cerebrospinal fluid barrier]];<ref name="Comprehensive review" /><ref name="trophic factor signaling" /><ref name="Serum-brain IGF-1">{{vcite2 journal | vauthors = Torres-Aleman I | title = Toward a comprehensive neurobiology of IGF-I | journal = Dev Neurobiol | volume = 70 | issue = 5 | pages = 384–96 | year = 2010 | pmid = 20186710 | doi = 10.1002/dneu.20778 | quote =  However, the adult brain appears to have an external input from serum IGF-I, where this anabolic peptide is abundant. Thus, serum IGF-I has been proven to be an important modulator of brain activity, including higher functions such as cognition. Many of these functions can be ascribed to its tissue-remodeling activity as IGF-I modulates adult neurogenesis and angiogenesis. Other activities are cytoprotective; indeed, IGF-I can be considered a key neuroprotective peptide. Still others pertain to the functional characteristics of brain cells, such as cell excitability. Through modulation of membrane channels and neurotransmission, IGF-I impinges directly on neuronal plasticity, the cellular substrate of cognition. However, to fully understand the role of IGF-I in the brain, we have to sum the actions of locally produced IGF-I to those of serum IGF-I&nbsp;... An operational approach to overcome this limitation would be to consider IGF-I as a signal coupling environmental influences on body metabolism with brain function. Or in a more colloquial way, we may say that IGF-I links body "fitness" with brain fitness}}</ref><ref name="IGF-1 neuroplasticity" /> consequently one review noted that IGF-1 is a key mediator of exercise-induced adult neurogenesis, while a second review characterized it as a factor which links "body fitness" with "brain fitness".<ref name="Serum-brain IGF-1" /><ref name="IGF-1 neuroplasticity" />  The amount of IGF-1 released during exercise is positively correlated with exercise intensity and duration.<ref name="pmid22714057">{{vcite2 journal | vauthors = Gatti R, De Palo EF, Antonelli G, Spinella P | title = IGF-I/IGFBP system: metabolism outline and physical exercise | journal = J. Endocrinol. Invest. | volume = 35 | issue = 7 | pages = 699–707 | year = 2012 | pmid = 22714057 | doi = 10.3275/8456 |url=}}</ref>
+{{abbr|IGF-1|Insulin-like growth factor 1}} is a [[peptide]] that mediates some of the effects of [[growth hormone]] and acts through the [[IGF-1 receptor]] to control body growth and tissue remodeling.<ref name="Serum-brain IGF-1" /> In the brain, IGF-1 functions as a neurotrophic factor that, like {{abbr|BDNF|brain-derived neurotrophic factor}}, plays a significant role in cognition, neurogenesis, and neuronal survival.<ref name="trophic factor signaling" /><ref name="IGF-1 neuroplasticity">{{cite journal | vauthors = Aberg D | title = Role of the growth hormone/insulin-like growth factor 1 axis in neurogenesis | journal = Endocr Dev | volume = 17 | issue = | pages = 63–76 | year = 2010 | pmid = 19955757 | doi = 10.1159/000262529 | quote = The growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis is not only involved in brain growth, development and myelination, but also in brain plasticity as indexed by neurogenesis. This may have links to various cognitive effects of GH and IGF-1. GH and IGF-1 affect the genesis of neurons, astrocytes, endothelial cells and oligodendrocytes. Specifically, IGF-1 increases progenitor cell proliferation and numbers of new neurons, oligodendrocytes, and blood vessels in the dentate gyrus of the hippocampus. In the adult cerebral cortex IGF-1 only affects oligodendrogenesis.&nbsp;... Altogether, data suggest that both exogenous and endogenous GH and/or IGF-1 may be used as agents to enhance cell genesis and neurogenesis in the adult brain. &nbsp;... GH and IGF-1 have been shown to affect a multitude of mechanisms, including neurogenesis, oligodendrogenesis, angiogenesis, glutamate receptor activation, cholinergic system, dopaminergic reward system, monoamine abundance, dendritic arborization, astrocyte communication via connexin 43, and opioid receptor abundance&nbsp;... IGF-1 also reaches the brain via both the capillary bed BBB and via the blood-CSF barrier. It appears that IGF-1 uptake is mediated by a specific carrier both in the capillary bed BBB [40] and in the blood-CSF barrier [41, 42]. Moreover, IGF-1 transport across the BBB can be either increased, such as by exercise [43]&nbsp;... Thus, although not fully characterized, there appear to be mechanisms for transport of both GH and IGF-1 across the BBB.&nbsp;...  Interestingly, exercise is a factor known to enhance cell genesis in the brain, and it appears that IGF-1 is a key mediator of the effect of exercise in terms of cell genesis in the adult brain [52, 53].&nbsp;... IGF-1 treatment enhances neurogenesis [52, 53, 55], oligodendrogenesis [56, 58] and angiogenesis [59].&nbsp;... As physical exercise has positive effects in many diseases as well as in normal health, it is of interest that circulating IGF-1 as been shown to be one of the mediators of enhanced neurogenesis in the hippocampus.}}</ref><ref name="NHM IGF-1 VEGF">{{cite book | author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 221, 412 | edition = 2nd | quote= BDNF, CNTF, insulin-like growth factor-1 (IGF-1), and VEGF have been proven to support motor neuron survival in vitro and in vivo.&nbsp;... VEGF exerts its effects through two receptor tyrosine kinases, VEGFR1 (also known as flt-1) and VEGFR2 (or flk-1). VEGF and its receptors are expressed in neurons and glia, and this expression is highly up-regulated by hypoxia. The neurotrophic properties of VEGF were first identified when mutations in the VEGF promoter of mice resulted in ALS-like symptoms. Subsequently, VEGF was found to rescue hypoxia-induced motor neuron death both in vivo and in vitro. Recently, a polymorphism in the VEGF promoter sequence was identified in a subset of ALS patients. It is thought that low VEGF levels may underlie motor neuron degeneration in at least one group of patients, but measurement of VEGF in ALS patients has proven difficult. VEGF may also be important for response to stroke and other forms of neural injury.&nbsp;... One of the prototypical triggers for apoptosis, at least in vitro, is the withdrawal of neurotrophic factors. Neurotrophic factor receptors, such as the TrkA receptor for NGF or the IGF-I receptor for insulin-like growth factor, activate prosurvival signaling cascades}}</ref> Physical activity is associated with increased levels of serum IGF-1, which is known to contribute to neuroplasticity along with locally produced IGF-1 in the brain due to its capacity to cross the [[blood–brain barrier]] in the [[capillary bed]] and [[blood–cerebrospinal fluid barrier]];<ref name="Comprehensive review" /><ref name="trophic factor signaling" /><ref name="Serum-brain IGF-1">{{cite journal | vauthors = Torres-Aleman I | title = Toward a comprehensive neurobiology of IGF-I | journal = Dev Neurobiol | volume = 70 | issue = 5 | pages = 384–96 | year = 2010 | pmid = 20186710 | doi = 10.1002/dneu.20778 | quote =  However, the adult brain appears to have an external input from serum IGF-I, where this anabolic peptide is abundant. Thus, serum IGF-I has been proven to be an important modulator of brain activity, including higher functions such as cognition. Many of these functions can be ascribed to its tissue-remodeling activity as IGF-I modulates adult neurogenesis and angiogenesis. Other activities are cytoprotective; indeed, IGF-I can be considered a key neuroprotective peptide. Still others pertain to the functional characteristics of brain cells, such as cell excitability. Through modulation of membrane channels and neurotransmission, IGF-I impinges directly on neuronal plasticity, the cellular substrate of cognition. However, to fully understand the role of IGF-I in the brain, we have to sum the actions of locally produced IGF-I to those of serum IGF-I&nbsp;... An operational approach to overcome this limitation would be to consider IGF-I as a signal coupling environmental influences on body metabolism with brain function. Or in a more colloquial way, we may say that IGF-I links body "fitness" with brain fitness}}</ref><ref name="IGF-1 neuroplasticity" /> consequently one review noted that IGF-1 is a key mediator of exercise-induced adult neurogenesis, while a second review characterized it as a factor which links "body fitness" with "brain fitness".<ref name="Serum-brain IGF-1" /><ref name="IGF-1 neuroplasticity" />  The amount of IGF-1 released during exercise is positively correlated with exercise intensity and duration.<ref name="pmid22714057">{{cite journal | vauthors = Gatti R, De Palo EF, Antonelli G, Spinella P | title = IGF-I/IGFBP system: metabolism outline and physical exercise | journal = J. Endocrinol. Invest. | volume = 35 | issue = 7 | pages = 699–707 | year = 2012 | pmid = 22714057 | doi = 10.3275/8456 |url=}}</ref>
 ====VEGF signaling====
 {{See also|Vascular endothelial growth factor}}
-{{abbr|VEGF|Vascular endothelial growth factor}} is a neurotrophic and [[angiogenesis|angiogenic]] (i.e., blood vessel growth promoting) [[Cell signaling|signaling protein]] that binds to two receptor tyrosine kinases, [[VEGFR1]] and [[VEGFR2]],  which are expressed in [[neurons]] and [[glial cell]]s the brain.<ref name="NHM IGF-1 VEGF" /> [[Hypoxia (medical)|Hypoxia]], or inadequate cellular oxygen supply, strongly upregulates VEGF expression and VEGF exerts a neuroprotective effect in hypoxic neurons.<ref name="NHM IGF-1 VEGF" /> Like {{abbr|BDNF|brain-derived neurotrophic factor}} and {{abbr|IGF-1|Insulin-like growth factor 1}}, aerobic exercise has been shown to increase VEGF biosynthesis in peripheral tissue which subsequently crosses the blood–brain barrier and promotes neurogenesis and [[Angiogenesis|blood vessel formation]] the [[central nervous system]].<ref name="Cerebral hemodynamics and AD">{{vcite2 journal | vauthors = Tarumi T, Zhang R | title = Cerebral hemodynamics of the aging brain: risk of Alzheimer disease and benefit of aerobic exercise | journal = Front Physiol | volume = 5 | issue = | pages = 6 | date = January 2014 | pmid = 24478719 | pmc = 3896879 | doi = 10.3389/fphys.2014.00006 | quote = Exercise-related improvements in brain function and structure may be conferred by the concurrent adaptations in vascular function and structure. Aerobic exercise increases the peripheral levels of growth factors (e.g., BDNF, IFG-1, and VEGF) which cross the blood-brain barrier (BBB) and stimulate neurogenesis and angiogenesis (Trejo et al., 2001; Lee et al., 2002; Fabel et al., 2003; Lopez-Lopez et al., 2004).}}</ref><ref name="Fitness mechanism" /><ref name="VEGF aging brain">{{vcite2 journal | vauthors = Bouchard J, Villeda SA | title = Aging and brain rejuvenation as systemic events | journal = J. Neurochem. | volume = 132 | issue = 1 | pages = 5–19 | year = 2015 | pmid = 25327899 | pmc = 4301186 | doi = 10.1111/jnc.12969 | quote = The beneficial effects of exercise extend beyond peripheral tissues to also include the brain.&nbsp;... Because of the blood–brain barrier, it was traditionally thought that the beneficial effects of exercise on the CNS were not orchestrated through systemic changes in the periphery. However, recent studies suggest that the effects of exercise are, in part, mediated by changes in the systemic environment. Investigations looking at magnetic resonance imaging (MRI) measurements of cerebral blood volume in the hippocampus have demonstrated that exercise selectively increased the cerebral blood volume of the dentate gyrus, correlating with post-mortem increase in neurogenesis (Pereira et al. 2007). From a molecular perspective, elevated systemic levels of circulating growth factors such as vascular endothelial growth factor and insulin-like growth factor 1 (IGF-1) in blood elicited by increased exercise have been shown to mediate, in part, enhancements in neurogenesis (Trejo et al. 2001; Fabel et al. 2003). Coincidently, circulating levels of IGF-1 decrease with age and the restoration to levels resembling a younger systemic environment up-regulate neurogenesis and improve learning and memory (Lichtenwalner et al. 2001; Darnaudery et al. 2006).}}</ref> Exercise-induced increases in VEGF signaling have been shown to improve cerebral blood volume and contribute to exercise-induced neurogenesis in the hippocampus.<ref name="Comprehensive review" /><ref name="Fitness mechanism" /><ref name="VEGF aging brain" />
+{{abbr|VEGF|Vascular endothelial growth factor}} is a neurotrophic and [[angiogenesis|angiogenic]] (i.e., blood vessel growth promoting) [[Cell signaling|signaling protein]] that binds to two receptor tyrosine kinases, [[VEGFR1]] and [[VEGFR2]],  which are expressed in [[neurons]] and [[glial cell]]s the brain.<ref name="NHM IGF-1 VEGF" /> [[Hypoxia (medical)|Hypoxia]], or inadequate cellular oxygen supply, strongly upregulates VEGF expression and VEGF exerts a neuroprotective effect in hypoxic neurons.<ref name="NHM IGF-1 VEGF" /> Like {{abbr|BDNF|brain-derived neurotrophic factor}} and {{abbr|IGF-1|Insulin-like growth factor 1}}, aerobic exercise has been shown to increase VEGF biosynthesis in peripheral tissue which subsequently crosses the blood–brain barrier and promotes neurogenesis and [[Angiogenesis|blood vessel formation]] the [[central nervous system]].<ref name="Cerebral hemodynamics and AD">{{cite journal | vauthors = Tarumi T, Zhang R | title = Cerebral hemodynamics of the aging brain: risk of Alzheimer disease and benefit of aerobic exercise | journal = Front Physiol | volume = 5 | issue = | pages = 6 | date = January 2014 | pmid = 24478719 | pmc = 3896879 | doi = 10.3389/fphys.2014.00006 | quote = Exercise-related improvements in brain function and structure may be conferred by the concurrent adaptations in vascular function and structure. Aerobic exercise increases the peripheral levels of growth factors (e.g., BDNF, IFG-1, and VEGF) which cross the blood-brain barrier (BBB) and stimulate neurogenesis and angiogenesis (Trejo et al., 2001; Lee et al., 2002; Fabel et al., 2003; Lopez-Lopez et al., 2004).}}</ref><ref name="Fitness mechanism" /><ref name="VEGF aging brain">{{cite journal | vauthors = Bouchard J, Villeda SA | title = Aging and brain rejuvenation as systemic events | journal = J. Neurochem. | volume = 132 | issue = 1 | pages = 5–19 | year = 2015 | pmid = 25327899 | pmc = 4301186 | doi = 10.1111/jnc.12969 | quote = The beneficial effects of exercise extend beyond peripheral tissues to also include the brain.&nbsp;... Because of the blood–brain barrier, it was traditionally thought that the beneficial effects of exercise on the CNS were not orchestrated through systemic changes in the periphery. However, recent studies suggest that the effects of exercise are, in part, mediated by changes in the systemic environment. Investigations looking at magnetic resonance imaging (MRI) measurements of cerebral blood volume in the hippocampus have demonstrated that exercise selectively increased the cerebral blood volume of the dentate gyrus, correlating with post-mortem increase in neurogenesis (Pereira et al. 2007). From a molecular perspective, elevated systemic levels of circulating growth factors such as vascular endothelial growth factor and insulin-like growth factor 1 (IGF-1) in blood elicited by increased exercise have been shown to mediate, in part, enhancements in neurogenesis (Trejo et al. 2001; Fabel et al. 2003). Coincidently, circulating levels of IGF-1 decrease with age and the restoration to levels resembling a younger systemic environment up-regulate neurogenesis and improve learning and memory (Lichtenwalner et al. 2001; Darnaudery et al. 2006).}}</ref> Exercise-induced increases in VEGF signaling have been shown to improve cerebral blood volume and contribute to exercise-induced neurogenesis in the hippocampus.<ref name="Comprehensive review" /><ref name="Fitness mechanism" /><ref name="VEGF aging brain" />
 ====ΔFosB and addiction{{anchor|ΔFosB}}====
 {{transcluded-section|source=FOSB|part=yes}}
-Similar to other [[natural reward]]s and [[addictive drug]]s, consistent aerobic exercise [[inducible gene|increases gene expression]] of the [[gene transcription factor]] that causes and maintains [[addiction]], [[ΔFosB]], in the [[nucleus accumbens]];<ref name="Nestler">{{cite journal | author = Robison AJ, Nestler EJ | title = Transcriptional and epigenetic mechanisms of addiction | journal = Nat. Rev. Neurosci. | volume = 12 | issue = 11 | pages = 623–637 |date=November 2011  | pmid = 21989194 | pmc = 3272277 | doi = 10.1038/nrn3111 | quote = ΔFosB has been linked directly to several addiction-related behaviors&nbsp;... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the {{abbr|NAc|nucleus accumbens}} or {{abbr|OFC|orbitofrontal cortex}} blocks these key effects of drug exposure<sup>14,22–24</sup>. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc {{abbr|MSNs|medium spiny neurons}} by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption<sup>14,26–30</sup>. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. }}</ref><ref name="Natural and drug addictions" /> however, exercise also increases {{nowrap|[[c-Fos]]}} expression as well, thereby opposing the long-term accumulation of ΔFosB.<ref name="epigenome" /><ref name="c-Fos NAcc exercise">{{vcite2 journal | vauthors = Zlebnik NE, Hedges VL, Carroll ME, Meisel RL | title = Chronic wheel running affects cocaine-induced c-Fos expression in brain reward areas in rats | journal = Behav. Brain Res. | volume = 261 | issue = | pages = 71–78 | year = 2014 | pmid = 24342748 | doi = 10.1016/j.bbr.2013.12.012 |url=}}</ref><ref name="c-Fos repression">{{cite journal |author=Nestler EJ |title=Review. Transcriptional mechanisms of addiction: role of DeltaFosB |journal=Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences |volume=363 |issue=1507 |pages=3245–3255 |date=October 2008 |pmid=18640924 |doi=10.1098/rstb.2008.0067 |url=|pmc=2607320|quote=Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure—cited earlier (Renthal et al. in press). The mechanism responsible for ΔFosB repression of c-fos expression is complex and is covered below.&nbsp;... <br />Examples of validated targets for ΔFosB in nucleus accumbens&nbsp;... GluR2&nbsp;... dynorphin&nbsp;... Cdk5&nbsp;... NFκB&nbsp;... c-Fos}}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2607320/table/tbl3/ Table 3]</ref>  Clinical and preclinical evidence indicate that consistent aerobic exercise, especially endurance exercise (e.g., [[marathon running]]), actually prevents the development of certain [[drug addiction]]s and is an effective adjunct treatment for drug addiction, and for psychostimulant addiction in particular.<ref name="Natural and drug addictions">{{cite journal | author = Olsen CM | title = Natural rewards, neuroplasticity, and non-drug addictions | journal = Neuropharmacology | volume = 61 | issue = 7 | pages = 1109–1122 |date=December 2011  | pmid = 21459101 | pmc = 3139704 | doi = 10.1016/j.neuropharm.2011.03.010 | quote = Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005).&nbsp;... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader, 2008).}}</ref><ref name="Running vs addiction">{{cite journal | author = Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA | title = Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis | journal = Neurosci Biobehav Rev | volume = 37 | issue = 8 | pages = 1622–44 |date=September 2013  | pmid = 23806439 | pmc = 3788047 | doi = 10.1016/j.neubiorev.2013.06.011 | quote =  [exercise] efficacy may be related to its ability to normalize glutamatergic and dopaminergic signaling and reverse drug-induced changes in chromatin via epigenetic interactions with brain-derived neurotrophic factor (BDNF) in the reward pathway.&nbsp;... these data show that exercise can affect dopaminergic signaling at many different levels, which may underlie its ability to modify vulnerability during drug use initiation. Exercise also produces neuroadaptations that may influence an individual's vulnerability to initiate drug use. Consistent with this idea, chronic moderate levels of forced treadmill running blocks not only subsequent methamphetamine-induced conditioned place preference, but also stimulant-induced increases in dopamine release in the {{abbr|NAc|nucleus accumbens}} (Chen et al., 2008) and striatum (Marques et al., 2008).&nbsp;... [These] findings indicate the efficacy of exercise at reducing drug intake in drug-dependent individuals&nbsp;... wheel running [reduces] methamphetamine self-administration under extended access conditions (Engelmann et al., 2013)&nbsp;... These findings suggest that exercise may "magnitude"-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuro-adaptive changes that develop during and following extended access to the drug.&nbsp;... Exercise has been proposed as a treatment for drug addiction that may reduce drug craving and risk of relapse. Although few clinical studies have investigated the efficacy of exercise for preventing relapse, the few studies that have been conducted generally report a reduction in drug craving and better treatment outcomes (see Table 4).&nbsp;... Taken together, these data suggest that the potential benefits of exercise during relapse, particularly for relapse to psychostimulants, may be mediated via chromatin remodeling and possibly lead to greater treatment outcomes.}}</ref><ref name="Exercise Rev 3" />  Consistent aerobic exercise magnitude-dependently (i.e., by duration and intensity) reduces drug addiction risk, which appears to occur through the reversal of drug induced addiction-related neuroplasticity.<ref name="Natural and drug addictions" /><ref name="Running vs addiction" /> In particular, aerobic exercise decreases psychostimulant self-administration, reduces the [[reinstatement]] (i.e., relapse) of drug-seeking, and induces opposite effects on [[striatum|striatal]] [[dopamine receptor D2|dopamine receptor D<sub>2</sub>]] (DRD2) signaling (increased DRD2 density) to those induced by pathological stimulant use (decreased DRD2 density).<ref name="Natural and drug addictions" /><ref name="Running vs addiction" /> Consequently, consistent aerobic exercise leads to better treatment outcomes when used as an adjunct treatment for addiction.<ref name="Running vs addiction" /><ref name="Exercise Rev 3">{{vcite2 journal | vauthors = Linke SE, Ussher M | title = Exercise-based treatments for substance use disorders: evidence, theory, and practicality | journal = Am J Drug Alcohol Abuse | volume = 41 | issue = 1 | pages = 7–15 | year = 2015 | pmid = 25397661 | doi = 10.3109/00952990.2014.976708 | quote = The limited research conducted suggests that exercise may be an effective adjunctive treatment for SUDs. In contrast to the scarce intervention trials to date, a relative abundance of literature on the theoretical and practical reasons supporting the investigation of this topic has been published.&nbsp;... numerous theoretical and practical reasons support exercise-based treatments for SUDs, including psychological, behavioral, neurobiological, nearly universal safety profile, and overall positive health effects.}}</ref>
+Similar to other [[natural reward]]s and [[addictive drug]]s, consistent aerobic exercise [[inducible gene|increases gene expression]] of the [[gene transcription factor]] that causes and maintains [[addiction]], [[ΔFosB]], in the [[nucleus accumbens]];<ref name="Nestler">{{cite journal | author = Robison AJ, Nestler EJ | title = Transcriptional and epigenetic mechanisms of addiction | journal = Nat. Rev. Neurosci. | volume = 12 | issue = 11 | pages = 623–637 |date=November 2011  | pmid = 21989194 | pmc = 3272277 | doi = 10.1038/nrn3111 | quote = ΔFosB has been linked directly to several addiction-related behaviors&nbsp;... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the {{abbr|NAc|nucleus accumbens}} or {{abbr|OFC|orbitofrontal cortex}} blocks these key effects of drug exposure<sup>14,22–24</sup>. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc {{abbr|MSNs|medium spiny neurons}} by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption<sup>14,26–30</sup>. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. }}</ref><ref name="Natural and drug addictions" /> however, exercise also increases {{nowrap|[[c-Fos]]}} expression as well, thereby opposing the long-term accumulation of ΔFosB.<ref name="epigenome" /><ref name="c-Fos NAcc exercise">{{cite journal | vauthors = Zlebnik NE, Hedges VL, Carroll ME, Meisel RL | title = Chronic wheel running affects cocaine-induced c-Fos expression in brain reward areas in rats | journal = Behav. Brain Res. | volume = 261 | issue = | pages = 71–78 | year = 2014 | pmid = 24342748 | doi = 10.1016/j.bbr.2013.12.012 |url=}}</ref><ref name="c-Fos repression">{{cite journal |author=Nestler EJ |title=Review. Transcriptional mechanisms of addiction: role of DeltaFosB |journal=Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences |volume=363 |issue=1507 |pages=3245–3255 |date=October 2008 |pmid=18640924 |doi=10.1098/rstb.2008.0067 |url=|pmc=2607320|quote=Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure—cited earlier (Renthal et al. in press). The mechanism responsible for ΔFosB repression of c-fos expression is complex and is covered below.&nbsp;... <br />Examples of validated targets for ΔFosB in nucleus accumbens&nbsp;... GluR2&nbsp;... dynorphin&nbsp;... Cdk5&nbsp;... NFκB&nbsp;... c-Fos}}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2607320/table/tbl3/ Table 3]</ref>  Clinical and preclinical evidence indicate that consistent aerobic exercise, especially endurance exercise (e.g., [[marathon running]]), actually prevents the development of certain [[drug addiction]]s and is an effective adjunct treatment for drug addiction, and for psychostimulant addiction in particular.<ref name="Natural and drug addictions">{{cite journal | author = Olsen CM | title = Natural rewards, neuroplasticity, and non-drug addictions | journal = Neuropharmacology | volume = 61 | issue = 7 | pages = 1109–1122 |date=December 2011  | pmid = 21459101 | pmc = 3139704 | doi = 10.1016/j.neuropharm.2011.03.010 | quote = Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005).&nbsp;... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader, 2008).}}</ref><ref name="Running vs addiction">{{cite journal | author = Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA | title = Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis | journal = Neurosci Biobehav Rev | volume = 37 | issue = 8 | pages = 1622–44 |date=September 2013  | pmid = 23806439 | pmc = 3788047 | doi = 10.1016/j.neubiorev.2013.06.011 | quote =  [exercise] efficacy may be related to its ability to normalize glutamatergic and dopaminergic signaling and reverse drug-induced changes in chromatin via epigenetic interactions with brain-derived neurotrophic factor (BDNF) in the reward pathway.&nbsp;... these data show that exercise can affect dopaminergic signaling at many different levels, which may underlie its ability to modify vulnerability during drug use initiation. Exercise also produces neuroadaptations that may influence an individual's vulnerability to initiate drug use. Consistent with this idea, chronic moderate levels of forced treadmill running blocks not only subsequent methamphetamine-induced conditioned place preference, but also stimulant-induced increases in dopamine release in the {{abbr|NAc|nucleus accumbens}} (Chen et al., 2008) and striatum (Marques et al., 2008).&nbsp;... [These] findings indicate the efficacy of exercise at reducing drug intake in drug-dependent individuals&nbsp;... wheel running [reduces] methamphetamine self-administration under extended access conditions (Engelmann et al., 2013)&nbsp;... These findings suggest that exercise may "magnitude"-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuro-adaptive changes that develop during and following extended access to the drug.&nbsp;... Exercise has been proposed as a treatment for drug addiction that may reduce drug craving and risk of relapse. Although few clinical studies have investigated the efficacy of exercise for preventing relapse, the few studies that have been conducted generally report a reduction in drug craving and better treatment outcomes (see Table 4).&nbsp;... Taken together, these data suggest that the potential benefits of exercise during relapse, particularly for relapse to psychostimulants, may be mediated via chromatin remodeling and possibly lead to greater treatment outcomes.}}</ref><ref name="Exercise Rev 3" />  Consistent aerobic exercise magnitude-dependently (i.e., by duration and intensity) reduces drug addiction risk, which appears to occur through the reversal of drug induced addiction-related neuroplasticity.<ref name="Natural and drug addictions" /><ref name="Running vs addiction" /> In particular, aerobic exercise decreases psychostimulant self-administration, reduces the [[reinstatement]] (i.e., relapse) of drug-seeking, and induces opposite effects on [[striatum|striatal]] [[dopamine receptor D2|dopamine receptor D<sub>2</sub>]] (DRD2) signaling (increased DRD2 density) to those induced by pathological stimulant use (decreased DRD2 density).<ref name="Natural and drug addictions" /><ref name="Running vs addiction" /> Consequently, consistent aerobic exercise leads to better treatment outcomes when used as an adjunct treatment for addiction.<ref name="Running vs addiction" /><ref name="Exercise Rev 3">{{cite journal | vauthors = Linke SE, Ussher M | title = Exercise-based treatments for substance use disorders: evidence, theory, and practicality | journal = Am J Drug Alcohol Abuse | volume = 41 | issue = 1 | pages = 7–15 | year = 2015 | pmid = 25397661 | doi = 10.3109/00952990.2014.976708 | quote = The limited research conducted suggests that exercise may be an effective adjunctive treatment for SUDs. In contrast to the scarce intervention trials to date, a relative abundance of literature on the theoretical and practical reasons supporting the investigation of this topic has been published.&nbsp;... numerous theoretical and practical reasons support exercise-based treatments for SUDs, including psychological, behavioral, neurobiological, nearly universal safety profile, and overall positive health effects.}}</ref>
 {{:FOSB|Table title=Summary of addiction-related plasticity}}
 ===Structural growth{{anchor|Memory|Growth}}===
-Reviews of neuroimaging studies indicate that consistent aerobic exercise increases [[gray matter]] volume in several brain regions associated with memory, cognitive control, [[motor function]], and [[reward system|reward processing]];<ref name="Comprehensive review" /><ref name="gray matter" /><ref name="BDNF depression" /> the most prominent gains are seen in the prefrontal cortex and hippocampus, which are primarily associated with cognitive control and memory processing respectively.<ref name="gray matter" /><ref name="cognitive control of exercise" /><ref name="BDNF depression" /> Moreover, the left and right halves of the prefrontal cortex, which is divided by the [[medial longitudinal fissure]], appear to become more interconnected in response to consistent aerobic exercise.<ref name="exercise benefits" /> Two reviews indicate that marked improvements in prefrontal and hippocampal gray matter volume occur in healthy adults that engage in medium intensity exercise for several months.<ref name="gray matter" /><ref name="Mind over matter">{{vcite2 journal | vauthors = Valkanova V, Eguia Rodriguez R, Ebmeier KP | title = Mind over matter—what do we know about neuroplasticity in adults? | journal = Int Psychogeriatr | volume = 26 | issue = 6 | pages = 891–909 | date = June 2014 | pmid = 24382194 | doi = 10.1017/S1041610213002482 | quote = Control group: Active<br />Intervention: Aerobic exercise<br /> [Increased GMV in:] Lobes (dorsal anterior cingulate cortex, supplementary motor area, middle frontal gyrus bilaterally); R inferior frontal gyrus, middle frontal gyrus and L superior temporal lobe; increase in the volume of anterior white matter tracts&nbsp;... ↑GMV anterior hippocampus}}</ref> Other regions of the brain that demonstrate moderate or less significant gains in gray matter volume during neuroimaging include the [[anterior cingulate cortex]], [[parietal cortex]], [[cerebellum]], [[caudate nucleus]], and [[nucleus accumbens]].<ref name="Comprehensive review" /><ref name="gray matter" /><ref name="BDNF depression" /><ref name="Ruscheweyh">{{cite journal | author = Ruscheweyh R, Willemer C, Krüger K, Duning T, Warnecke T, Sommer J, Völker K, Ho HV, Mooren F, Knecht S, Flöel A | title = Physical activity and memory functions: an interventional study | journal = Neurobiol. Aging | volume = 32 | issue = 7 | pages = 1304–19 |date=July 2011 | pmid = 19716631 | doi = 10.1016/j.neurobiolaging.2009.08.001 |url=}}</ref>
+Reviews of neuroimaging studies indicate that consistent aerobic exercise increases [[gray matter]] volume in several brain regions associated with memory, cognitive control, [[motor function]], and [[reward system|reward processing]];<ref name="Comprehensive review" /><ref name="gray matter" /><ref name="BDNF depression" /> the most prominent gains are seen in the prefrontal cortex and hippocampus, which are primarily associated with cognitive control and memory processing respectively.<ref name="gray matter" /><ref name="cognitive control of exercise" /><ref name="BDNF depression" /> Moreover, the left and right halves of the prefrontal cortex, which is divided by the [[medial longitudinal fissure]], appear to become more interconnected in response to consistent aerobic exercise.<ref name="exercise benefits" /> Two reviews indicate that marked improvements in prefrontal and hippocampal gray matter volume occur in healthy adults that engage in medium intensity exercise for several months.<ref name="gray matter" /><ref name="Mind over matter">{{cite journal | vauthors = Valkanova V, Eguia Rodriguez R, Ebmeier KP | title = Mind over matter—what do we know about neuroplasticity in adults? | journal = Int Psychogeriatr | volume = 26 | issue = 6 | pages = 891–909 | date = June 2014 | pmid = 24382194 | doi = 10.1017/S1041610213002482 | quote = Control group: Active<br />Intervention: Aerobic exercise<br /> [Increased GMV in:] Lobes (dorsal anterior cingulate cortex, supplementary motor area, middle frontal gyrus bilaterally); R inferior frontal gyrus, middle frontal gyrus and L superior temporal lobe; increase in the volume of anterior white matter tracts&nbsp;... ↑GMV anterior hippocampus}}</ref> Other regions of the brain that demonstrate moderate or less significant gains in gray matter volume during neuroimaging include the [[anterior cingulate cortex]], [[parietal cortex]], [[cerebellum]], [[caudate nucleus]], and [[nucleus accumbens]].<ref name="Comprehensive review" /><ref name="gray matter" /><ref name="BDNF depression" /><ref name="Ruscheweyh">{{cite journal | author = Ruscheweyh R, Willemer C, Krüger K, Duning T, Warnecke T, Sommer J, Völker K, Ho HV, Mooren F, Knecht S, Flöel A | title = Physical activity and memory functions: an interventional study | journal = Neurobiol. Aging | volume = 32 | issue = 7 | pages = 1304–19 |date=July 2011 | pmid = 19716631 | doi = 10.1016/j.neurobiolaging.2009.08.001 |url=}}</ref>
-Regular exercise has been shown to counter the shrinking of the hippocampus and memory impairment that naturally occurs in late adulthood.<ref name="Comprehensive review" /><ref name="gray matter" /><ref name="BDNF depression" /> Sedentary adults over age&nbsp;55 show a 1–2%&nbsp;decline in hippocampal volume annually.<ref name="BDNF depression" /><ref name="Hippocampus" /> A neuroimaging study with a sample of 120&nbsp;adults revealed that participating in regular aerobic exercise increased the volume of the left hippocampus by 2.12% and the right hippocampus by 1.97% over a one-year period.<ref name="BDNF depression" /><ref name="Hippocampus" /> Subjects in the low intensity stretching group who had higher fitness levels at baseline showed less hippocampal volume loss, providing evidence for exercise being protective against age-related cognitive decline.<ref name="Hippocampus">{{cite journal | author = Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, Kim JS, Heo S, Alves H, White SM, Wojcicki TR, Mailey E, Vieira VJ, Martin SA, Pence BD, Woods JA, McAuley E, Kramer AF | title = Exercise training increases size of hippocampus and improves memory | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 108 | issue = 7 | pages = 3017–22 |date=February 2011 | pmid = 21282661 | pmc = 3041121 | doi = 10.1073/pnas.1015950108 |url=}}</ref> In general, individuals that exercise more over a given period have greater hippocampal volumes and better memory function.<ref name="Comprehensive review" /><ref name="BDNF depression">{{vcite2 journal | vauthors = Erickson KI, Miller DL, Roecklein KA | title = The aging hippocampus: interactions between exercise, depression, and BDNF | journal = Neuroscientist | volume = 18 | issue = 1 | pages = 82–97 | year = 2012 | pmid = 21531985 | pmc = 3575139 | quote = Late adulthood is associated with increased hippocampal atrophy and dysfunction. &nbsp;... However, there is strong evidence that decreased BDNF is associated with age-related hippocampal dysfunction, memory impairment, and increased risk for depression, whereas increasing BDNF by aerobic exercise appears to ameliorate hippocampal atrophy, improve memory function, and reduce depression.&nbsp;...  For example, longitudinal studies have reported between 1% and 2% annual hippocampal atrophy in adults older than 55 years without dementia&nbsp;... Over a nine-year period, greater amounts of physical activity in the form of walking are associated with greater gray matter volume in several regions including prefrontal, temporal, and hippocampal areas.&nbsp;... The prefrontal cortex and hippocampus deteriorate in late adulthood, preceding and leading to deficits in executive and memory function. We examined in this review the evidence that age-related changes in BDNF might at least partially explain hippocampal atrophy and increased risk for memory impairment. We can conclude that 1) decreases in BDNF protein expression are associated with poorer hippocampal function and increased rates of geriatric depression and AD.&nbsp;... 3) Aerobic exercise enhances executive and memory function and reduces hippocampal atrophy in late adulthood, and this may be partially mediated through a BDNF pathway. | doi=10.1177/1073858410397054}}</ref>  Aerobic exercise has also been shown to induce growth in the [[white matter]] tracts in the anterior [[corpus callosum]], which normally shrink with age.<ref name="Comprehensive review" /><ref name="Mind over matter" />
+Regular exercise has been shown to counter the shrinking of the hippocampus and memory impairment that naturally occurs in late adulthood.<ref name="Comprehensive review" /><ref name="gray matter" /><ref name="BDNF depression" /> Sedentary adults over age&nbsp;55 show a 1–2%&nbsp;decline in hippocampal volume annually.<ref name="BDNF depression" /><ref name="Hippocampus" /> A neuroimaging study with a sample of 120&nbsp;adults revealed that participating in regular aerobic exercise increased the volume of the left hippocampus by 2.12% and the right hippocampus by 1.97% over a one-year period.<ref name="BDNF depression" /><ref name="Hippocampus" /> Subjects in the low intensity stretching group who had higher fitness levels at baseline showed less hippocampal volume loss, providing evidence for exercise being protective against age-related cognitive decline.<ref name="Hippocampus">{{cite journal | author = Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, Kim JS, Heo S, Alves H, White SM, Wojcicki TR, Mailey E, Vieira VJ, Martin SA, Pence BD, Woods JA, McAuley E, Kramer AF | title = Exercise training increases size of hippocampus and improves memory | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 108 | issue = 7 | pages = 3017–22 |date=February 2011 | pmid = 21282661 | pmc = 3041121 | doi = 10.1073/pnas.1015950108 |url=}}</ref> In general, individuals that exercise more over a given period have greater hippocampal volumes and better memory function.<ref name="Comprehensive review" /><ref name="BDNF depression">{{cite journal | vauthors = Erickson KI, Miller DL, Roecklein KA | title = The aging hippocampus: interactions between exercise, depression, and BDNF | journal = Neuroscientist | volume = 18 | issue = 1 | pages = 82–97 | year = 2012 | pmid = 21531985 | pmc = 3575139 | quote = Late adulthood is associated with increased hippocampal atrophy and dysfunction. &nbsp;... However, there is strong evidence that decreased BDNF is associated with age-related hippocampal dysfunction, memory impairment, and increased risk for depression, whereas increasing BDNF by aerobic exercise appears to ameliorate hippocampal atrophy, improve memory function, and reduce depression.&nbsp;...  For example, longitudinal studies have reported between 1% and 2% annual hippocampal atrophy in adults older than 55 years without dementia&nbsp;... Over a nine-year period, greater amounts of physical activity in the form of walking are associated with greater gray matter volume in several regions including prefrontal, temporal, and hippocampal areas.&nbsp;... The prefrontal cortex and hippocampus deteriorate in late adulthood, preceding and leading to deficits in executive and memory function. We examined in this review the evidence that age-related changes in BDNF might at least partially explain hippocampal atrophy and increased risk for memory impairment. We can conclude that 1) decreases in BDNF protein expression are associated with poorer hippocampal function and increased rates of geriatric depression and AD.&nbsp;... 3) Aerobic exercise enhances executive and memory function and reduces hippocampal atrophy in late adulthood, and this may be partially mediated through a BDNF pathway. | doi=10.1177/1073858410397054}}</ref>  Aerobic exercise has also been shown to induce growth in the [[white matter]] tracts in the anterior [[corpus callosum]], which normally shrink with age.<ref name="Comprehensive review" /><ref name="Mind over matter" />
 The various functions of the brain structures that show exercise-induced increases in gray matter volume include:
@@ Line 54: / Line 54: @@
 * [[Nucleus accumbens]]&nbsp;– responsible for [[reward system|reward perception]], [[motivation]], and [[positive reinforcement]]; implicated in addiction<ref name="NAcc function">{{cite book | author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 147, 266, 376 | edition = 2nd | quote= VTA DA neurons play a critical role in motivation, reward-related behavior (Chapter 15), attention, and multiple forms of memory. This organization of the DA system, wide projection from a limited number of cell bodies, permits coordinated responses to potent new rewards. Thus, acting in diverse terminal fields, dopamine confers motivational salience (“wanting”) on the reward itself or associated cues (nucleus accumbens shell region)&nbsp;...  Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward.&nbsp;... The NAc and VTA are central components of the circuitry underlying reward and memory of reward. As previously mentioned, the activity of dopaminergic neurons in the VTA appears to be linked to reward prediction. The NAc is involved in learning associated with reinforcement&nbsp;... The shell of the NAc appears to be particularly important to initial drug actions within reward circuitry; addictive drugs appear to have a greater effect on dopamine release in the shell than in the core of the NAc.}}</ref>
 * [[Hippocampus]]&nbsp;– responsible for storage and consolidation of [[declarative memory]] and [[spatial memory]];<ref name="gray matter" /><ref name="NHM-Caudate Hippocampus" /> implicated in [[major depressive disorder|depression]]<ref name="BDNF depression" />
-* [[Cerebellum]]&nbsp;– responsible for [[motor coordination]] and [[motor learning]]<ref name="Cerebellum">{{vcite2 journal | vauthors = Grimaldi G, Argyropoulos GP, Bastian A, Cortes M, Davis NJ, Edwards DJ, Ferrucci R, Fregni F, Galea JM, Hamada M, Manto M, Miall RC, Morales-Quezada L, Pope PA, Priori A, Rothwell J, Tomlinson SP, Celnik P | title = Cerebellar Transcranial Direct Current Stimulation (ctDCS): A Novel Approach to Understanding Cerebellar Function in Health and Disease | journal = Neuroscientist | volume = | issue = | pages = | year = 2014 | pmid = 25406224 | doi = 10.1177/1073858414559409 |url=}}</ref>
+* [[Cerebellum]]&nbsp;– responsible for [[motor coordination]] and [[motor learning]]<ref name="Cerebellum">{{cite journal | vauthors = Grimaldi G, Argyropoulos GP, Bastian A, Cortes M, Davis NJ, Edwards DJ, Ferrucci R, Fregni F, Galea JM, Hamada M, Manto M, Miall RC, Morales-Quezada L, Pope PA, Priori A, Rothwell J, Tomlinson SP, Celnik P | title = Cerebellar Transcranial Direct Current Stimulation (ctDCS): A Novel Approach to Understanding Cerebellar Function in Health and Disease | journal = Neuroscientist | volume = | issue = | pages = | year = 2014 | pmid = 25406224 | doi = 10.1177/1073858414559409 |url=}}</ref>
 * [[Caudate nucleus]]&nbsp;– responsible for [[Classical conditioning|stimulus-response learning]] and inhibitory control; implicated in [[Parkinson's disease]], [[Huntington's disease]] and ADHD<ref name="NHM-Cognitive Control" /><ref name="NHM-Caudate Hippocampus">{{cite book | author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 148, 324–328, 438 | edition = 2nd | quote = [dopamine] helps consolidate multiple forms of memory (amygdala and hippocampus)&nbsp;... the specific crucial structures underlying the ability to store declarative memories are the hippocampus, the subicular complex, and the entorhinal cortex&nbsp;... These findings strongly suggest that LTP in the hippocampus is required for at least some forms of learning and memory known to be dependent on this brain region.&nbsp;... Evidence that the caudate nucleus and putamen influence stimulus-response learning comes from lesion studies in rodents and primates and from neuroimaging studies in humans and from studies of human disease. In Parkinson disease, the dopaminergic innervation of the caudate and putamen is severely compromised by the death of dopamine neurons in the substantia nigra pars compacta (Chapter 17). Patients with Parkinson disease have normal declarative memory&nbsp;... However, they have marked impairments of stimulus-response learning. Patients with Parkinson disease or other basal ganglia disorders such as Huntington disease (in which caudate neurons themselves are damaged) have deficits in other procedural learning tasks, such as the acquisition of new motor programs.&nbsp;... Huntington disease is associated with degenerative changes that are most apparent in the caudate nucleus and putamen.}}</ref>
-* [[Parietal cortex]]&nbsp;– responsible for [[sensory perception]], working memory, and attention<ref name="NHM-Cognitive Control">{{cite book | author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 313–321 | edition = 2nd | chapter = Chapter 13: Higher Cognitive Function and Behavioral Control | quote ={{bull}} Executive function, the cognitive control of behavior, depends on the prefrontal cortex, which is highly developed in higher primates and especially humans.<br />{{bull}} Working memory is a short-term, capacity-limited cognitive buffer that stores information and permits its manipulation to guide decision-making and behavior.&nbsp;...<br /> These diverse inputs and back projections to both cortical and subcortical structures put the prefrontal cortex in a position to exert what is often called “top-down” control or cognitive control of behavior.&nbsp;... The prefrontal cortex receives inputs not only from other cortical regions, including association cortex, but also, via the thalamus, inputs from subcortical structures subserving emotion and motivation, such as the amygdala (Chapter 14) and ventral striatum (or nucleus accumbens; Chapter 15).&nbsp;...<br />In conditions in which prepotent responses tend to dominate behavior, such as in '''drug addiction''', where drug cues can elicit drug seeking (Chapter 15), or in '''attention deficit hyperactivity disorder''' ('''ADHD'''; described below), significant negative consequences can result.&nbsp;... ADHD can be conceptualized as a disorder of executive function; specifically, ADHD is characterized by reduced ability to exert and maintain cognitive control of behavior. Compared with healthy individuals, those with ADHD have diminished ability to suppress inappropriate prepotent responses to stimuli (impaired response inhibition) and diminished ability to inhibit responses to irrelevant stimuli (impaired interference suppression).&nbsp;... <!--Inhibitory control brain structures-->Functional neuroimaging in humans demonstrates activation of the prefrontal cortex and caudate nucleus (part of the striatum) in tasks that demand inhibitory control of behavior.&nbsp;... Early results with structural MRI show thinning of the cerebral cortex in ADHD subjects compared with age-matched controls in prefrontal cortex and posterior parietal cortex, areas involved in working memory and attention.}}</ref><ref name="parietal ">{{vcite2 journal | vauthors = Sereno MI, Huang RS | title = Multisensory maps in parietal cortex | journal = Curr. Opin. Neurobiol. | volume = 24 | issue = 1 | pages = 39–46 | year = 2014 | pmid = 24492077 | pmc = 3969294 | doi = 10.1016/j.conb.2013.08.014 |url=}}</ref>
+* [[Parietal cortex]]&nbsp;– responsible for [[sensory perception]], working memory, and attention<ref name="NHM-Cognitive Control">{{cite book | author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 313–321 | edition = 2nd | chapter = Chapter 13: Higher Cognitive Function and Behavioral Control | quote ={{bull}} Executive function, the cognitive control of behavior, depends on the prefrontal cortex, which is highly developed in higher primates and especially humans.<br />{{bull}} Working memory is a short-term, capacity-limited cognitive buffer that stores information and permits its manipulation to guide decision-making and behavior.&nbsp;...<br /> These diverse inputs and back projections to both cortical and subcortical structures put the prefrontal cortex in a position to exert what is often called “top-down” control or cognitive control of behavior.&nbsp;... The prefrontal cortex receives inputs not only from other cortical regions, including association cortex, but also, via the thalamus, inputs from subcortical structures subserving emotion and motivation, such as the amygdala (Chapter 14) and ventral striatum (or nucleus accumbens; Chapter 15).&nbsp;...<br />In conditions in which prepotent responses tend to dominate behavior, such as in '''drug addiction''', where drug cues can elicit drug seeking (Chapter 15), or in '''attention deficit hyperactivity disorder''' ('''ADHD'''; described below), significant negative consequences can result.&nbsp;... ADHD can be conceptualized as a disorder of executive function; specifically, ADHD is characterized by reduced ability to exert and maintain cognitive control of behavior. Compared with healthy individuals, those with ADHD have diminished ability to suppress inappropriate prepotent responses to stimuli (impaired response inhibition) and diminished ability to inhibit responses to irrelevant stimuli (impaired interference suppression).&nbsp;... <!--Inhibitory control brain structures-->Functional neuroimaging in humans demonstrates activation of the prefrontal cortex and caudate nucleus (part of the striatum) in tasks that demand inhibitory control of behavior.&nbsp;... Early results with structural MRI show thinning of the cerebral cortex in ADHD subjects compared with age-matched controls in prefrontal cortex and posterior parietal cortex, areas involved in working memory and attention.}}</ref><ref name="parietal ">{{cite journal | vauthors = Sereno MI, Huang RS | title = Multisensory maps in parietal cortex | journal = Curr. Opin. Neurobiol. | volume = 24 | issue = 1 | pages = 39–46 | year = 2014 | pmid = 24492077 | pmc = 3969294 | doi = 10.1016/j.conb.2013.08.014 |url=}}</ref>
 ====Cognitive control and memory====
 {{see also|Executive functions}}
-Concordant with the functional roles of the brain structures that exhibit increased gray matter volumes, exercise has been shown to improve numerous aspects of cognitive control and memory function.<ref name="Comprehensive review" /><ref name="exercise benefits" /><ref name="cognitive control of exercise" /><ref name="Executive functions" /><ref name="Attention-acute exercise" />  In particular, consistent aerobic exercise has been shown to improve [[attentional control]],{{#tag:ref|Attentional control allows an individual to focus their attention on a specific source and ignore other stimuli that compete for one's attention,<ref name="Malenka pathways" /> such as in the [[cocktail party effect]]. |group="note"}} [[attention span]], [[Mental chronometry|information processing speed]], [[cognitive flexibility]] (e.g., [[task switching (psychology)|task switching]]), [[inhibitory control]],{{#tag:ref| Inhibitory control is the process of altering one's learned behavioral responses, sometimes called "prepotent responses", in a way that makes it easier to complete a particular goal.<ref name="NHM-Cognitive Control" /><ref name="Cognitive and motivational effects">{{vcite2 journal | vauthors = Ilieva IP, Hook CJ, Farah MJ | title = Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis | journal = J Cogn Neurosci | volume = | issue = | pages = 1–21 | year = 2015 | pmid = 25591060 | doi = 10.1162/jocn_a_00776}}</ref> Inhibitory control allows individuals to control their impulses and habits when necessary or desired,<ref name="NHM-Cognitive Control" /><ref name="Executive functions" /><ref name="Cognitive and motivational effects" /> e.g., to overcome [[procrastination]]. |group="note"}} [[working memory]] updating and capacity,{{#tag:ref|Working memory is the form of memory used by an individual at any given moment for active information processing,<ref name="Malenka pathways" /> such as when reading or writing an encyclopedia article. Working memory has a limited capacity and functions as an information buffer, analogous to a computer's [[data buffer]], that permits the manipulation of information for comprehension, decision-making, and guidance of behavior.<ref name="NHM-Cognitive Control" />|group="note"}} [[declarative memory]],{{#tag:ref|Declarative memory, also known as [[explicit memory]], is the form of memory that pertains to facts and events.<ref name="NHM-Caudate Hippocampus" />|group="note"}} and [[spatial memory]].<ref name="Comprehensive review" /><ref name="gray matter" /><ref name="exercise benefits">{{cite journal | author = Guiney H, Machado L | title = Benefits of regular aerobic exercise for executive functioning in healthy populations | journal = Psychon Bull Rev | volume = 20 | issue = 1 | pages = 73–86 | year = February 2013 | pmid = 23229442 | doi = 10.3758/s13423-012-0345-4 | quote = Executive functions are strategic in nature and depend on higher-order cognitive processes that underpin planning, sustained attention, selective attention, resistance to interference, volitional inhibition, working memory, and mental flexibility&nbsp;... Data to date from studies of aging provide strong evidence of exercise-linked benefits related to task switching, selective attention, inhibition of prepotent responses, and working memory capacity; furthermore, cross-sectional fitness data suggest that working memory updating could potentially benefit as well. In young adults, working memory updating is the main executive function shown to benefit from regular exercise, but cross-sectional data further suggest that task-switching and post-error performance may also benefit. In children, working memory capacity has been shown to benefit, and cross-sectional data suggest potential benefits for selective attention and inhibitory control.&nbsp;... Support for the idea that higher levels of aerobic activity may be associated with superior brain structure has been gained through cross-sectional studies in older adults and children (for a recent review, see Voss, Nagamatsu, et al., 2011).&nbsp;... only those in the aerobic exercise group exhibited improved connectivity between the left and right prefrontal cortices, two areas that are crucial to the effective functioning of the fronto-executive network.&nbsp;... <!--Selective attention-->Together, these studies provide evidence that regular aerobic exercise benefits control over responses during selective attention in older adults.&nbsp;... <!--Inhibitory control-->aerobic fitness is a good predictor of performance on tasks that rely relatively heavily on inhibitory control over prepotent responses (e.g., Colcombe et al., 2004, Study 1; Prakash et al., 2011) and also that regular aerobic exercise ''improves'' performance on such tasks&nbsp;... <!--Working memory-->Overall, the results from the span and Sternberg tasks suggest that regular exercise can also confer benefits for the volume of information that children and older adults can hold in mind at one time.}}</ref><ref name="cognitive control of exercise">{{cite journal | author = Buckley J, Cohen JD, Kramer AF, McAuley E, Mullen SP | title = Cognitive control in the self-regulation of physical activity and sedentary behavior | journal = Front Hum Neurosci | volume = 8 | issue = | page = 747 | year = 2014 | pmid = 25324754 | pmc = 4179677 | doi = 10.3389/fnhum.2014.00747 | quote = Recent theory (e.g., Temporal Self-Regulation Theory; Hall and Fong, 2007, 2010, 2013) and evidence suggest that the relation between physical activity and cognitive control is reciprocal (Daly et al., 2013). Most research has focused on the beneficial effects of regular physical activity on executive functions-the set of neural processes that define cognitive control. Considerable evidence shows that regular physical activity is associated with enhanced cognitive functions, including attention, processing speed, task switching<!--cognitive flexibility-->, inhibition of prepotent responses<!--inhibitory control--> and declarative memory (for reviews see Colcombe and Kramer, 2003; Smith et al., 2010; Guiney and Machado, 2013; McAuley et al., 2013). Recent research demonstrates a dose-response relationship between fitness and spatial memory (Erickson et al., 2011)&nbsp;... The effects of physical activity on cognitive control appear to be underpinned by a variety of brain processes including: increased hippocampal volume, increased gray matter density in the prefrontal cortex (PFC), upregulation of neurotrophins and greater microvascular density&nbsp;... Together, this research suggests that an improvement in control processes, such as attention and inhibition or interference control, is associated with an improvement in self-regulation of physical activity.&nbsp;... Hoang et al. (2013) found that young adults who initially exhibited low levels of physical activity and remained relatively inactive for 25 years had nearly twofold greater odds of impaired executive function compared with those who exhibited higher activity levels; very-low physical activity patterns were associated with even more pronounced declines in executive functioning.&nbsp;… sedentary behavior indirectly led to poor executive function through depressive symptoms (Vance et al., 2005).&nbsp;… sedentary individuals display less capacity to quickly and accurately switch between tasks. }}</ref><ref name="Executive functions">{{cite journal | author = Diamond A | title = Executive functions | journal = Annu Rev Psychol | volume = 64 | issue = | pages = 135–168 | year = 2013 | pmid = 23020641 | pmc = 4084861 | doi = 10.1146/annurev-psych-113011-143750 | quote = Core EFs are inhibition [response inhibition (self-control—resisting temptations and resisting acting impulsively) and interference control (selective attention and cognitive inhibition)], working memory, and cognitive flexibility (including creatively thinking “outside the box,” seeing anything from different perspectives, and quickly and flexibly adapting to changed circumstances).&nbsp;... EFs and prefrontal cortex are the first to suffer, and suffer disproportionately, if something is not right in your life. They suffer first, and most, if you are stressed (Arnsten 1998, Liston et al. 2009, Oaten & Cheng 2005), sad (Hirt et al. 2008, von Hecker & Meiser 2005), lonely (Baumeister et al. 2002, Cacioppo & Patrick 2008, Campbell et al. 2006, Tun et al. 2012), sleep deprived (Barnes et al. 2012, Huang et al. 2007), or not physically fit (Best 2010, Chaddock et al. 2011, Hillman et al. 2008). Any of these can cause you to appear to have a disorder of EFs, such as ADHD, when you do not. You can see the deleterious effects of stress, sadness, loneliness, and lack of physical health or fitness at the physiological and neuroanatomical level in prefrontal cortex and at the behavioral level in worse EFs (poorer reasoning and problem solving, forgetting things, and impaired ability to exercise discipline and self-control).&nbsp;...<br />EFs can be improved (Diamond & Lee 2011, Klingberg 2010).&nbsp;... At any age across the life cycle EFs can be improved, including in the elderly and in infants. There has been much work with excellent results on improving EFs in the elderly by improving physical fitness (Erickson & Kramer 2009, Voss et al. 2011)&nbsp;... Inhibitory control (one of the core EFs) involves being able to control one’s attention, behavior, thoughts, and/or emotions to override a strong internal predisposition or external lure, and instead do what’s more appropriate or needed. Without inhibitory control we would be at the mercy of impulses, old habits of thought or action (conditioned responses), and/or stimuli in the environment that pull us this way or that. Thus, inhibitory control makes it possible for us to change and for us to choose how we react and how we behave rather than being unthinking creatures of habit. It doesn’t make it easy. Indeed, we usually are creatures of habit and our behavior is under the control of environmental stimuli far more than we usually realize, but having the ability to exercise inhibitory control creates the possibility of change and choice.}}</ref><ref name="Attention-acute exercise">{{vcite2 journal | vauthors = Janssen M, Toussaint HM, van Mechelen W, Verhagen EA | title = Effects of acute bouts of physical activity on children's attention: a systematic review of the literature | journal = Springerplus | volume = 3 | issue = | pages = 410 | year = 2014 | pmid = 25133092 | pmc = 4132441 | doi = 10.1186/2193-1801-3-410 | quote = There is weak evidence for the effect of acute bouts of physical activity on attention.&nbsp;... Fortunately, the literature-base on the acute effect of PA on the underlying cognitive processes of academic performance is growing. Hillman et al. (2011) found in their review a positive effect of acute PA on brain health and cognition in children, but concluded it was complicated to compare the different studies due to the different outcome measures (e.g. memory, response time and accuracy, attention, and comprehension). Therefore, this review focuses on the sole outcome measure ‘attention’ as a mediator for cognition and achievement.}}</ref> Individuals who have a sedentary lifestyle tend to have impaired cognitive control relative to other more physically active non-exercisers.<ref name="cognitive control of exercise" /><ref name="Executive functions" /> A reciprocal relationship between exercise and cognitive control has also been noted: improvements in control processes, such as attentional control and inhibitory control, increase an individual's tendency to exercise.<ref name="cognitive control of exercise" /> A systematic review of studies conducted on children suggests that some of the exercise-induced improvements in executive function are apparent after single bouts of exercise, while other aspects (e.g., attentional control) only improve following consistent exercise on a regular basis.<ref name="Attention-acute exercise" />
+Concordant with the functional roles of the brain structures that exhibit increased gray matter volumes, exercise has been shown to improve numerous aspects of cognitive control and memory function.<ref name="Comprehensive review" /><ref name="exercise benefits" /><ref name="cognitive control of exercise" /><ref name="Executive functions" /><ref name="Attention-acute exercise" />  In particular, consistent aerobic exercise has been shown to improve [[attentional control]],{{#tag:ref|Attentional control allows an individual to focus their attention on a specific source and ignore other stimuli that compete for one's attention,<ref name="Malenka pathways" /> such as in the [[cocktail party effect]]. |group="note"}} [[attention span]], [[Mental chronometry|information processing speed]], [[cognitive flexibility]] (e.g., [[task switching (psychology)|task switching]]), [[inhibitory control]],{{#tag:ref| Inhibitory control is the process of altering one's learned behavioral responses, sometimes called "prepotent responses", in a way that makes it easier to complete a particular goal.<ref name="NHM-Cognitive Control" /><ref name="Cognitive and motivational effects">{{cite journal | vauthors = Ilieva IP, Hook CJ, Farah MJ | title = Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis | journal = J Cogn Neurosci | volume = | issue = | pages = 1–21 | year = 2015 | pmid = 25591060 | doi = 10.1162/jocn_a_00776}}</ref> Inhibitory control allows individuals to control their impulses and habits when necessary or desired,<ref name="NHM-Cognitive Control" /><ref name="Executive functions" /><ref name="Cognitive and motivational effects" /> e.g., to overcome [[procrastination]]. |group="note"}} [[working memory]] updating and capacity,{{#tag:ref|Working memory is the form of memory used by an individual at any given moment for active information processing,<ref name="Malenka pathways" /> such as when reading or writing an encyclopedia article. Working memory has a limited capacity and functions as an information buffer, analogous to a computer's [[data buffer]], that permits the manipulation of information for comprehension, decision-making, and guidance of behavior.<ref name="NHM-Cognitive Control" />|group="note"}} [[declarative memory]],{{#tag:ref|Declarative memory, also known as [[explicit memory]], is the form of memory that pertains to facts and events.<ref name="NHM-Caudate Hippocampus" />|group="note"}} and [[spatial memory]].<ref name="Comprehensive review" /><ref name="gray matter" /><ref name="exercise benefits">{{cite journal | author = Guiney H, Machado L | title = Benefits of regular aerobic exercise for executive functioning in healthy populations | journal = Psychon Bull Rev | volume = 20 | issue = 1 | pages = 73–86 | year = February 2013 | pmid = 23229442 | doi = 10.3758/s13423-012-0345-4 | quote = Executive functions are strategic in nature and depend on higher-order cognitive processes that underpin planning, sustained attention, selective attention, resistance to interference, volitional inhibition, working memory, and mental flexibility&nbsp;... Data to date from studies of aging provide strong evidence of exercise-linked benefits related to task switching, selective attention, inhibition of prepotent responses, and working memory capacity; furthermore, cross-sectional fitness data suggest that working memory updating could potentially benefit as well. In young adults, working memory updating is the main executive function shown to benefit from regular exercise, but cross-sectional data further suggest that task-switching and post-error performance may also benefit. In children, working memory capacity has been shown to benefit, and cross-sectional data suggest potential benefits for selective attention and inhibitory control.&nbsp;... Support for the idea that higher levels of aerobic activity may be associated with superior brain structure has been gained through cross-sectional studies in older adults and children (for a recent review, see Voss, Nagamatsu, et al., 2011).&nbsp;... only those in the aerobic exercise group exhibited improved connectivity between the left and right prefrontal cortices, two areas that are crucial to the effective functioning of the fronto-executive network.&nbsp;... <!--Selective attention-->Together, these studies provide evidence that regular aerobic exercise benefits control over responses during selective attention in older adults.&nbsp;... <!--Inhibitory control-->aerobic fitness is a good predictor of performance on tasks that rely relatively heavily on inhibitory control over prepotent responses (e.g., Colcombe et al., 2004, Study 1; Prakash et al., 2011) and also that regular aerobic exercise ''improves'' performance on such tasks&nbsp;... <!--Working memory-->Overall, the results from the span and Sternberg tasks suggest that regular exercise can also confer benefits for the volume of information that children and older adults can hold in mind at one time.}}</ref><ref name="cognitive control of exercise">{{cite journal | author = Buckley J, Cohen JD, Kramer AF, McAuley E, Mullen SP | title = Cognitive control in the self-regulation of physical activity and sedentary behavior | journal = Front Hum Neurosci | volume = 8 | issue = | page = 747 | year = 2014 | pmid = 25324754 | pmc = 4179677 | doi = 10.3389/fnhum.2014.00747 | quote = Recent theory (e.g., Temporal Self-Regulation Theory; Hall and Fong, 2007, 2010, 2013) and evidence suggest that the relation between physical activity and cognitive control is reciprocal (Daly et al., 2013). Most research has focused on the beneficial effects of regular physical activity on executive functions-the set of neural processes that define cognitive control. Considerable evidence shows that regular physical activity is associated with enhanced cognitive functions, including attention, processing speed, task switching<!--cognitive flexibility-->, inhibition of prepotent responses<!--inhibitory control--> and declarative memory (for reviews see Colcombe and Kramer, 2003; Smith et al., 2010; Guiney and Machado, 2013; McAuley et al., 2013). Recent research demonstrates a dose-response relationship between fitness and spatial memory (Erickson et al., 2011)&nbsp;... The effects of physical activity on cognitive control appear to be underpinned by a variety of brain processes including: increased hippocampal volume, increased gray matter density in the prefrontal cortex (PFC), upregulation of neurotrophins and greater microvascular density&nbsp;... Together, this research suggests that an improvement in control processes, such as attention and inhibition or interference control, is associated with an improvement in self-regulation of physical activity.&nbsp;... Hoang et al. (2013) found that young adults who initially exhibited low levels of physical activity and remained relatively inactive for 25 years had nearly twofold greater odds of impaired executive function compared with those who exhibited higher activity levels; very-low physical activity patterns were associated with even more pronounced declines in executive functioning.&nbsp;… sedentary behavior indirectly led to poor executive function through depressive symptoms (Vance et al., 2005).&nbsp;… sedentary individuals display less capacity to quickly and accurately switch between tasks. }}</ref><ref name="Executive functions">{{cite journal | author = Diamond A | title = Executive functions | journal = Annu Rev Psychol | volume = 64 | issue = | pages = 135–168 | year = 2013 | pmid = 23020641 | pmc = 4084861 | doi = 10.1146/annurev-psych-113011-143750 | quote = Core EFs are inhibition [response inhibition (self-control—resisting temptations and resisting acting impulsively) and interference control (selective attention and cognitive inhibition)], working memory, and cognitive flexibility (including creatively thinking “outside the box,” seeing anything from different perspectives, and quickly and flexibly adapting to changed circumstances).&nbsp;... EFs and prefrontal cortex are the first to suffer, and suffer disproportionately, if something is not right in your life. They suffer first, and most, if you are stressed (Arnsten 1998, Liston et al. 2009, Oaten & Cheng 2005), sad (Hirt et al. 2008, von Hecker & Meiser 2005), lonely (Baumeister et al. 2002, Cacioppo & Patrick 2008, Campbell et al. 2006, Tun et al. 2012), sleep deprived (Barnes et al. 2012, Huang et al. 2007), or not physically fit (Best 2010, Chaddock et al. 2011, Hillman et al. 2008). Any of these can cause you to appear to have a disorder of EFs, such as ADHD, when you do not. You can see the deleterious effects of stress, sadness, loneliness, and lack of physical health or fitness at the physiological and neuroanatomical level in prefrontal cortex and at the behavioral level in worse EFs (poorer reasoning and problem solving, forgetting things, and impaired ability to exercise discipline and self-control).&nbsp;...<br />EFs can be improved (Diamond & Lee 2011, Klingberg 2010).&nbsp;... At any age across the life cycle EFs can be improved, including in the elderly and in infants. There has been much work with excellent results on improving EFs in the elderly by improving physical fitness (Erickson & Kramer 2009, Voss et al. 2011)&nbsp;... Inhibitory control (one of the core EFs) involves being able to control one’s attention, behavior, thoughts, and/or emotions to override a strong internal predisposition or external lure, and instead do what’s more appropriate or needed. Without inhibitory control we would be at the mercy of impulses, old habits of thought or action (conditioned responses), and/or stimuli in the environment that pull us this way or that. Thus, inhibitory control makes it possible for us to change and for us to choose how we react and how we behave rather than being unthinking creatures of habit. It doesn’t make it easy. Indeed, we usually are creatures of habit and our behavior is under the control of environmental stimuli far more than we usually realize, but having the ability to exercise inhibitory control creates the possibility of change and choice.}}</ref><ref name="Attention-acute exercise">{{cite journal | vauthors = Janssen M, Toussaint HM, van Mechelen W, Verhagen EA | title = Effects of acute bouts of physical activity on children's attention: a systematic review of the literature | journal = Springerplus | volume = 3 | issue = | pages = 410 | year = 2014 | pmid = 25133092 | pmc = 4132441 | doi = 10.1186/2193-1801-3-410 | quote = There is weak evidence for the effect of acute bouts of physical activity on attention.&nbsp;... Fortunately, the literature-base on the acute effect of PA on the underlying cognitive processes of academic performance is growing. Hillman et al. (2011) found in their review a positive effect of acute PA on brain health and cognition in children, but concluded it was complicated to compare the different studies due to the different outcome measures (e.g. memory, response time and accuracy, attention, and comprehension). Therefore, this review focuses on the sole outcome measure ‘attention’ as a mediator for cognition and achievement.}}</ref> Individuals who have a sedentary lifestyle tend to have impaired cognitive control relative to other more physically active non-exercisers.<ref name="cognitive control of exercise" /><ref name="Executive functions" /> A reciprocal relationship between exercise and cognitive control has also been noted: improvements in control processes, such as attentional control and inhibitory control, increase an individual's tendency to exercise.<ref name="cognitive control of exercise" /> A systematic review of studies conducted on children suggests that some of the exercise-induced improvements in executive function are apparent after single bouts of exercise, while other aspects (e.g., attentional control) only improve following consistent exercise on a regular basis.<ref name="Attention-acute exercise" />
 {{abbr|ADHD|Attention deficit hyperactivity disorder}} is a [[neurodevelopmental disorder|developmental neuropsychiatric disorder]] in which there are deficits in certain aspects of cognitive control, particularly attentional control and inhibitory control.<ref name="NHM-Cognitive Control" /> Regular physical exercise, particularly aerobic exercise, is an effective [[wikt:adjunct treatment|adjunct treatment]] for ADHD, although the best type and intensity is not currently known.<ref name="ADHD Exercise 2014">{{cite journal | authors = Kamp CF, Sperlich B, Holmberg HC | title = Exercise reduces the symptoms of attention-deficit/hyperactivity disorder and improves social behaviour, motor skills, strength and neuropsychological parameters | journal = Acta Paediatr. | volume = 103 | issue = 7 | pages = 709–14 | date = July 2014 | pmid = 24612421 | doi = 10.1111/apa.12628 | quote = The present review summarises the impact of exercise interventions (1–10 weeks in duration with at least two sessions each week) on parameters related to ADHD in 7-to 13-year-old children. We may conclude that all different types of exercise (here yoga, active games with and without the involvement of balls, walking and athletic training) attenuate the characteristic symptoms of ADHD and improve social behaviour, motor skills, strength and neuropsychological parameters without any undesirable side effects. Available reports do not reveal which type, intensity, duration and frequency of exercise is most effective in this respect and future research focusing on this question with randomised and controlled long-term interventions is warranted. |url=http://onlinelibrary.wiley.com/doi/10.1111/apa.12628/epdf | accessdate = 14 March 2015 }}</ref><ref name="ADHD Exercise 2013">{{cite journal | authors = Rommel AS, Halperin JM, Mill J, Asherson P, Kuntsi J | title = Protection from genetic diathesis in attention-deficit/hyperactivity disorder: possible complementary roles of exercise | journal = J Am Acad Child Adolesc Psychiatry | volume = 52 | issue = 9 | pages = 900–10 | date = September 2013 | pmid = 23972692 | doi = 10.1016/j.jaac.2013.05.018 | quote = As exercise has been found to enhance neural growth and development, and improve cognitive and behavioural functioning in [healthy] individuals and animal studies, we reviewed the literature on the effects of exercise in children and adolescents with ADHD and animal models of ADHD behaviours.<br /> A limited number of undersized non-randomized, retrospective and cross-sectional studies have investigated the impact of exercise on ADHD and the emotional, behavioural and neuropsychological problems associated with the disorder. The findings from these studies provide some support for the notion that exercise has the potential to act as a protective factor for ADHD. &nbsp;... Although it remains unclear which role, if any, BDNF plays in the pathophysiology of ADHD, enhanced neural functioning has been suggested to be associated with the reduction of remission of ADHD symptoms.<sup>49,50,72</sup> As exercise can elicit gene expression changes mediated by alterations in DNA methylation<sup>38</sup>, the possibility emerges that some of the positive effects of exercise could be caused by epigenetic mechanisms, which may set off a cascade of processes instigated by altered gene expression that could ultimately link to a change in brain function.}}</ref> In non-randomized trials, physical exercise has been shown to result in better behavior and motor abilities without causing any side effects in ADHD populations.<ref name="ADHD Exercise 2014" /><ref name="ADHD Exercise 2013" />
@@ Line 70: / Line 70: @@
 ===Psychological stress and cortisol===
 {{See also|Effects of stress on memory}}
-The "stress hormone", [[cortisol]], is a [[glucocorticoid]] that binds to [[glucocorticoid receptor]]s.<ref name="NHM-Stress" /><ref name="Exercise neuroendocrine effects" /><ref name="Endocrine cognition" /> [[Psychological stress]] induces the release of cortisol from the [[adrenal gland]] by activating the [[hypothalamic–pituitary–adrenal axis]] (HPA axis).<ref name="NHM-Stress">{{cite book | author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 350–359 | chapter = Chapter 14: Mood and Emotion | edition = 2nd | quote = The excessive release of stress hormones, such as cortisol, which occurs in many individuals with mood disorders, may result from hyperfunctioning of the PVN of the hypothalamus, hyperfunctioning of the amygdala (which activates the PVN), or hypofunctioning of the hippocampus (which exerts a potent inhibitory influence on the PVN).&nbsp;... Chronic stress decreases the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus, which in turn may contribute to the atrophy of CA3 neurons and their increased vulnerability to a variety of neuronal insults. Chronic elevation of glucocorticoid levels is also known to decrease the survival of these neurons. Such activity may increase the dendritic arborizations and survival of the neurons, or help repair or protect the neurons from further damage.&nbsp;... Stress and glucocorticoids inhibit, and a wide variety of antidepressant drugs, exercise, and enriched environments activate hippocampal neurogenesis.}}</ref><ref name="Exercise neuroendocrine effects">{{vcite2 journal | vauthors = Fuqua JS, Rogol AD | title = Neuroendocrine alterations in the exercising human: implications for energy homeostasis | journal = Metab. Clin. Exp. | volume = 62 | issue = 7 | pages = 911–921 | date = July 2013 | pmid = 23415825 | doi = 10.1016/j.metabol.2013.01.016 | quote = Cortisol has wide-ranging effects, including alterations of carbohydrate, protein, and lipid metabolism; catabolic effects on skin, muscle, connective tissue, and bone; immunomodulatory effects; blood pressure and circulatory system regulation; and effects on mood and central nervous system function. In the short term, activation of the HPA axis in response to stress is adaptive. However, long-term stress promoting chronic exposure of tissues to high cortisol concentrations becomes maladaptive.&nbsp;... Exercise, particularly sustained aerobic activity, is a potent stimulus of cortisol secretion. The circulating concentrations of cortisol are directly proportional to the intensity of exercise as measured by oxygen uptake. As is the case for the GH/IGF-1 and HPG axes, the HPA axis also receives many other inputs, including the light/dark cycle, feeding schedules, immune regulation, and many neurotransmitters that mediate the effects of exercise and physical and psychic stress [52].&nbsp;... The HPA is activated by stress, whether physical (exercise) or psychological.&nbsp;...<!--energy balance – stress&cortisol HPA axis--> Thus, a negative net energy balance leads to activation of the HPA axis and the circulating concomitants of the catabolic state in an attempt to keep core processes functional, realizing that the stress of exercise has no effect on cortisol and circulating metabolic substrates beyond the impact of the exercise energy expenditure on energy availability [60]. Thuma et al. [61] had already made the important observation that the reported differences in cortisol levels pre- and post-exercise depended on whether this difference was measured from a single pre-test level or from the physiologic circadian baseline as determined in an independent session in the resting state. By this analytical technique, these investigators showed that increasing energy expenditure led to significant cortisol release. This release was apparent if they subtracted the physiologic circadian baseline from the post-exercise value.}}</ref><ref name="Endocrine cognition" />  Short-term increases in cortisol levels are associated with adaptive cognitive improvements, such as enhanced inhibitory control;<ref name="Fitness mechanism" /><ref name="Exercise neuroendocrine effects" /><ref name="Endocrine cognition" /> however, excessively high exposure or prolonged exposure to high levels of cortisol causes impairments in cognitive control and has [[neurotoxic]] effects in the human brain.<ref name="Fitness mechanism" /><ref name="Executive functions" /><ref name="Endocrine cognition">{{vcite2 journal | vauthors = Ebner NC, Kamin H, Diaz V, Cohen RA, MacDonald K | title = Hormones as "difference makers" in cognitive and socioemotional aging processes | journal = Front Psychol | volume = 5 | issue = | pages = 1595 | date = January 2015 | pmid = 25657633 | pmc = 4302708 | doi = 10.3389/fpsyg.2014.01595 | quote =  It is known that chronically elevated levels of the stress hormone cortisol exert neurotoxic effects on the aging brain with negative impacts on cognition and socioemotional functioning.&nbsp;... Cortisol is a steroid hormone released by the HPA axis in response to challenging situations. As the primary effector of the biological stress response in humans, it is implicated in a diverse array of physiologic, metabolic, immunologic, and psychological processes directed toward successful coping (Sapolsky et al., 2000; Kassel and Herrlich, 2007). Cortisol receptors are well-represented in limbic structures involved in affective response (i.e., hippocampus, hypothalamus, amygdala) and in regions central to executive function such as the prefrontal cortex and anterior cingulate cortex (Dedovic et al., 2009; Joëls and Baram, 2009). As a result, the effects of cortisol extend beyond the stress and threat response system to impact mood, attention, and memory (Lupien and McEwen, 1997; Sapolsky et al., 2000; de Kloet et al., 2005).&nbsp;... In contrast, evidence indicated positive associations between cortisol levels that were acutely elevated by stress or hydrocortisone administration and inhibitory control (Schlosser et al., 2013) as well as spatial learning (Meyer et al., 2013). Regarding cortisol’s effect on memory, the evidence is currently mixed (Schwabe et al., 2012; van Ast et al., 2013).&nbsp;... There also is evidence that effects of cortisol on cognition vary in a dose-dependent fashion. In particular, there is evidence of cognitive improvements under conditions of moderate, time-limited cortisol elevation but evidence of cognitive impairments when cortisol concentrations are persistent or excessively high (Lupien et al., 1999; Abercrombie et al., 2003; Hupbach and Fieman, 2012; Schilling et al., 2013; Moriarty et al., 2014). }}</ref> For example, chronic psychological stress decreases {{abbr|BDNF|brain-derived neurotrophic factor}} expression which has detrimental effects on hippocampal volume and can lead to [[depression (mood)|depression]].<ref name="Fitness mechanism" /><ref name="NHM-Stress" />
+The "stress hormone", [[cortisol]], is a [[glucocorticoid]] that binds to [[glucocorticoid receptor]]s.<ref name="NHM-Stress" /><ref name="Exercise neuroendocrine effects" /><ref name="Endocrine cognition" /> [[Psychological stress]] induces the release of cortisol from the [[adrenal gland]] by activating the [[hypothalamic–pituitary–adrenal axis]] (HPA axis).<ref name="NHM-Stress">{{cite book | author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 350–359 | chapter = Chapter 14: Mood and Emotion | edition = 2nd | quote = The excessive release of stress hormones, such as cortisol, which occurs in many individuals with mood disorders, may result from hyperfunctioning of the PVN of the hypothalamus, hyperfunctioning of the amygdala (which activates the PVN), or hypofunctioning of the hippocampus (which exerts a potent inhibitory influence on the PVN).&nbsp;... Chronic stress decreases the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus, which in turn may contribute to the atrophy of CA3 neurons and their increased vulnerability to a variety of neuronal insults. Chronic elevation of glucocorticoid levels is also known to decrease the survival of these neurons. Such activity may increase the dendritic arborizations and survival of the neurons, or help repair or protect the neurons from further damage.&nbsp;... Stress and glucocorticoids inhibit, and a wide variety of antidepressant drugs, exercise, and enriched environments activate hippocampal neurogenesis.}}</ref><ref name="Exercise neuroendocrine effects">{{cite journal | vauthors = Fuqua JS, Rogol AD | title = Neuroendocrine alterations in the exercising human: implications for energy homeostasis | journal = Metab. Clin. Exp. | volume = 62 | issue = 7 | pages = 911–921 | date = July 2013 | pmid = 23415825 | doi = 10.1016/j.metabol.2013.01.016 | quote = Cortisol has wide-ranging effects, including alterations of carbohydrate, protein, and lipid metabolism; catabolic effects on skin, muscle, connective tissue, and bone; immunomodulatory effects; blood pressure and circulatory system regulation; and effects on mood and central nervous system function. In the short term, activation of the HPA axis in response to stress is adaptive. However, long-term stress promoting chronic exposure of tissues to high cortisol concentrations becomes maladaptive.&nbsp;... Exercise, particularly sustained aerobic activity, is a potent stimulus of cortisol secretion. The circulating concentrations of cortisol are directly proportional to the intensity of exercise as measured by oxygen uptake. As is the case for the GH/IGF-1 and HPG axes, the HPA axis also receives many other inputs, including the light/dark cycle, feeding schedules, immune regulation, and many neurotransmitters that mediate the effects of exercise and physical and psychic stress [52].&nbsp;... The HPA is activated by stress, whether physical (exercise) or psychological.&nbsp;...<!--energy balance – stress&cortisol HPA axis--> Thus, a negative net energy balance leads to activation of the HPA axis and the circulating concomitants of the catabolic state in an attempt to keep core processes functional, realizing that the stress of exercise has no effect on cortisol and circulating metabolic substrates beyond the impact of the exercise energy expenditure on energy availability [60]. Thuma et al. [61] had already made the important observation that the reported differences in cortisol levels pre- and post-exercise depended on whether this difference was measured from a single pre-test level or from the physiologic circadian baseline as determined in an independent session in the resting state. By this analytical technique, these investigators showed that increasing energy expenditure led to significant cortisol release. This release was apparent if they subtracted the physiologic circadian baseline from the post-exercise value.}}</ref><ref name="Endocrine cognition" />  Short-term increases in cortisol levels are associated with adaptive cognitive improvements, such as enhanced inhibitory control;<ref name="Fitness mechanism" /><ref name="Exercise neuroendocrine effects" /><ref name="Endocrine cognition" /> however, excessively high exposure or prolonged exposure to high levels of cortisol causes impairments in cognitive control and has [[neurotoxic]] effects in the human brain.<ref name="Fitness mechanism" /><ref name="Executive functions" /><ref name="Endocrine cognition">{{cite journal | vauthors = Ebner NC, Kamin H, Diaz V, Cohen RA, MacDonald K | title = Hormones as "difference makers" in cognitive and socioemotional aging processes | journal = Front Psychol | volume = 5 | issue = | pages = 1595 | date = January 2015 | pmid = 25657633 | pmc = 4302708 | doi = 10.3389/fpsyg.2014.01595 | quote =  It is known that chronically elevated levels of the stress hormone cortisol exert neurotoxic effects on the aging brain with negative impacts on cognition and socioemotional functioning.&nbsp;... Cortisol is a steroid hormone released by the HPA axis in response to challenging situations. As the primary effector of the biological stress response in humans, it is implicated in a diverse array of physiologic, metabolic, immunologic, and psychological processes directed toward successful coping (Sapolsky et al., 2000; Kassel and Herrlich, 2007). Cortisol receptors are well-represented in limbic structures involved in affective response (i.e., hippocampus, hypothalamus, amygdala) and in regions central to executive function such as the prefrontal cortex and anterior cingulate cortex (Dedovic et al., 2009; Joëls and Baram, 2009). As a result, the effects of cortisol extend beyond the stress and threat response system to impact mood, attention, and memory (Lupien and McEwen, 1997; Sapolsky et al., 2000; de Kloet et al., 2005).&nbsp;... In contrast, evidence indicated positive associations between cortisol levels that were acutely elevated by stress or hydrocortisone administration and inhibitory control (Schlosser et al., 2013) as well as spatial learning (Meyer et al., 2013). Regarding cortisol’s effect on memory, the evidence is currently mixed (Schwabe et al., 2012; van Ast et al., 2013).&nbsp;... There also is evidence that effects of cortisol on cognition vary in a dose-dependent fashion. In particular, there is evidence of cognitive improvements under conditions of moderate, time-limited cortisol elevation but evidence of cognitive impairments when cortisol concentrations are persistent or excessively high (Lupien et al., 1999; Abercrombie et al., 2003; Hupbach and Fieman, 2012; Schilling et al., 2013; Moriarty et al., 2014). }}</ref> For example, chronic psychological stress decreases {{abbr|BDNF|brain-derived neurotrophic factor}} expression which has detrimental effects on hippocampal volume and can lead to [[depression (mood)|depression]].<ref name="Fitness mechanism" /><ref name="NHM-Stress" />
 As a physical stressor, aerobic exercise stimulates cortisol secretion in an intensity-dependent manner;<ref name="Exercise neuroendocrine effects" /> however, it does not result in long-term increases in cortisol production since this exercise-induced effect on cortisol is a response to transient negative [[Energy homeostasis|energy balance]].{{#tag:ref|In healthy individuals, this energy deficit resolves simply from eating and drinking a sufficient amount of food and beverage after exercising.|group="note"}}<ref name="Exercise neuroendocrine effects" /> Individuals who have recently exercised exhibit improvements in stress coping behaviors.<ref name="epigenome" /><ref name="sports epigenetics" /><ref name="Fitness mechanism">{{cite journal | author = Silverman MN, Deuster PA | title = Biological mechanisms underlying the role of physical fitness in health and resilience | journal = Interface Focus | volume = 4 | issue = 5 | pages = 20140040 | date = October 2014 | pmid = 25285199 | doi = 10.1098/rsfs.2014.0040 | quote = Physical fitness, achieved through regular exercise and/or spontaneous physical activity, can protect against the development of chronic stress- and inflammatory-related disease by optimizing physiological and neuroendocrine stress responsivity, promoting an anti-inflammatory state, and enhancing neuroplasticity and growth factor expression. stress responsive systems are adaptive when activated and terminated in a timely manner, prolonged (or insufficient) activation of these systems can cause a variety of maladaptive responses.&nbsp;... For example, Rimelle et al. [123] documented significantly lower cortisol and heart rate responses to psychosocial stress (Trier social stress test) in trained men compared with untrained men. Moreover, significantly greater calmness and better mood, and a trend towards lower state anxiety, were noted in these trained men during the stress protocol.&nbsp;... Whereas hippocampal and/or serum/plasma BDNF levels are downregulated by chronic psychosocial stress and inflammation [138,180,201], central and peripheral BDNF levels can be upregulated by acute exercise [33,198,202,203].&nbsp;... Exercise-induced increases in brain monoamines (norepinephrine and serotonin) may also contribute to increased expression of hippocampal BDNF [194]. In addition, other growth factors—insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor—have been shown to play an important role in BDNF-induced effects on neuroplasticity [33,172,190,192], as well as exerting neuroprotective effects of their own [33,214,215], thereby contributing to the beneficial effects of exercise on brain health. Like BDNF, increases in circulating IGF-1 levels in response to acute exercise are only transient and possibly time-dependent as it relates to chronic training (i.e. increases seen after 12 weeks of training) [216].&nbsp;... Whereas reduced HPA axis reactivity to a given stressor has repeatedly been reported in physically fit individuals, the finding of reduced sympathetic reactivity is less consistent. }}</ref> Aerobic exercise increases [[physical fitness]] and lowers neuroendocrine (i.e., {{abbr|HPA axis|hypothalamic–pituitary–adrenal axis}}) reactivity and therefore reduces the biological response to psychological stress in humans (e.g., reduced cortisol release and attenuated [[heart rate]] response).<ref name="Fitness mechanism" /><ref name="Exercise mental disorders">{{cite journal | author = Zschucke E, Gaudlitz K, Ströhle A | title = Exercise and physical activity in mental disorders: clinical and experimental evidence | journal = J Prev Med Public Health | volume = 46 Suppl 1 | issue = | pages = S12–521 | date = January 2013 | pmid = 23412549 | pmc = 3567313 | doi = 10.3961/jpmph.2013.46.S.S12 | quote = In psychiatric patients, different mechanisms of action for {{abbr|PA|physical activity}} and {{abbr|EX|exercise}} have been discussed: On a neurochemical and physiological level, a number of acute changes occur during and following bouts of EX, and several long-term adaptations are related to regular EX training. For instance, EX has been found to normalize reduced levels of brain-derived neurotrophic factor (BDNF) and therefore has neuroprotective or even neurotrophic effects [7–9]. Animal studies found EX-induced changes in different neurotransmitters such as serotonin and endorphins [10,11], which relate to mood, and positive effects of EX on stress reactivity (e.g., the hypothalamus-pituitary-adrenal axis [12,13]). Finally, anxiolytic effects of EX mediated by atrial natriuretic peptide have been reported [14]. Potential psychological mechanisms of action include learning and extinction, changes in body scheme and health attitudes/behaviors, social reinforcement, experience of mastery, shift of external to more internal locus of control, improved coping strategies, or simple distraction [15,16]. }}</ref>  Exercise also reverses stress-induced decreases in {{abbr|BDNF|brain-derived neurotrophic factor}} expression and signaling in the brain, thereby acting as a buffer against stress-related diseases like depression.<ref name="Fitness mechanism" /><ref name="NHM-Stress" /><ref name="Exercise mental disorders" />
@@ Line 76: / Line 76: @@
 ===Euphoria===
 <!--Runner's high and Rower's high redirect here.  These terms are bolded per MOS:BOLD-->
-Continuous exercise can produce short-term [[euphoria]], an [[Affect (psychology)|affective state]] associated with feelings of profound contentment, elation, and well-being, which is colloquially known as a "'''runner's high'''" in [[distance running]] or a "'''rower's high'''" in [[Rowing (sport)|crew]].<ref name="Primary-Runner's high definition">{{vcite2 journal | vauthors = Raichlen DA, Foster AD, Gerdeman GL, Seillier A, Giuffrida A | title = Wired to run: exercise-induced endocannabinoid signaling in humans and cursorial mammals with implications for the 'runner's high' | journal = J. Exp. Biol. | volume = 215 | issue = Pt 8 | pages = 1331–6 | year = 2012 | pmid = 22442371 | doi = 10.1242/jeb.063677 | quote = Humans report a wide range of neurobiological rewards following moderate and intense aerobic activity, popularly referred to as the 'runner's high', which may function to encourage habitual aerobic exercise.&nbsp;... Thus, a neurobiological reward for endurance exercise may explain why humans and other cursorial mammals habitually engage in aerobic exercise despite the higher associated energy costs and injury risks}}</ref><ref name="Primary-Rower's high definition">{{vcite2 journal | vauthors = Cohen EE, Ejsmond-Frey R, Knight N, Dunbar RI | title = Rowers' high: behavioural synchrony is correlated with elevated pain thresholds | journal = Biol. Lett. | volume = 6 | issue = 1 | pages = 106–8 | year = 2010 | pmid = 19755532 | pmc = 2817271 | doi = 10.1098/rsbl.2009.0670 |url=}}</ref>  Current medical reviews indicate that several endogenous [[euphoriant]]s are responsible for producing exercise-related euphoria, specifically [[phenethylamine]] (a [[stimulant]]), [[β-endorphin]] (an [[opioid]]), and [[anandamide]] (a [[cannabinoid]]).<ref name="PEA exercise primary" /><ref name="Renaissance" /><ref name="Neuropsychiatric" /><ref name="Endorphin" /><ref name="endocannabinoids" />
+Continuous exercise can produce short-term [[euphoria]], an [[Affect (psychology)|affective state]] associated with feelings of profound contentment, elation, and well-being, which is colloquially known as a "'''runner's high'''" in [[distance running]] or a "'''rower's high'''" in [[Rowing (sport)|crew]].<ref name="Primary-Runner's high definition">{{cite journal | vauthors = Raichlen DA, Foster AD, Gerdeman GL, Seillier A, Giuffrida A | title = Wired to run: exercise-induced endocannabinoid signaling in humans and cursorial mammals with implications for the 'runner's high' | journal = J. Exp. Biol. | volume = 215 | issue = Pt 8 | pages = 1331–6 | year = 2012 | pmid = 22442371 | doi = 10.1242/jeb.063677 | quote = Humans report a wide range of neurobiological rewards following moderate and intense aerobic activity, popularly referred to as the 'runner's high', which may function to encourage habitual aerobic exercise.&nbsp;... Thus, a neurobiological reward for endurance exercise may explain why humans and other cursorial mammals habitually engage in aerobic exercise despite the higher associated energy costs and injury risks}}</ref><ref name="Primary-Rower's high definition">{{cite journal | vauthors = Cohen EE, Ejsmond-Frey R, Knight N, Dunbar RI | title = Rowers' high: behavioural synchrony is correlated with elevated pain thresholds | journal = Biol. Lett. | volume = 6 | issue = 1 | pages = 106–8 | year = 2010 | pmid = 19755532 | pmc = 2817271 | doi = 10.1098/rsbl.2009.0670 |url=}}</ref>  Current medical reviews indicate that several endogenous [[euphoriant]]s are responsible for producing exercise-related euphoria, specifically [[phenethylamine]] (a [[stimulant]]), [[β-endorphin]] (an [[opioid]]), and [[anandamide]] (a [[cannabinoid]]).<ref name="PEA exercise primary" /><ref name="Renaissance" /><ref name="Neuropsychiatric" /><ref name="Endorphin" /><ref name="endocannabinoids" />
 ===Neurotransmitters, neuromodulators, and neuropeptides===
@@ Line 83: / Line 83: @@
 {{see also|Phenethylamine#Pharmacology}}
-[[β-Phenylethylamine]], commonly referred to as phenethylamine, is a potent endogenous [[trace amine]] [[neuromodulator]] which has the same [[biomolecular target]]s as [[amphetamine]];<ref name="PEA">{{cite web|title=β-phenylethylamine: Biological activity|url=http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=2144|website=Guide to Pharmacology|publisher=The International Union  of Basic and Clinical Pharmacology|accessdate=10 February 2015}}</ref><ref name="Amph">{{cite web|title=Dexamfetamine: Biological activity|url=http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=2147|website=Guide to Pharmacology|publisher=The International Union  of Basic and Clinical Pharmacology|accessdate=10 February 2015}}</ref> consequently, both compounds interact with monoamine neurons in the [[central nervous system]] in an identical manner. Thirty minutes of moderate to high intensity physical exercise has been shown to induce an enormous increase in urinary [[β-phenylacetic acid]], the primary metabolite of phenethylamine.<ref name="PEA exercise primary">{{vcite2 journal | vauthors = Szabo A, Billett E, Turner J | title = Phenylethylamine, a possible link to the antidepressant effects of exercise? | journal = Br J Sports Med | volume = 35 | issue = 5 | pages = 342–343 | year = 2001 | pmid = 11579070 | pmc = 1724404 | doi = 10.1136/bjsm.35.5.342| quote = The 24 hour mean urinary concentration of phenylacetic acid was increased by 77% after exercise.&nbsp;... These results show substantial increases in urinary phenylacetic acid levels 24 hours after moderate to high intensity aerobic exercise. As phenylacetic acid reflects phenylethylamine levels<sup>3</sup> , and the latter has antidepressant effects, the antidepressant effects of exercise appear to be linked to increased phenylethylamine concentrations. Furthermore, considering the structural and pharmacological analogy between amphetamines and phenylethylamine, it is conceivable that phenylethylamine plays a role in the commonly reported "runners high" thought to be linked to cerebral β-endorphin activity. The substantial increase in phenylacetic acid excretion in this study implies that phenylethylamine levels are affected by exercise.&nbsp;... A 30 minute bout of moderate to high intensity aerobic exercise increases phenylacetic acid levels in healthy regularly exercising men. The findings may be linked to the antidepressant effects of exercise.}}</ref><ref name="Renaissance">{{vcite2 journal | vauthors = Lindemann L, Hoener MC | title = A renaissance in trace amines inspired by a novel GPCR family | journal = Trends Pharmacol. Sci. | volume = 26 | issue = 5 | pages = 274–281 | year = 2005 | pmid = 15860375 | doi = 10.1016/j.tips.2005.03.007 | quote = The pharmacology of TAs might also contribute to a molecular understanding of the well-recognized antidepressant effect of physical exercise [51]. In addition to the various beneficial effects for brain function mainly attributed to an upregulation of peptide growth factors [52,53], exercise induces a rapidly enhanced excretion of the main β-PEA metabolite β-phenylacetic acid (b-PAA) by on average 77%, compared with resting control subjects [54], which mirrors increased β-PEA synthesis in view of its limited endogenous pool half-life of ~30 s [18,55].}}</ref><ref name="Neuropsychiatric">{{vcite2 journal | vauthors = Berry MD | title = The potential of trace amines and their receptors for treating neurological and psychiatric diseases | journal = Rev Recent Clin Trials | volume = 2 | issue = 1 | pages = 3–19 | year = 2007 | pmid = 18473983 | doi = 10.2174/157488707779318107| quote = It has also been suggested that the antidepressant effects of exercise are due to an exercise-induced elevation of PE [151].}}</ref> Two reviews noted a study where the mean 24&nbsp;hour urinary β-phenylacetic acid concentration following just 30&nbsp;minutes of intense exercise rose 77% above its base level;<ref name="PEA exercise primary" /><ref name="Renaissance" /><ref name="Neuropsychiatric" /> the reviews suggest that phenethylamine synthesis sharply increases during physical exercise during which it is rapidly metabolized due to its short half-life of roughly 30&nbsp;seconds.<ref name="PEA exercise primary" /><ref name="Renaissance" /><ref name="Neuropsychiatric" /><ref name="Vascular" /> In a resting state, phenethylamine is synthesized in [[catecholamine]] neurons from {{smallcaps all|L}}-[[phenylalanine]] by [[aromatic amino acid decarboxylase]] at approximately the same rate at which dopamine is produced.<ref name="Vascular">{{cite journal | author = Broadley KJ | title = The vascular effects of trace amines and amphetamines | journal = Pharmacol. Ther. | volume = 125 | issue = 3 | pages = 363–375 |date=March 2010 | pmid = 19948186 | doi = 10.1016/j.pharmthera.2009.11.005 | quote= Trace amines are metabolized in the mammalian body via monoamine oxidase (MAO; EC 1.4.3.4) (Berry, 2004) (Fig. 2)&nbsp;... It deaminates primary and secondary amines that are free in the neuronal cytoplasm but not those bound in storage vesicles of the sympathetic neurone&nbsp;... Similarly, β-PEA would not be deaminated in the gut as it is a selective substrate for MAO-B which is not found in the gut&nbsp;...<br /> Brain levels of endogenous trace amines are several hundred-fold below those for the classical neurotransmitters noradrenaline, dopamine and serotonin but their rates of synthesis are equivalent to those of noradrenaline and dopamine and they have a very rapid turnover rate (Berry, 2004). Endogenous extracellular tissue levels of trace amines measured in the brain are in the low nanomolar range. These low concentrations arise because of their very short half-life&nbsp;...}}</ref>
+[[β-Phenylethylamine]], commonly referred to as phenethylamine, is a potent endogenous [[trace amine]] [[neuromodulator]] which has the same [[biomolecular target]]s as [[amphetamine]];<ref name="PEA">{{cite web|title=β-phenylethylamine: Biological activity|url=http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=2144|website=Guide to Pharmacology|publisher=The International Union  of Basic and Clinical Pharmacology|accessdate=10 February 2015}}</ref><ref name="Amph">{{cite web|title=Dexamfetamine: Biological activity|url=http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=2147|website=Guide to Pharmacology|publisher=The International Union  of Basic and Clinical Pharmacology|accessdate=10 February 2015}}</ref> consequently, both compounds interact with monoamine neurons in the [[central nervous system]] in an identical manner. Thirty minutes of moderate to high intensity physical exercise has been shown to induce an enormous increase in urinary [[β-phenylacetic acid]], the primary metabolite of phenethylamine.<ref name="PEA exercise primary">{{cite journal | vauthors = Szabo A, Billett E, Turner J | title = Phenylethylamine, a possible link to the antidepressant effects of exercise? | journal = Br J Sports Med | volume = 35 | issue = 5 | pages = 342–343 | year = 2001 | pmid = 11579070 | pmc = 1724404 | doi = 10.1136/bjsm.35.5.342| quote = The 24 hour mean urinary concentration of phenylacetic acid was increased by 77% after exercise.&nbsp;... These results show substantial increases in urinary phenylacetic acid levels 24 hours after moderate to high intensity aerobic exercise. As phenylacetic acid reflects phenylethylamine levels<sup>3</sup> , and the latter has antidepressant effects, the antidepressant effects of exercise appear to be linked to increased phenylethylamine concentrations. Furthermore, considering the structural and pharmacological analogy between amphetamines and phenylethylamine, it is conceivable that phenylethylamine plays a role in the commonly reported "runners high" thought to be linked to cerebral β-endorphin activity. The substantial increase in phenylacetic acid excretion in this study implies that phenylethylamine levels are affected by exercise.&nbsp;... A 30 minute bout of moderate to high intensity aerobic exercise increases phenylacetic acid levels in healthy regularly exercising men. The findings may be linked to the antidepressant effects of exercise.}}</ref><ref name="Renaissance">{{cite journal | vauthors = Lindemann L, Hoener MC | title = A renaissance in trace amines inspired by a novel GPCR family | journal = Trends Pharmacol. Sci. | volume = 26 | issue = 5 | pages = 274–281 | year = 2005 | pmid = 15860375 | doi = 10.1016/j.tips.2005.03.007 | quote = The pharmacology of TAs might also contribute to a molecular understanding of the well-recognized antidepressant effect of physical exercise [51]. In addition to the various beneficial effects for brain function mainly attributed to an upregulation of peptide growth factors [52,53], exercise induces a rapidly enhanced excretion of the main β-PEA metabolite β-phenylacetic acid (b-PAA) by on average 77%, compared with resting control subjects [54], which mirrors increased β-PEA synthesis in view of its limited endogenous pool half-life of ~30 s [18,55].}}</ref><ref name="Neuropsychiatric">{{cite journal | vauthors = Berry MD | title = The potential of trace amines and their receptors for treating neurological and psychiatric diseases | journal = Rev Recent Clin Trials | volume = 2 | issue = 1 | pages = 3–19 | year = 2007 | pmid = 18473983 | doi = 10.2174/157488707779318107| quote = It has also been suggested that the antidepressant effects of exercise are due to an exercise-induced elevation of PE [151].}}</ref> Two reviews noted a study where the mean 24&nbsp;hour urinary β-phenylacetic acid concentration following just 30&nbsp;minutes of intense exercise rose 77% above its base level;<ref name="PEA exercise primary" /><ref name="Renaissance" /><ref name="Neuropsychiatric" /> the reviews suggest that phenethylamine synthesis sharply increases during physical exercise during which it is rapidly metabolized due to its short half-life of roughly 30&nbsp;seconds.<ref name="PEA exercise primary" /><ref name="Renaissance" /><ref name="Neuropsychiatric" /><ref name="Vascular" /> In a resting state, phenethylamine is synthesized in [[catecholamine]] neurons from {{smallcaps all|L}}-[[phenylalanine]] by [[aromatic amino acid decarboxylase]] at approximately the same rate at which dopamine is produced.<ref name="Vascular">{{cite journal | author = Broadley KJ | title = The vascular effects of trace amines and amphetamines | journal = Pharmacol. Ther. | volume = 125 | issue = 3 | pages = 363–375 |date=March 2010 | pmid = 19948186 | doi = 10.1016/j.pharmthera.2009.11.005 | quote= Trace amines are metabolized in the mammalian body via monoamine oxidase (MAO; EC 1.4.3.4) (Berry, 2004) (Fig. 2)&nbsp;... It deaminates primary and secondary amines that are free in the neuronal cytoplasm but not those bound in storage vesicles of the sympathetic neurone&nbsp;... Similarly, β-PEA would not be deaminated in the gut as it is a selective substrate for MAO-B which is not found in the gut&nbsp;...<br /> Brain levels of endogenous trace amines are several hundred-fold below those for the classical neurotransmitters noradrenaline, dopamine and serotonin but their rates of synthesis are equivalent to those of noradrenaline and dopamine and they have a very rapid turnover rate (Berry, 2004). Endogenous extracellular tissue levels of trace amines measured in the brain are in the low nanomolar range. These low concentrations arise because of their very short half-life&nbsp;...}}</ref>
 In light of this observation, the original paper and both reviews suggest that phenethylamine plays a prominent role in mediating the mood-enhancing [[euphoria|euphoric]] effects of a runner's high, as both phenethylamine and amphetamine are potent [[euphoriant]]s.<ref name="PEA exercise primary" /><ref name="Renaissance" /><ref name="Neuropsychiatric" />
@@ Line 89: / Line 89: @@
 ====β-Endorphin====
-[[β-Endorphin]]s (contracted from "endogenous morphine") are endogenous [[opioid]] [[neuropeptide]]s that bind to [[μ-opioid receptor]]s, in turn producing [[euphoria]] and [[analgesia|pain relief]].<ref name="Endorphin">{{vcite2 journal | vauthors = Dinas PC, Koutedakis Y, Flouris AD | title = Effects of exercise and physical activity on depression | journal = Ir J Med Sci | volume = 180 | issue = 2 | pages = 319–325 | year = 2011 | pmid = 21076975 | doi = 10.1007/s11845-010-0633-9 | quote = According to the 'endorphins hypothesis', exercise augments the secretion of endogenous opioid peptides in the brain, reducing pain and causing general euphoria.&nbsp;... Based upon a large effect size, the results confirmed the endorphins hypothesis demonstrating that exercise leads to an increased secretion of endorphins which, in turn, improved mood states.<br />β-Endorphin, an endogenous μ-opioid receptor selective ligand, has received much attention in the literature linking endorphins and depression or mood states.&nbsp;... exercise of sufficient intensity and duration can increase circulating β-endorphin levels.&nbsp;... Moreover, a recent study demonstrated that exercise and physical activity increased β-endorphin levels in plasma with positive effects on mood.  Interestingly, the researchers reported that, independently of sex and age, dynamic anaerobic exercises increased β-endorphin, while resistance and aerobic exercises seem to only have small effects on β-endorphins.&nbsp;... The results showed that mood tends to be higher in a day an individual exercises as well as that daily activity and exercise overall are strongly linked with mood states.  In line with these findings, a recent study showed that exercise significantly improved mood states in non-exercises, recreational exercisers, as well as marathon runners.  More importantly, the effects of exercise on mood were twofold in recreational exercisers and marathon runners.}}</ref> A [[meta-analytic]] review found that exercise significantly increases the secretion of β-endorphins and that this secretion is correlated with improved mood states.<ref name="Endorphin" />  Moderate intensity exercise produces the greatest increase in β-endorphin synthesis, while higher and lower intensity forms of exercise are associated with smaller increases in β-endorphin synthesis.<ref name="Endorphin" />
+[[β-Endorphin]]s (contracted from "endogenous morphine") are endogenous [[opioid]] [[neuropeptide]]s that bind to [[μ-opioid receptor]]s, in turn producing [[euphoria]] and [[analgesia|pain relief]].<ref name="Endorphin">{{cite journal | vauthors = Dinas PC, Koutedakis Y, Flouris AD | title = Effects of exercise and physical activity on depression | journal = Ir J Med Sci | volume = 180 | issue = 2 | pages = 319–325 | year = 2011 | pmid = 21076975 | doi = 10.1007/s11845-010-0633-9 | quote = According to the 'endorphins hypothesis', exercise augments the secretion of endogenous opioid peptides in the brain, reducing pain and causing general euphoria.&nbsp;... Based upon a large effect size, the results confirmed the endorphins hypothesis demonstrating that exercise leads to an increased secretion of endorphins which, in turn, improved mood states.<br />β-Endorphin, an endogenous μ-opioid receptor selective ligand, has received much attention in the literature linking endorphins and depression or mood states.&nbsp;... exercise of sufficient intensity and duration can increase circulating β-endorphin levels.&nbsp;... Moreover, a recent study demonstrated that exercise and physical activity increased β-endorphin levels in plasma with positive effects on mood.  Interestingly, the researchers reported that, independently of sex and age, dynamic anaerobic exercises increased β-endorphin, while resistance and aerobic exercises seem to only have small effects on β-endorphins.&nbsp;... The results showed that mood tends to be higher in a day an individual exercises as well as that daily activity and exercise overall are strongly linked with mood states.  In line with these findings, a recent study showed that exercise significantly improved mood states in non-exercises, recreational exercisers, as well as marathon runners.  More importantly, the effects of exercise on mood were twofold in recreational exercisers and marathon runners.}}</ref> A [[meta-analytic]] review found that exercise significantly increases the secretion of β-endorphins and that this secretion is correlated with improved mood states.<ref name="Endorphin" />  Moderate intensity exercise produces the greatest increase in β-endorphin synthesis, while higher and lower intensity forms of exercise are associated with smaller increases in β-endorphin synthesis.<ref name="Endorphin" />
 A review on β-endorphins and exercise noted that an individual's mood improves for the remainder of the day following physical exercise and that one's mood is positively correlated with overall daily physical activity level.<ref name="Endorphin" /> Exercise-induced improvements in mood occur in [[sedentary lifestyle|sedentary individuals]], recreational exercisers, and marathoner runners, but recreational athletes and marathon runners experience more pronounced mood-lifting effects from exercising.<ref name="Endorphin" />
@@ Line 95: / Line 95: @@
 ====Anandamide====
-[[Anandamide]] is an [[endocannabinoid|endogenous cannabinoid]] neurotransmitter that binds to [[cannabinoid receptor]]s.<ref name="endocannabinoids">{{vcite2 journal | vauthors = Tantimonaco M, Ceci R, Sabatini S, Catani MV, Rossi A, Gasperi V, Maccarrone M | title = Physical activity and the endocannabinoid system: an overview | journal = Cell. Mol. Life Sci. | volume = 71 | issue = 14 | pages = 2681–2698 | year = 2014 | pmid = 24526057 | doi = 10.1007/s00018-014-1575-6 | quote = The traditional view that {{abbr|PA|physical activity}} engages the monoaminergic and endorphinergic systems has been challenged by the discovery of the endocannabinoid system (ECS), composed of endogenous lipids, their target receptors, and metabolic enzymes. Indeed, direct and indirect evidence suggests that the {{abbr|ECS|endocannabinoid system}} might mediate some of the {{abbr|PA|physical activity}}-triggered effects throughout the body.&nbsp;... the evidence that {{abbr|PA|physical activity}} induces some of the psychotropic effects elicited by the Cannabis sativa active ingredient Δ9-tetrahydrocannabinol (Δ9-THC, Fig. 1), like bliss, euphoria, and peacefulness, strengthened the hypothesis that endocannabinoids (eCBs) might mediate, at least in part, the central and peripheral effects of exercise [14].&nbsp;... To our knowledge, the first experimental study aimed at investigating the influence of PA on ECS in humans was carried out in 2003 by Sparling and coworkers [63], who showed increased plasma {{abbr|AEA|anandamide}} content after 45 min of moderate intensity exercise on a treadmill or cycle ergometer. Since then, other human studies have shown increased blood concentrations of {{abbr|AEA|anandamide}}&nbsp;... A dependence of the increase of {{abbr|AEA|anandamide}} concentration on exercise intensity has also been documented. Plasma levels of {{abbr|AEA|anandamide}} significantly increased upon 30 min of moderate exercise (heart rate of 72 and 83 %), but not at lower and significantly higher exercise intensities, where the age-adjusted maximal heart rate was 44 and 92 %, respectively&nbsp;... Several experimental data support the hypothesis that ECS might, at least in part, explain PA effects on brain functions, because: (1) CB1 is the most abundant GPCR in the brain participating in neuronal plasticity [18]; (2) {{abbr|eCBs|endocannabinoids}} are involved in several brain responses that greatly overlap with the positive effects of exercise; (3) {{abbr|eCBs|endocannabinoids}} are able to cross the blood–brain barrier [95]; and (4) exercise increases {{abbr|eCB|endocannabinoid}} plasma levels [64–67].}}</ref> It has been shown that aerobic exercise causes an increase in plasma anandamide levels, where the magnitude of this increase is highest at moderate exercise intensity (i.e., exercising at ~70–80%&nbsp;maximum heart rate).<ref name="endocannabinoids" /> Increases in plasma anandamide levels are associated with psychoactive effects because anandamide is able to cross the [[blood–brain barrier]] and act within the central nervous system.<ref name="endocannabinoids" /> Thus, because anandamide is a euphoriant and aerobic exercise is associated with euphoric effects, it has been proposed that anandamide partly mediates the short-term mood-lifting effects of exercise (e.g., the euphoria of a runner's high) via exercise-induced increases in its synthesis.<ref name="Primary-Runner's high definition" /><ref name="endocannabinoids" />
+[[Anandamide]] is an [[endocannabinoid|endogenous cannabinoid]] neurotransmitter that binds to [[cannabinoid receptor]]s.<ref name="endocannabinoids">{{cite journal | vauthors = Tantimonaco M, Ceci R, Sabatini S, Catani MV, Rossi A, Gasperi V, Maccarrone M | title = Physical activity and the endocannabinoid system: an overview | journal = Cell. Mol. Life Sci. | volume = 71 | issue = 14 | pages = 2681–2698 | year = 2014 | pmid = 24526057 | doi = 10.1007/s00018-014-1575-6 | quote = The traditional view that {{abbr|PA|physical activity}} engages the monoaminergic and endorphinergic systems has been challenged by the discovery of the endocannabinoid system (ECS), composed of endogenous lipids, their target receptors, and metabolic enzymes. Indeed, direct and indirect evidence suggests that the {{abbr|ECS|endocannabinoid system}} might mediate some of the {{abbr|PA|physical activity}}-triggered effects throughout the body.&nbsp;... the evidence that {{abbr|PA|physical activity}} induces some of the psychotropic effects elicited by the Cannabis sativa active ingredient Δ9-tetrahydrocannabinol (Δ9-THC, Fig. 1), like bliss, euphoria, and peacefulness, strengthened the hypothesis that endocannabinoids (eCBs) might mediate, at least in part, the central and peripheral effects of exercise [14].&nbsp;... To our knowledge, the first experimental study aimed at investigating the influence of PA on ECS in humans was carried out in 2003 by Sparling and coworkers [63], who showed increased plasma {{abbr|AEA|anandamide}} content after 45 min of moderate intensity exercise on a treadmill or cycle ergometer. Since then, other human studies have shown increased blood concentrations of {{abbr|AEA|anandamide}}&nbsp;... A dependence of the increase of {{abbr|AEA|anandamide}} concentration on exercise intensity has also been documented. Plasma levels of {{abbr|AEA|anandamide}} significantly increased upon 30 min of moderate exercise (heart rate of 72 and 83 %), but not at lower and significantly higher exercise intensities, where the age-adjusted maximal heart rate was 44 and 92 %, respectively&nbsp;... Several experimental data support the hypothesis that ECS might, at least in part, explain PA effects on brain functions, because: (1) CB1 is the most abundant GPCR in the brain participating in neuronal plasticity [18]; (2) {{abbr|eCBs|endocannabinoids}} are involved in several brain responses that greatly overlap with the positive effects of exercise; (3) {{abbr|eCBs|endocannabinoids}} are able to cross the blood–brain barrier [95]; and (4) exercise increases {{abbr|eCB|endocannabinoid}} plasma levels [64–67].}}</ref> It has been shown that aerobic exercise causes an increase in plasma anandamide levels, where the magnitude of this increase is highest at moderate exercise intensity (i.e., exercising at ~70–80%&nbsp;maximum heart rate).<ref name="endocannabinoids" /> Increases in plasma anandamide levels are associated with psychoactive effects because anandamide is able to cross the [[blood–brain barrier]] and act within the central nervous system.<ref name="endocannabinoids" /> Thus, because anandamide is a euphoriant and aerobic exercise is associated with euphoric effects, it has been proposed that anandamide partly mediates the short-term mood-lifting effects of exercise (e.g., the euphoria of a runner's high) via exercise-induced increases in its synthesis.<ref name="Primary-Runner's high definition" /><ref name="endocannabinoids" />
 ====Classical monoamines====
@@ Line 103: / Line 103: @@
 ====Glutamate====
-[[Glutamate]], one of the most common neurochemicals in the brain, is an excitatory neurotransmitter involved in many aspects of brain function, including learning and memory.<ref name="NHM-glutamate">{{cite book | author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 117–130  | edition = 2nd | chapter = Chapter 5: Excitatory and Inhibitory Amino Acids | quote= {{bull}} The major excitatory neurotransmitter in the brain is glutamate; the major inhibitory neurotransmitter is GABA.&nbsp;...<br />{{bull}} The most extensively studied form of synaptic plasticity is long-term potentiation (LTP) in the hippocampus, which is triggered by strong activation of NMDA receptors and the consequent large rise in postsynaptic calcium concentration.<br />{{bull}} Long-term depression (LTD), a long-lasting decrease in synaptic strength, also occurs at most excitatory and some inhibitory synapses in the brain.&nbsp;... The bidirectional control of synaptic strength by LTP and LTD is believed to underlie some forms of learning and memory in the mammalian brain.}}</ref> Glutamate regulates certain exercise-related memory processes primarily via [[cotransmission]] with dopamine in the [[dopaminergic projection]]s from the [[ventral tegmental area#Outputs|ventral tegmental area]];<ref name="Glutamate-dopamine cotransmission review"><!--Note: this is a review of literature according to the article text (not pubmed)-->{{vcite2 journal | vauthors = Broussard JI | title = Co-transmission of dopamine and glutamate | journal = J. Gen. Physiol. | volume = 139 | issue = 1 | pages = 93–6 | year = 2012 | pmid = 22200950 | pmc = 3250102 | doi = 10.1085/jgp.201110659 | quote = Coincident and convergent input often induces plasticity on a postsynaptic neuron. The {{abbr|NAc|nucleus accumbens}} integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.}}</ref><ref name="Glutamate-dopamine cotransmission review 2">{{vcite2 journal | vauthors = Descarries L, Bérubé-Carrière N, Riad M, Bo GD, Mendez JA, Trudeau LE | title = Glutamate in dopamine neurons: synaptic versus diffuse transmission | journal = Brain Res Rev | volume = 58 | issue = 2 | pages = 290–302 | year = 2008 | pmid = 18042492 | doi = 10.1016/j.brainresrev.2007.10.005 | quote = Moreover, all {{abbr|TH|tyrosine hydroxylase}} varicosities which co-localize VGluT2 are synaptic, as if there was a link between the potential of {{abbr|DA|dopamine}} axon terminals to release glutamate and their establishment of synaptic junctions. Together with the RT-PCR and in situ hybridization data demonstrating the co-localization of TH and VGluT2 mRNA in mesencephalic neurons of the {{abbr|VTA|ventral tegmental area}}, these observations raise a number of fundamental questions regarding the functioning of the meso-telencephalic DA system in healthy or diseased brain. }}</ref> in particular, exercise has been shown to modulate (normalize) glutamatergic cotransmission in the [[mesocorticolimbic pathway|mesocorticolimbic dopamine pathway]].<ref name="Running vs addiction" />
+[[Glutamate]], one of the most common neurochemicals in the brain, is an excitatory neurotransmitter involved in many aspects of brain function, including learning and memory.<ref name="NHM-glutamate">{{cite book | author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 117–130  | edition = 2nd | chapter = Chapter 5: Excitatory and Inhibitory Amino Acids | quote= {{bull}} The major excitatory neurotransmitter in the brain is glutamate; the major inhibitory neurotransmitter is GABA.&nbsp;...<br />{{bull}} The most extensively studied form of synaptic plasticity is long-term potentiation (LTP) in the hippocampus, which is triggered by strong activation of NMDA receptors and the consequent large rise in postsynaptic calcium concentration.<br />{{bull}} Long-term depression (LTD), a long-lasting decrease in synaptic strength, also occurs at most excitatory and some inhibitory synapses in the brain.&nbsp;... The bidirectional control of synaptic strength by LTP and LTD is believed to underlie some forms of learning and memory in the mammalian brain.}}</ref> Glutamate regulates certain exercise-related memory processes primarily via [[cotransmission]] with dopamine in the [[dopaminergic projection]]s from the [[ventral tegmental area#Outputs|ventral tegmental area]];<ref name="Glutamate-dopamine cotransmission review"><!--Note: this is a review of literature according to the article text (not pubmed)-->{{cite journal | vauthors = Broussard JI | title = Co-transmission of dopamine and glutamate | journal = J. Gen. Physiol. | volume = 139 | issue = 1 | pages = 93–6 | year = 2012 | pmid = 22200950 | pmc = 3250102 | doi = 10.1085/jgp.201110659 | quote = Coincident and convergent input often induces plasticity on a postsynaptic neuron. The {{abbr|NAc|nucleus accumbens}} integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.}}</ref><ref name="Glutamate-dopamine cotransmission review 2">{{cite journal | vauthors = Descarries L, Bérubé-Carrière N, Riad M, Bo GD, Mendez JA, Trudeau LE | title = Glutamate in dopamine neurons: synaptic versus diffuse transmission | journal = Brain Res Rev | volume = 58 | issue = 2 | pages = 290–302 | year = 2008 | pmid = 18042492 | doi = 10.1016/j.brainresrev.2007.10.005 | quote = Moreover, all {{abbr|TH|tyrosine hydroxylase}} varicosities which co-localize VGluT2 are synaptic, as if there was a link between the potential of {{abbr|DA|dopamine}} axon terminals to release glutamate and their establishment of synaptic junctions. Together with the RT-PCR and in situ hybridization data demonstrating the co-localization of TH and VGluT2 mRNA in mesencephalic neurons of the {{abbr|VTA|ventral tegmental area}}, these observations raise a number of fundamental questions regarding the functioning of the meso-telencephalic DA system in healthy or diseased brain. }}</ref> in particular, exercise has been shown to modulate (normalize) glutamatergic cotransmission in the [[mesocorticolimbic pathway|mesocorticolimbic dopamine pathway]].<ref name="Running vs addiction" />
 ==Children==
@@ Line 118: / Line 118: @@
 ===Alzheimer's disease===
-[[Alzheimer's Disease]] is a cortical neurodegenerative disorder and the most prevalent form of [[dementia]], representing approximately 65% of all cases of dementia; it is characterized by impaired cognitive function, behavioral abnormalities, and a reduced capacity to perform [[Activities of daily living|basic activities of daily life]].<ref name="Alz 1">{{vcite2 journal | vauthors = Farina N, Rusted J, Tabet N | title = The effect of exercise interventions on cognitive outcome in Alzheimer's disease: a systematic review | journal = Int Psychogeriatr | volume = 26 | issue = 1 | pages = 9–18 | date = January 2014 | pmid = 23962667 | doi = 10.1017/S1041610213001385 | quote = Six RCTs were identified that exclusively considered the effect of exercise in AD patients. Exercise generally had a positive effect on rate of cognitive decline in AD. A meta-analysis found that exercise interventions have a positive effect on global cognitive function, 0.75 (95% CI = 0.32–1.17).&nbsp;... The most prevalent subtype of dementia is Alzheimer’s disease (AD), accounting for up to 65.0% of all dementia cases&nbsp;... Cognitive decline in AD is attributable at least in part to the buildup of amyloid and tau proteins, which promote neuronal dysfunction and death (Hardy and Selkoe, 2002; Karran et al., 2011). Evidence in transgenic mouse models of AD, in which the mice have artificially elevated amyloid load, suggests that exercise programs are able to improve cognitive function (Adlard et al., 2005; Nichol et al., 2007). Adlard and colleagues also determined that the improvement in cognitive performance occurred in conjunction with a reduced amyloid load. Research that includes direct indices of change in such biomarkers will help to determine the mechanisms by which exercise may act on cognition in AD.}}</ref><!--
+[[Alzheimer's Disease]] is a cortical neurodegenerative disorder and the most prevalent form of [[dementia]], representing approximately 65% of all cases of dementia; it is characterized by impaired cognitive function, behavioral abnormalities, and a reduced capacity to perform [[Activities of daily living|basic activities of daily life]].<ref name="Alz 1">{{cite journal | vauthors = Farina N, Rusted J, Tabet N | title = The effect of exercise interventions on cognitive outcome in Alzheimer's disease: a systematic review | journal = Int Psychogeriatr | volume = 26 | issue = 1 | pages = 9–18 | date = January 2014 | pmid = 23962667 | doi = 10.1017/S1041610213001385 | quote = Six RCTs were identified that exclusively considered the effect of exercise in AD patients. Exercise generally had a positive effect on rate of cognitive decline in AD. A meta-analysis found that exercise interventions have a positive effect on global cognitive function, 0.75 (95% CI = 0.32–1.17).&nbsp;... The most prevalent subtype of dementia is Alzheimer’s disease (AD), accounting for up to 65.0% of all dementia cases&nbsp;... Cognitive decline in AD is attributable at least in part to the buildup of amyloid and tau proteins, which promote neuronal dysfunction and death (Hardy and Selkoe, 2002; Karran et al., 2011). Evidence in transgenic mouse models of AD, in which the mice have artificially elevated amyloid load, suggests that exercise programs are able to improve cognitive function (Adlard et al., 2005; Nichol et al., 2007). Adlard and colleagues also determined that the improvement in cognitive performance occurred in conjunction with a reduced amyloid load. Research that includes direct indices of change in such biomarkers will help to determine the mechanisms by which exercise may act on cognition in AD.}}</ref><!--
---><ref name="Alz 2">{{vcite2 journal | vauthors = Rao AK, Chou A, Bursley B, Smulofsky J, Jezequel J | title = Systematic review of the effects of exercise on activities of daily living in people with Alzheimer's disease | journal = Am J Occup Ther | volume = 68 | issue = 1 | pages = 50–56 | date = January 2014 | pmid = 24367955 | doi = 10.5014/ajot.2014.009035 | quote = Alzheimer’s disease (AD) is a progressive neurological disorder characterized by loss in cognitive function, abnormal behavior, and decreased ability to perform basic activities of daily living [(ADLs)]&nbsp;... All studies included people with AD who completed an exercise program consisting of aerobic, strength, or balance training or any combination of the three. The length of the exercise programs varied from 12 weeks to 12 months.&nbsp;... Six studies involving 446 participants tested the effect of exercise on ADL performance&nbsp;... exercise had a large and significant effect on ADL performance (z = 4.07, p < .0001; average effect size = 0.80).&nbsp;... These positive effects were apparent with programs ranging in length from 12 wk (Santana-Sosa et al., 2008; Teri et al., 2003) and intermediate length of 16 wk (Roach et al., 2011; Vreugdenhil et al., 2012) to 6 mo (Venturelli et al., 2011) and 12 mo (Rolland et al., 2007). Furthermore, the positive effects of a 3-mo intervention lasted 24 mo (Teri et al., 2003).&nbsp;... No adverse effects of exercise on ADL performance were noted.&nbsp;... The study with the largest effect size implemented a walking and aerobic program of only 30 min four times a week (Venturelli et al., 2011).}}</ref> Two meta-analytic systematic reviews of [[randomized controlled trial]]s with durations of 3–12&nbsp;months have examined the effects of physical exercise on the aforementioned characteristics of Alzheimer's disease.<ref name="Alz 1" /><ref name="Alz 2" /> The reviews found beneficial effects of physical exercise on cognitive function, the rate of cognitive decline, and the ability to perform activities of daily living in individuals with Alzheimer's disease.<ref name="Alz 1" /><ref name="Alz 2" /> One review suggested that, based upon transgenic mouse models, the cognitive effects of exercise on Alzheimer's disease may result from a reduction in the quantity of [[amyloid plaque]].<ref name="Alz 1" /><ref name=adlard>{{vcite2 journal | vauthors = Adlard PA, Perreau VM, Pop V, Cotman CW | title = Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer's disease | journal = J. Neurosci. | volume = 25 | issue = 17 | pages = 4217–21 | year = 2005 | pmid = 15858047 | doi = 10.1523/JNEUROSCI.0496-05.2005 }}</ref>
+--><ref name="Alz 2">{{cite journal | vauthors = Rao AK, Chou A, Bursley B, Smulofsky J, Jezequel J | title = Systematic review of the effects of exercise on activities of daily living in people with Alzheimer's disease | journal = Am J Occup Ther | volume = 68 | issue = 1 | pages = 50–56 | date = January 2014 | pmid = 24367955 | doi = 10.5014/ajot.2014.009035 | quote = Alzheimer’s disease (AD) is a progressive neurological disorder characterized by loss in cognitive function, abnormal behavior, and decreased ability to perform basic activities of daily living [(ADLs)]&nbsp;... All studies included people with AD who completed an exercise program consisting of aerobic, strength, or balance training or any combination of the three. The length of the exercise programs varied from 12 weeks to 12 months.&nbsp;... Six studies involving 446 participants tested the effect of exercise on ADL performance&nbsp;... exercise had a large and significant effect on ADL performance (z = 4.07, p < .0001; average effect size = 0.80).&nbsp;... These positive effects were apparent with programs ranging in length from 12 wk (Santana-Sosa et al., 2008; Teri et al., 2003) and intermediate length of 16 wk (Roach et al., 2011; Vreugdenhil et al., 2012) to 6 mo (Venturelli et al., 2011) and 12 mo (Rolland et al., 2007). Furthermore, the positive effects of a 3-mo intervention lasted 24 mo (Teri et al., 2003).&nbsp;... No adverse effects of exercise on ADL performance were noted.&nbsp;... The study with the largest effect size implemented a walking and aerobic program of only 30 min four times a week (Venturelli et al., 2011).}}</ref> Two meta-analytic systematic reviews of [[randomized controlled trial]]s with durations of 3–12&nbsp;months have examined the effects of physical exercise on the aforementioned characteristics of Alzheimer's disease.<ref name="Alz 1" /><ref name="Alz 2" /> The reviews found beneficial effects of physical exercise on cognitive function, the rate of cognitive decline, and the ability to perform activities of daily living in individuals with Alzheimer's disease.<ref name="Alz 1" /><ref name="Alz 2" /> One review suggested that, based upon transgenic mouse models, the cognitive effects of exercise on Alzheimer's disease may result from a reduction in the quantity of [[amyloid plaque]].<ref name="Alz 1" /><ref name=adlard>{{cite journal | vauthors = Adlard PA, Perreau VM, Pop V, Cotman CW | title = Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer's disease | journal = J. Neurosci. | volume = 25 | issue = 17 | pages = 4217–21 | year = 2005 | pmid = 15858047 | doi = 10.1523/JNEUROSCI.0496-05.2005 }}</ref>
-The [[Caerphilly Prospective study]] followed 2,375&nbsp;male subjects over 30&nbsp;years and examined the association between healthy lifestyles and dementia, among other factors.<ref name="Caerphilly primary" /> Analyses of the Caerphilly study data have found that exercise is associated with a lower incidence of dementia and a reduction in cognitive impairment.<ref name="Caerphilly primary">{{vcite2 journal | vauthors = Elwood P, Galante J, Pickering J, Palmer S, Bayer A, Ben-Shlomo Y, Longley M, Gallacher J | title = Healthy lifestyles reduce the incidence of chronic diseases and dementia: evidence from the Caerphilly cohort study | journal = PLoS ONE | volume = 8 | issue = 12 | pages = e81877 | date = December 2013 | pmid = 24349147 | pmc = 3857242 | doi = 10.1371/journal.pone.0081877 | url = }}</ref><ref name="Caerphilly meta-analysis">{{vcite2 journal | vauthors = Morgan GS, Gallacher J, Bayer A, Fish M, Ebrahim S, Ben-Shlomo Y | title = Physical activity in middle-age and dementia in later life: findings from a prospective cohort of men in Caerphilly, South Wales and a meta-analysis | journal = J. Alzheimers Dis. | volume = 31 | issue = 3 | pages = 569–80 | year = 2012 | pmid = 22647258 | doi = 10.3233/JAD-2012-112171 | url = }}</ref> A subsequent systematic review of [[longitudinal studies]] also found higher levels of physical activity to be associated with a reduction in the risk of dementia and cognitive decline;<ref name="Longitudinal SystRev dementia" /> this review further asserted that increased physical activity appears to be causally related with these reduced risks.<ref name="Longitudinal SystRev dementia">{{vcite2 journal | vauthors = Blondell SJ, Hammersley-Mather R, Veerman JL | title = Does physical activity prevent cognitive decline and dementia?: A systematic review and meta-analysis of longitudinal studies | journal = BMC Public Health | volume = 14 | issue = | pages = 510 | date = May 2014 | pmid = 24885250 | pmc = 4064273 | doi = 10.1186/1471-2458-14-510 | quote = Longitudinal observational studies show an association between higher levels of physical activity and a reduced risk of cognitive decline and dementia. A case can be made for a causal interpretation. Future research should use objective measures of physical activity, adjust for the full range of confounders and have adequate follow-up length. Ideally, randomised controlled trials will be conducted.&nbsp;... On the whole the results do, however, lend support to the notion of a causal relationship between physical activity, cognitive decline and dementia, according to the established criteria for causal inference.}}</ref>
+The [[Caerphilly Prospective study]] followed 2,375&nbsp;male subjects over 30&nbsp;years and examined the association between healthy lifestyles and dementia, among other factors.<ref name="Caerphilly primary" /> Analyses of the Caerphilly study data have found that exercise is associated with a lower incidence of dementia and a reduction in cognitive impairment.<ref name="Caerphilly primary">{{cite journal | vauthors = Elwood P, Galante J, Pickering J, Palmer S, Bayer A, Ben-Shlomo Y, Longley M, Gallacher J | title = Healthy lifestyles reduce the incidence of chronic diseases and dementia: evidence from the Caerphilly cohort study | journal = PLoS ONE | volume = 8 | issue = 12 | pages = e81877 | date = December 2013 | pmid = 24349147 | pmc = 3857242 | doi = 10.1371/journal.pone.0081877 | url = }}</ref><ref name="Caerphilly meta-analysis">{{cite journal | vauthors = Morgan GS, Gallacher J, Bayer A, Fish M, Ebrahim S, Ben-Shlomo Y | title = Physical activity in middle-age and dementia in later life: findings from a prospective cohort of men in Caerphilly, South Wales and a meta-analysis | journal = J. Alzheimers Dis. | volume = 31 | issue = 3 | pages = 569–80 | year = 2012 | pmid = 22647258 | doi = 10.3233/JAD-2012-112171 | url = }}</ref> A subsequent systematic review of [[longitudinal studies]] also found higher levels of physical activity to be associated with a reduction in the risk of dementia and cognitive decline;<ref name="Longitudinal SystRev dementia" /> this review further asserted that increased physical activity appears to be causally related with these reduced risks.<ref name="Longitudinal SystRev dementia">{{cite journal | vauthors = Blondell SJ, Hammersley-Mather R, Veerman JL | title = Does physical activity prevent cognitive decline and dementia?: A systematic review and meta-analysis of longitudinal studies | journal = BMC Public Health | volume = 14 | issue = | pages = 510 | date = May 2014 | pmid = 24885250 | pmc = 4064273 | doi = 10.1186/1471-2458-14-510 | quote = Longitudinal observational studies show an association between higher levels of physical activity and a reduced risk of cognitive decline and dementia. A case can be made for a causal interpretation. Future research should use objective measures of physical activity, adjust for the full range of confounders and have adequate follow-up length. Ideally, randomised controlled trials will be conducted.&nbsp;... On the whole the results do, however, lend support to the notion of a causal relationship between physical activity, cognitive decline and dementia, according to the established criteria for causal inference.}}</ref>
 ===Huntington's disease===

Revision as of 21:09, 4 August 2015

Long-term effects

Neuroplasticity and neurogenesis

BDNF signaling

Antidepressant effect

IGF-1 signaling

VEGF signaling

ΔFosB and addiction

DeltaFosB

Role in addiction

Plasticity in cocaine addiction

Summary of addiction-related plasticity

Other functions in the brain

See also

Notes

References

Further reading

External links

Structural growth

Cognitive control and memory

Short-term effects

Psychological stress and cortisol

Euphoria

Neurotransmitters, neuromodulators, and neuropeptides

β-Phenylethylamine

β-Endorphin

Anandamide

Classical monoamines

Glutamate

Children

Education and learning implications

Elderly and neurodegenerative disorders

Alzheimer's disease

Huntington's disease

Parkinson's disease

See also

Notes

Reference notes

References