Neurobiological effects of physical exercise

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Neurobiological effects of
physical exercise
Exercise therapy – medical intervention
Image of a woman running
A woman engaging in aerobic exercise
ICD-9-CM 93.19
MeSH D005081
LOINC: 73986-2
eMedicine 324583

The neurobiological effects of physical exercise are numerous and involve a wide range 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 neural 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 to 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[edit]

Neuroplasticity and neurogenesis[edit]

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) and Insulin-like growth factor 1 (IGF-1).[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.[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;[5][8] moderate improvements seen in the anterior cingulate cortex, parietal cortex, cerebellum, caudate nucleus, and nucleus accumbens.[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).[2][12]

BDNF signaling[edit]

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).[2][13][14] This increase in BDNF signaling in the brain is associated with beneficial epigenetic changes, improved cognitive function, improved mood, and improved memory.[2][3][8][13] Furthermore, research has provided a great deal of support for the role of BDNF in hippocampal neurogenesis, synaptic plasticity, and neural repair.[13] 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;[2][13][14] exercise intensity affects the magnitude of increased BDNF synthesis and expression.[2][13][14] 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[edit]

Exercise has a marked persistent antidepressant effect in humans,[15][16][17][18] an effect believed to be mediated through enhanced BDNF signaling in the brain.[8][16] 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.[15] 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;[16] 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[17] and mental illness in general.[18]

IGF-1 signaling[edit]

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.[19] In the brain, IGF-1 functions as a neurotrophic factor that, like BDNF, plays a significant role in cognition, neurogenesis, and neuronal survival.[4][13][20] 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][13][19] 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".[4][19] The amount of IGF-1 released during exercise is positively correlated with exercise intensity and duration.[21]

ΔFosB and addiction[edit]

Part of this section is transcluded from FOSB. (edit | history)

Similar to other natural rewards and addictive drugs, consistent aerobic exercise induces expression of the gene transcription factor that causes and maintains addiction, ΔFosB, in the nucleus accumbens,[22][23] but also increases c-Fos expression as well, thereby opposing the long-term accumulation of ΔFosB.[2][24][25] 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.[23][26][27] 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.[23][26] 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).[23][26] Consequently, consistent aerobic exercise leads to better treatment outcomes when used as an adjunct treatment for addiction.[26][27]

Summary of addiction-related plasticity
Form of neural or behavioral plasticity Type of reinforcer Sources
Opiates Psychostimulants High fat or sugar food Sexual reward Physical exercise
(aerobic)
Environmental
enrichment
ΔFosB expression
in the nucleus accumbens
[23]
Behavioral Plasticity
Escalation of intake Yes Yes Yes [23]
Psychostimulant
cross-sensitization
Yes Not applicable Yes Yes Attenuated Attenuated [23]
Psychostimulant
self-administration
[23]
Psychostimulant
conditioned place preference
[23]
Reinstatement of drug-seeking behavior [23]
Neurochemical Plasticity
CREB phosphorylation
in the nucleus accumbens
[23]
Sensitized dopamine response
in the nucleus accumbens
No Yes No Yes [23]
Altered striatal dopamine signaling DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD2 DRD2 [23]
Altered striatal opioid signaling μ-opioid receptors μ-opioid receptors
κ-opioid receptors
μ-opioid receptors μ-opioid receptors No change No change [23]
Changes in striatal opioid peptides dynorphin dynorphin enkephalin dynorphin dynorphin [23]
Mesocorticolimbic Synaptic Plasticity
Number of dendrites in the nucleus accumbens [23]
Dendritic spine density in
the nucleus accumbens
No change [23]

Structural growth[edit]

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;[5][8] the most prominent gains are seen in the prefrontal cortex and hippocampus, which are primarily associated with cognitive control and memory processing respectively.[5][7][8] Moreover, the left and right halves of the prefrontal cortex, which is divided by the medial longitudinal fissure, appears to become more interconnected in response to consistent aerobic exercise.[6] One review asserted that marked improvements in prefrontal and hippocampal gray matter volume occur in healthy adults that engage in medium intensity exercise for several months.[5] 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.[5][8][28]

Regular exercise has been shown to counter the shrinking of the hippocampus and memory impairment that naturally occurs in late adulthood.[5][8][29] Sedentary adults over age 55 show a 1–2% decline in hippocampal volume annually.[8][29] 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.[8][29] 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.[29] In general, individuals that exercise more over a given period have greater hippocampal volumes and better memory function.[8]

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

Cognitive control and memory[edit]

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.[6][7][36][37] 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.[5][6][7][36][37] Individuals who have a sedentary lifestyle tend to have impaired cognitive control relative to other more physically active non-exercisers.[7][36] 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.[7] 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.[37]

Short-term effects[edit]

Euphoria[edit]

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.[39][40] Current medical reviews indicate that several endogenous euphoriants are responsible for producing exercise-related euphoria, specifically β-phenylethylamine (a psychostimulant), β-endorphin (an opioid), and anandamide (a cannabinoid).[41][42][43][44][45]

Effects on neurotransmitters, neuromodulators, and neuropeptides[edit]

β-Phenylethylamine[edit]

β-Phenylethylamine, commonly referred to as phenethylamine, is a potent endogenous trace amine neuromodulator which has the same biomolecular targets as amphetamine;[46][47] 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.[41][42][43] 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;[41][42][43] 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.[41][42][43][48] In a resting state, phenethylamine is synthesized in catecholamine neurons from L-phenylalanine by aromatic amino acid decarboxylase at approximately the same rate as dopamine is produced.[48]

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.[41][42][43]

β-Endorphin[edit]

β-Endorphins (contracted from "endogenous morphine") are endogenous opioid neuropeptides that bind to μ-opioid receptors, in turn producing euphoria and pain relief.[44] A meta-analytic review found that exercise significantly increases the secretion of β-endorphins and that this secretion is correlated with improved mood states.[44] 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.[44]

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.[44] 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.[44]

Anandamide[edit]

Anandamide is an endogenous cannabinoid neurotransmitter that binds to cannabinoid receptors.[45] 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).[45] 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.[45] 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.[39][45]

Classical monoamines[edit]

Glutamate[edit]

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.[49] Glutamate regulates certain exercise-related memory processes primarily via cotransmission with dopamine in the dopaminergic projections from the ventral tegmental area;[50][51] in particular, exercise has been shown to modulate (normalize) glutamatergic cotransmission in the mesocorticolimbic dopamine pathway.[26]

Reduced stress[edit]

Stress has many physiological effects and pathological impacts on the body. Significant decrease in the volume of the hippocampus has been observed in artificially stressed rats. Similarly, prolonged depression has also been linked to hippocampal atrophy.[52]

When exposed to a psychosocial laboratory stress, subjects with high stress-induced cortisol levels showed diminished memory performance, specifically in declarative memory.[53] If a patient is administered cortisol, independent of the psychological stress, they show impaired performance in declarative memory as well as in spatial tasks.[53] The negative impact of stress can also be seen at the genetic level. Physiologically, stress exposure induces a decrease in BDNF mRNA levels which can lead to depression.[54] Exercise can treat or prevent the stress-induced decrease in BDNF expression associated with acute stress exposure.To combat these detrimental effects on the body, exercise is a natural way of relieving everyday stress.

There are a number of ways in which exercise may serve to reduce stress and consequently free up one's attentional resources and improve memory:[55][unreliable medical source?]

  • Exercise relaxes muscles: When stressed the muscles in the body become tense and stiff. Physical activity improves circulation and oxygen delivery to the muscles, reducing tension and muscle soreness.
  • Exercise promotes a feeling of happiness: Through the production of endorphins, exercise reduces stress and promotes a peaceful feeling of euphoria.
  • Exercise reduces feelings of frustration: A good way to relieve yourself of stressful thoughts is to go for a walk or jog. Performing physical activity forces the brain to concentrate on your body and its surroundings, giving the mind a break from focusing solely on frustrations.
  • Exercise improves stress resiliency: People who exercise often are more likely to exhibit a decreased stress reaction to adverse situations.

Cortisol[edit]

Cortisol is a glucocorticoid that is released from the adrenal gland in response to stressful situations. Studies have shown that excessive cortisol interferes with the function of neurotransmitters and impairs the ability to retrieve long term memories.

Effects of cortisol on memory function[edit]

Rats stressed by an electrical shock thirty minutes before navigating through a familiar maze showed significantly lowered performance. This same result occurred in rats injected with cortisol directly, confirming its role in memory impairment.[medical citation needed]

A study at the University of Zurich further demonstrated the detrimental effects of cortisol on memory recall. Healthy adults were asked to memorize a series of unrelated nouns presented on a screen for four seconds each. Immediately after the learning trial, they were asked to recall these words. The following day, they were asked to do so again. Memory encoding appeared to remain unaffected both when subjects had been given cortisone (a precursor of cortisol) one hour before the initial learning trial and, in another case, immediately after it. In contrast, subjects who had been given cortisone one hour before the recall test, showed impaired memory performance when asked to recall these nouns the following day. These findings suggest that cortisol impairs the ability to recall older memories (long term memory), but not the ability to recall short term memories. Additionally, cortisol does not appear to affect the ability to encode new memories.[medical citation needed]

The primary effect of cortisol on memory function is due to its negative influence on the hippocampus. The natural stress response is mediated by the hypothalamic-pituitary-adrenal axis. When a stressor is present, the hypothalamus releases corticotropin-releasing hormone (CRF) which stimulates the anterior pituitary gland to release adrenocorticotropic hormone (ACTH). ACTH then travels to the adrenal glands which receive it as a signal to release cortisol. Cortisol is released into the body and travels to the hippocampus which triggers a negative feedback mechanism, signaling the hypothalamus to shut off CRF release, thereby shutting off the release of cortisol as well.[medical citation needed]

Cortisol has been found to accelerate the degeneration of the hippocampus. Since aging naturally results in hippocampal atrophy, this presents an even larger problem. As the hippocampus shrinks over time, it loses its ability to provide proper feedback to the hypothalamus during the stress response, causing cortisol release to occur for longer periods of time. This, in turn, leads to further hippocampal decay due to the greater amounts of cortisol.[medical citation needed]

Physical exercise's effects on cortisol[edit]

Moderately intense exercise produces stress on the body and therefore releases cortisol. However moderate to high intensity exercise urges the body to adapt, increasing the threshold for cortisol release and making the body more resilient to the effects of stress, as a result. The more physical activity you do, the more efficient the body becomes at dealing with both physical and mental stressors.[medical citation needed]

Engaging in regular exercise therefore serves as a protective function, warding off cortisol-induced hippocampal atrophy. This has serious implications for the prevention of neurological diseases such as Alzheimer's, since individuals with smaller hippocampi have been found to be at increased risk of developing the condition.[56][unreliable medical source?]

Physical activity and children[edit]

Education and learning implications[edit]

Physical activity has contributed to reducing childhood obesity and the incidences of cardiovascular disease, colon & breast cancer, and depression & anxiety across the adult lifespan.[57] 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.[58] The correlation was strongest for the age ranges of 4–7 and 11–13 years.[58] 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.[59] 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.[60] They concluded that hippocampal volume was positively associated with performance on relational memory tasks.[60] Their findings are the first to indicate that aerobic fitness may relate to the structure and function of the preadolescent human brain.[60] 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.[61] The second is acute exercise, which examines the immediate changes in cognitive functioning after each session.[61] The results of both suggest that aerobic exercise may briefly aid children’s executive function and also influence more lasting improvements to executive function.[61] Other studies have suggested that exercise is unrelated to academic performance, perhaps due to the parameters used to determine exactly what academic achievement is.[57] 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.[58]

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.[57] Neuroimaging of the human brain has yielded similar results, where exercise leads to changes in brain structure and function.[57] 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.[59]

Elderly[edit]

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.[62] Fitness is associated with better cognitive performance in individuals with cardiovascular disease,[63] 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 are though 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).

Implications in neurodegenerative disorders[edit]

Alzheimer's disease[edit]

Alzheimer's Disease (AD) is a cortical neurodegenerative disorder that progresses over time. It represents the eighth leading cause of death in people over the age of 65,[64] and is the most common form of dementia. AD is characterized by the destruction of specific cortical nerve cells, neuritic plaques, and neurofibrillary tangles.[65] Symptoms of AD can be divided into stages. Early, pre-dementia stages of the disease involve mild cognitive impairment (MCI), where minor memory problems and complex mental tasks may not affect an individual's daily routine, but may become clinical signs for the onset of AD.[66] The mild to moderate stages include a decline in independence, where normal activities such as getting dressed, and judgment and organization ability is impaired.[67] Late stage AD can be characterized by a loss of biographical memories, a reduction in language, and overall cognitive function is severely impaired.[67] Death in AD is most frequently caused by pneumonia that leads to myocardial infarction and septicaemia. There is no cure for AD, only means of slowing down the progression and improving the condition of symptoms, but no treatment targets the underlying mechanism of disease.[64] Many studies have been done to see if exercise preserves cognitive function, though results have varied. Exercise has been shown to play a role in decreasing the risk of developing AD, and may be protective against the development of cognitive impairment.[64]

Current literature focuses on how physical activity can reduce the chance of onset of AD, and what it can do to slow down symptom progression when the patient is already diagnosed. A study by Friedland and colleagues (2001) surveyed 193 AD patients and 358 healthy participants 20–60 years of age. They collected data based on 26 activities in passive, intellectual, and physical categories in early adulthood (20–39 years) and middle adulthood (40–59 years). It was observed that people who developed AD were those who participated in less intellectual, passive, and physically activities in their midlife.[68] The Caerphilly Heart Disease Study followed 2,375 male subjects over 30 years and examined the association between healthy lifestyles and dementia. The study identified that men who undertook regular physical exercise had a 59% reduction in dementia when compared to the men who did not exercise regularly.[69] A literature review by Rolland and colleagues (2008) found that AD individuals who incorporated physical activity in their daily lives would reduce cognitive decline and improve psychological and/or physical performance, as well as mobility, balance, and strength.[70] Reasons physical activity leads to a reduced risk of AD include lowering body weight, as obesity is a risk factor for AD,[71] a healthier diet, and improved blood pressure & cardiovascular health.[68] Depression, malnutrition and behavior disturbances, which can lead to faster cognitive decline, are also held off with exercise.[70]

Huntington's disease[edit]

Huntington's Disease (HD) is an autosomal dominant neurodegenerative disorder where protein aggregates in neurons, destroying them,[72] leading to a decline in motor skills, chorea, subcortical dementia, and other psychiatric symptoms.[73] These symptoms include mood change,[74] impaired memory formation, information-processing deficits and a disruption in spatial working memory.[73] Neurological alterations occur in the caudate nucleus, hippocampus, and in the putamen and globus pallidus to a lesser degree.[74] The onset of the disease is related to the CAG trinucleotide expansion in the Huntingtin gene that codes for the amino acid glutamine. The normal range is 10–35 repeats, while diseased individuals will generally have 36 or more repeats, although the excessive repeats do not necessarily mean symptoms will develop.[73] Environmental factors also have an impact on disease onset and progression.[73] Each generation, the number of repeats increases, thus the age of onset decreases every generation. As with AD, there is no cure for HD, only treatment to improve the various conditions associated with it. Patients generally die within 10–20 years of disease onset.

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.[73] 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.[72] 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.[72] 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.[72] Further research needs to be done before a solid conclusion can be reached about the effects of exercise on HD cognitive function, specifically in human models.

Parkinson's disease[edit]

Parkinson's disease (PD) is a neurodegenerative disorder. It is generally recognized as a movement disorder that produces symptoms such as bradykinesia, rigidity, shaking, and impaired gait.[75] It affects about 1 million people in the United States.[76] Motor symptoms of PD are caused by the death of dopamine-containing neurons in the substantia nigra pars compacta, which is located in the mesencephalon (midbrain),[76] and the accumulation of Lewy bodies and neurites.

While PD is classified as a disorder that leads to a deterioration of motor skill, progression of the disease will eventually result in cognitive and behavioral deficits. Psychosocial well-being is thought to be a contributing factor to the quality of life of PD patients,[77] and has become a key focus of research in recent years. Cognitive dysfunction will impair normal everyday activities of life. These disturbances mainly disrupt executive functions, such as multitasking, driving, and situations that require planning.[78] Certain methods to improve motor functions of PD patients do not generally impact the cognitive deficits.[79] For instance, dopamine replacement therapy, which releases the dopamine precursor L-DOPA within the brain and allows it to cross the blood-brain barrier,[80] will improve motor ability but has no association with cognitive function.[78] Deep brain stimulation that may result in improved motor function, may in turn have negative effects on cognitive function.[78]

A review by Kramer and colleagues (2006) found that some neurotransmitter systems are affected by exercise in a positive way.[79] A few studies reported seeing an improvement in brain health and cognitive function due to exercise.[79] 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.[81] 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.[78] 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,[78] providing evidence that such exercise regimens may be beneficial to patients with PD.

See also[edit]

Notes[edit]

  1. ^ Attentional control allows an individual to focus their attention on a specific source and ignore other stimuli that compete for one's attention,[9] such as in the cocktail party effect.
  2. ^ 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.[30][38] Inhibitory control allows individuals to control their impulses and habits when necessary or desired.[30][36][38]
  3. ^ Working memory is the form of memory used by an individual at any given moment for active information processing,[9] 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.[30]
  4. ^ Declarative memory, also known as explicit memory, is the form of memory that pertains to facts and events.[33]

References[edit]

  1. ^ 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 druginduced 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). 
  2. ^ a b c d e f g 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. 
  3. ^ 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 
  4. ^ a b c d 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. 
  5. ^ a b c d e f g h i j k l m 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. ... 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. 
  6. ^ a b c d 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. 
  7. ^ a b c d e f 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. 
  8. ^ a b c d e f g h i j k l m Erickson K, Miller D, Roecklein K (2012). "The aging hippocampus: interactions between exercise, depression, and BDNF". Neuroscientist 18 (1): 82–97. 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. 
  9. ^ a b c Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY. 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. ... 
  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. 
  11. ^ Carvalho A, Rea I, Parimon T, Cusack B (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. 
  12. ^ 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). 
  13. ^ 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. 
  14. ^ 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).
     
  15. ^ a b Cooney G, Dwan K, Greig C, Lawlor D, Rimer J, Waugh F et al. (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. 
  16. ^ a b c Mura G, Moro M, Patten S, Carta M (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.
     
  17. ^ 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. 
  18. ^ a b Rosenbaum S, Tiedemann A, Sherrington C, Curtis J, Ward P (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.
     
  19. ^ 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 
  20. ^ 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. ... 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 
  21. ^ Gatti R, De Palo E, 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. 
  22. ^ 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 exposure14,22–24. 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 consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. 
  23. ^ a b c d e f g h i j k l m n o p q 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). 
  24. ^ Zlebnik N, Hedges V, Carroll M, Meisel R (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. 
  25. ^ 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
  26. ^ a b c d e 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. 
  27. ^ a b Linke S, 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. 
  28. ^ 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. 
  29. ^ a b c d 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. 
  30. ^ a b c d e f g Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY. 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.
     
  31. ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY. 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. 
  32. ^ 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. 
  33. ^ 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. 
  34. ^ Grimaldi G, Argyropoulos G, Bastian A, Cortes M, Davis N, Edwards D et al. (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. 
  35. ^ Sereno M, Huang R (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. 
  36. ^ a b c d 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.
     
  37. ^ a b c Janssen M, Toussaint H, van Mechelen W, Verhagen E (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. 
  38. ^ a b Ilieva I, Hook C, Farah M (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. 
  39. ^ a b Raichlen D, Foster A, Gerdeman G, 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 
  40. ^ Cohen E, Ejsmond-Frey R, Knight N, Dunbar R (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. 
  41. ^ 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. 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. 
  42. ^ a b c d e Lindemann L, Hoener M (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]. 
  43. ^ a b c d e Berry M (2007). "The potential of trace amines and their receptors for treating neurological and psychiatric diseases". Rev Recent Clin Trials 2 (1): 3–19. PMID 18473983. It has also been suggested that the antidepressant effects of exercise are due to an exercise-induced elevation of PE [151]. 
  44. ^ a b c d e f Dinas P, Koutedakis Y, Flouris A (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.
     
  45. ^ a b c d e Tantimonaco M, Ceci R, Sabatini S, Catani M, Rossi A, Gasperi V et al. (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]. 
  46. ^ "β-phenylethylamine: Biological activity". Guide to Pharmacology. The International Union of Basic and Clinical Pharmacology. Retrieved 10 February 2015. 
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  48. ^ 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 ...
     
  49. ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 5: Excitatory and Inhibitory Amino Acids". In Sydor A, Brown RY. 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.
     
  50. ^ Broussard J (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. 
  51. ^ Descarries L, Bérubé-Carrière N, Riad M, Bo G, Mendez J, Trudeau L (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. 
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