FOSB

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FBJ murine osteosarcoma viral oncogene homolog B
Identifiers
Symbols FOSB ; AP-1; G0S3; GOS3; GOSB
External IDs OMIM164772 MGI95575 HomoloGene31403 GeneCards: FOSB Gene
RNA expression pattern
PBB GE FOSB 202768 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 2354 14282
Ensembl ENSG00000125740 ENSMUSG00000003545
UniProt P53539 P13346
RefSeq (mRNA) NM_001114171 NM_008036
RefSeq (protein) NP_001107643 NP_032062
Location (UCSC) Chr 19:
45.47 – 45.48 Mb
Chr 7:
19.3 – 19.31 Mb
PubMed search [1] [2]

FBJ murine osteosarcoma viral oncogene homolog B, also known as FOSB or FosB, is a protein that, in humans, is encoded by the FOSB gene.[1][2][3]

The FOS gene family consists of 4 members: FOS, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family (e.g., c-Jun, JunD), thereby forming the transcription factor complex AP-1. As such, the FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation.[1] FosB and its truncated splice variants ΔFosB and (further truncated) Δ2ΔFosB are all involved in osteosclerosis, even though Δ2ΔFosB lacks a known transactivation domain, preventing it from affecting gene transcription through the AP-1 complex.[4]

The ΔFosB splice variant has been identified as playing a central, crucial (necessary and sufficient)[5][6] role in the development and maintenance of pathological behavior and neural plasticity involved in both behavioral addictions (associated with natural rewards) and drug addictions.[5][7][8] E.g., ΔFosB overexpression causes the development addiction-related structural neuroplasticity to occur throughout the reward system.[9] ΔFosB differs from the full length FosB and further truncated Δ2ΔFosB in its capacity to produce these effects, as only accumbal ΔFosB overexpression is associated with pathological responses to drugs.[10]

ΔFosB[edit]

ΔFosB or Delta FosB is a truncated splice variant of FosB.[11] ΔFosB has been implicated as a critical factor in the development of virtually all forms of behavioral and drug addictions.[6][7][12] In the brain's reward system, it is linked to changes in a number of other gene products, such as CREB and sirtuins.[13][14][15] In the body, ΔFosB regulates the commitment of mesenchymal precursor cells to the adipocyte or osteoblast lineage.[16]

In the nucleus accumbens, ΔFosB functions as a "sustained molecular switch" and "master control protein" in the development of an addiction.[5][17][18] In other words, once "turned on" (sufficiently overexpressed) ΔFosB triggers a series of transcription events that ultimately produce an addictive state (i.e., compulsive reward-seeking involving a particular stimulus); this state is sustained for months after cessation of drug use due to the abnormal and exceptionally long half-life of ΔFosB isoforms.[5][17][18] ΔFosB expression in D1-type nucleus accumbens medium spiny neurons directly and positively regulates drug self-administration and reward sensitization through positive reinforcement while decreasing sensitivity to aversion.[5][8] Based upon the accumulated evidence, a medical review from late 2014 argued that accumbal ΔFosB expression can be used as an addiction biomarker and that the degree of accumbal ΔFosB induction by a drug is a metric for how addictive it is relative to others.[5]

Role in addiction[edit]

Addiction glossary[8][19][20]
addiction – a state characterized by compulsive engagement in rewarding stimuli despite adverse consequences
reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them
rewarding stimuli – stimuli that the brain interprets as intrinsically positive or as something to be approached
addictive drug – a drug that is both rewarding and reinforcing
addictive behavior – a behavior that is both rewarding and reinforcing
sensitization – an amplified response to a stimulus resulting from repeated exposure to it
drug tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose
drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose
dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake)
physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens)
psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia)
(edit | history)
Signaling cascade in the nucleus accumbens that results in psychostimulant addiction
v · t · e
This diagram depicts the signaling events in the brain's reward center that are induced by chronic high-dose exposure to psychostimulants that increase the concentration of synaptic dopamine, like amphetamine, methamphetamine, and phenethylamine. Following presynaptic dopamine and glutamate co-release by such psychostimulants,[21][22] postsynaptic receptors for these neurotransmitters trigger internal signaling events through a cAMP pathway and calcium-dependent pathway that ultimately result in increased CREB phosphorylation.[23][24][25] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-fos gene with the help of corepressors;[24] c-fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[26] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for one or two months, slowly accumulates following repeated exposure to stimulants through this process.[17][27] ΔFosB functions as "one of the master control proteins" that produces addiction-related structural changes in the brain, and upon sufficient accumulation, with the help of its downstream targets (e.g., nuclear factor kappa B), it induces an addictive state.[17][27] Desc-20.png

Addiction from chronic addictive drug use involves alterations in gene expression in the mesocorticolimbic projection, which arise through transcriptional and epigenetic mechanisms.[6][28][29] The most important transcription factors that produce these alterations are ΔFosB, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and nuclear factor kappa B (NF-κB).[6] ΔFosB is the most significant biomolecular mechanism in addiction since its viral or genetic overexpression (through chronic addictive drug use) in D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient for many of the neural adaptations and behavioral effects (e.g., expression-dependent increases in self-administration and reward sensitization) seen in drug addiction;[5][6][8] it has been implicated in addictions to alcohol (ethanol), cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.[5][6][28][30][31] ΔJunD, a transcription factor, and G9a, a histone methyltransferase, both directly oppose the induction of ΔFosB (i.e., increases in its expression).[6][8][32] Increases in nucleus accumbens ΔJunD expression using viral vectors (a genetically engineered virus) can reduce or, with a large increase, even block many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).[6]

ΔFosB also plays an important role in regulating behavioral responses to natural (non-drug) rewards, such as palatable food, sex, and exercise.[6][12] Natural rewards, like drugs of abuse, induce gene expression of ΔFosB in the nucleus accumbens, and chronic acquisition of these rewards can result in a similar pathological addictive state through ΔFosB overexpression.[6][7][12] Consequently, ΔFosB is the key mechanism involved in addictions to natural rewards (i.e., behavioral addictions) as well;[6][7][12] in particular, ΔFosB in the nucleus accumbens is critical for the reinforcing effects of sexual reward.[12] Research on the interaction between natural and drug rewards suggests that dopaminergic psychostimulants (e.g., amphetamine) and sexual behavior act on similar biomolecular mechanisms to induce ΔFosB in the nucleus accumbens and possess bidirectional cross-sensitization effects[note 1] that are mediated through ΔFosB.[7][33] This phenomenon is notable since, in humans, a dopamine dysregulation syndrome, characterized by drug-induced compulsive engagement in natural rewards (specifically, sexual activity, shopping, and gambling), has also been observed in some individuals taking dopaminergic medications.[7]

ΔFosB inhibitors (drugs or treatments that oppose its action or reduce its expression) may be an effective treatment for addiction and addictive disorders.[34]

Plasticity in cocaine addiction[edit]

ΔFosB levels have been found to increase upon the use of cocaine.[35] Each subsequent dose of cocaine continues to increase ΔFosB levels with no ceiling of tolerance. Elevated levels of ΔFosB leads to increases in brain-derived neurotrophic factor (BDNF) levels, which in turn increases the number of dendritic branches and spines present on neurons involved with the nucleus accumbens and prefrontal cortex areas of the brain. This change can be identified rather quickly, and may be sustained weeks after the last dose of the drug.

Transgenic mice exhibiting inducible expression of ΔFosB primarily in the nucleus accumbens and dorsal striatum exhibit sensitized behavioural responses to cocaine.[36] They self-administer cocaine at lower doses than control,[37] but have a greater likelihood of relapse when the drug is withheld.[18][37] ΔFosB increases the expression of AMPA receptor subunit GluR2[36] and also decreases expression of dynorphin, thereby enhancing sensitivity to reward.[18]

ΔFosB accumulation graph
Top: this depicts the acute expression of various Fos family proteins following an initial exposure to an addictive drug.
Bottom: this illustrates increasing ΔFosB expression from repeated twice daily drug binges, where these phosphorylated (35–37 kD) ΔFosB isoforms persist in mesolimbic dopamine neurons for up to 2 months.[18][27]
Neural and behavioral effects of validated ΔFosB transcriptional targets[5][13]
Target
gene
Target
expression
Neural effects Behavioral effects
c-Fos Molecular switch enabling the chronic
induction of ΔFosB[note 2]
dynorphin
[note 3]
 • Downregulation of κ-opioid feedback loop  • Increased drug reward
NF-κB  • Expansion of Nacc dendritic processes
 • NF-κB inflammatory response in the NAcc
 • NF-κB inflammatory response in the CP
 • Increased drug reward
 • Increased drug reward
 • Locomotor sensitization
GluR2  • Decreased sensitivity to glutamate  • Increased drug reward
Cdk5  • GluR1 synaptic protein phosphorylation
 • Expansion of NAcc dendritic processes
 • Decreased drug reward
(net effect)

Summary of addiction-related plasticity[edit]

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
nucleus accumbens D1-type MSNs
[7]
Behavioral plasticity
Escalation of intake Yes Yes Yes [7]
Psychostimulant
cross-sensitization
Yes Not applicable Yes Yes Attenuated Attenuated [7]
Psychostimulant
self-administration
[7]
Psychostimulant
conditioned place preference
[7]
Reinstatement of drug-seeking behavior [7]
Neurochemical plasticity
CREB phosphorylation
in the nucleus accumbens
[7]
Sensitized dopamine response
in the nucleus accumbens
No Yes No Yes [7]
Altered striatal dopamine signaling DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD2 DRD2 [7]
Altered striatal opioid signaling μ-opioid receptors μ-opioid receptors
κ-opioid receptors
μ-opioid receptors μ-opioid receptors No change No change [7]
Changes in striatal opioid peptides dynorphin dynorphin enkephalin dynorphin dynorphin [7]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens [7]
Dendritic spine density in
the nucleus accumbens
[7]

Other functions in the brain[edit]

ΔFosB overexpression in the dorsal striatum (nigrostriatal dopamine pathway) via viral vectors induces levodopa-induced dyskinesias in animal models of Parkinson's disease.[38][39] Dorsal striatal ΔFosB is overexpressed in rodents and primates with dyskinesias;[39] postmordem studies of individuals with Parkinson's disease that were treated with levodopa have also observed similar dorsal striatal ΔFosB overexpression.[39] Levetiracetam, an antiepileptic drug which has been demonstrated to reduce the severity of levodopa-induced dyskinesias, has been shown to dose-dependently decrease the induction of dorsal striatal ΔFosB expression in rats when co-administered with levodopa;[39] the signal transduction involved in this effect is unknown.[39]

ΔFosB expression in the nucleus accumbens shell increases resilience to stress and is induced in this region by acute exposure to social defeat stress.[40][41][42]

See also[edit]

Notes[edit]

  1. ^ In simplest terms, this means that when either amphetamine or sex is perceived as "more alluring or desirable" through reward sensitization, this effect occurs with the other as well.
  2. ^ In other words, c-Fos repression allows ΔFosB to accumulate within nucleus accumbens dopamine neurons more rapidly because it is selectively induced in this state.[8]
  3. ^ ΔFosB has been implicated in causing both increases and decreases in dynorphin expression in different studies;[5][13] this table entry reflects only a decrease.

References[edit]

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    Table 3
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Further reading[edit]

External links[edit]