FosB is essential for the enhancement of stress tolerance and antagonizes locomotor sensitization by ΔFosB.

Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA.
Biological psychiatry (Impact Factor: 9.47). 06/2011; 70(5):487-95. DOI: 10.1016/j.biopsych.2011.04.021
Source: PubMed

ABSTRACT Molecular mechanisms underlying stress tolerance and vulnerability are incompletely understood. The fosB gene is an attractive candidate for regulating stress responses, because ΔFosB, an alternative splice product of the fosB gene, accumulates after repeated stress or antidepressant treatments. On the other hand, FosB, the other alternative splice product of the fosB gene, expresses more transiently than ΔFosB but exerts higher transcriptional activity. However, the functional differences of these two fosB products remain unclear.
We established various mouse lines carrying three different types of fosB allele, wild-type (fosB(+)), fosB-null (fosB(G)), and fosB(d) allele, which encodes ΔFosB but not FosB, and analyzed them in stress-related behavioral tests.
Because fosB(+/d) mice show enhanced ΔFosB levels in the presence of FosB and fosB(d/d) mice show more enhanced ΔFosB levels in the absence of FosB, the function of FosB can be inferred from differences observed between these lines. The fosB(+/d) and fosB(d/d) mice showed increased locomotor activity and elevated Akt phosphorylation, whereas only fosB(+/d) mice showed antidepressive-like behaviors and increased E-cadherin expression in striatum compared with wild-type mice. In contrast, fosB-null mice showed increased depression-like behavior and lower E-cadherin expression.
These findings indicate that FosB is essential for stress tolerance mediated by ΔFosB. These data suggest that fosB gene products have a potential to regulate mood disorder-related behaviors.

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Available from: Yusaku Nakabeppu, Aug 23, 2015
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    • "To date, functions of Fosb gene products in brain have been characterized almost exclusively in neurons, because neurons uniquely express high levels of Fosb products in response to several brain stimuli (Hope et al., 1994; Mandelzys et al., 1997; McClung et al., 2004; Kurushima et al., 2005; Nestler, 2008; Ohnishi et al., 2011). In the present study, we revealed for the first time that the Fosb gene is also expressed in microglia as well as neurons in the brain, and regulates different target genes in each type of brain cell. "
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    ABSTRACT: The Fosb gene encodes subunits of the activator protein-1 transcription factor complex. Two mature mRNAs, Fosb and ΔFosb, encoding full-length FOSB and ΔFOSB proteins respectively, are formed by alternative splicing of Fosb mRNA. Fosb products are expressed in several brain regions. Moreover, Fosb-null mice exhibit depressive-like behaviors and adult-onset spontaneous epilepsy, demonstrating important roles in neurological and psychiatric disorders. Study of Fosb products has focused almost exclusively on neurons; their function in glial cells remains to be explored. In this study, we found that microglia express equivalent levels of Fosb and ΔFosb mRNAs to hippocampal neurons and, using microarray analysis, we identified six microglial genes whose expression is dependent on Fosb products. Of these genes, we focused on C5ar1 and C5ar2, which encode receptors for complement C5a. In isolated Fosb-null microglia, chemotactic responsiveness toward the truncated form of C5a was significantly lower than that in wild-type cells. Fosb-null mice were significantly resistant to kainate-induced seizures compared with wild-type mice. C5ar1 mRNA levels and C5aR1 immunoreactivity were increased in wild-type hippocampus 24 hours after kainate administration; however, such induction was significantly reduced in Fosb-null hippocampus. Furthermore, microglial activation after kainate administration was significantly diminished in Fosb-null hippocampus, as shown by significant reductions in CD68 immunoreactivity, morphological change and reduced levels of Il6 and Tnf mRNAs, although no change in the number of Iba-1-positive cells was observed. These findings demonstrate that, under excitotoxicity, Fosb products contribute to a neuroinflammatory response in the hippocampus through regulation of microglial C5ar1 and C5ar2 expression. GLIA 2014
    Glia 08/2014; 62(8). DOI:10.1002/glia.22680 · 6.03 Impact Factor
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    • "As a consequence, DeltaFosB have been viewed as a sustained molecular switch to mediate forms of long-lasting neural and behavioral plasticity. Interestingly, an elegant study using mouse lines expressing differentially FosB and DeltaFosB showed that FosB is essential for the enhancement of stress tolerance and also neutralizes the correlation between psychostimulant-induced locomotor sensitization and accumulation of DeltaFosB in the striatum (Ohnishi et al., 2011). Therefore, both proteins could play important roles in the experimental protocol used in the present study. "
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    ABSTRACT: Chronic drug exposure and drug withdrawal induce expressive neuronal plasticity which could be considered as both functional and pathological responses. It is well established that neuronal plasticity in the limbic system play a pivotal role in relapse as well as in compulsive characteristics of drug addiction. Although increases in FosB/DeltaFosB expression constitute one of the most important forms of neuronal plasticity in drug addiction, it is unclear whether they represent functional or pathological plasticity. It is of noteworthy importance the individual differences in the transition from recreational use to drug addiction. These differences have been reported in studies involving the ethanol-induced locomotor sensitization paradigm. In the present study we investigated whether sensitized and non-sensitized mice differ in terms of FosB/DeltaFosB expression. Adult male outbred Swiss mice were daily treated with ethanol or saline for 21days. According to the locomotor activity in the acquisition phase, they were classified as sensitized (EtOH_High) or non-sensitized (EtOH_Low). After 18hours or 5days, their brains were processed for FosB/DeltaFosB immunohistochemistry. On the 5th day of withdrawal, we could observe increased FosB/DeltaFosB expression in the EtOH_High group (in the motor cortex), in the EtOH_Low group (in the ventral tegmental area), and in both groups (in the striatum). Differences were more consistent in the EtOH_Low group. Therefore, behavioral variability observed in the acquisition phase of ethanol-induced locomotor sensitization was accompanied by differential neuronal plasticity during withdrawal period. Furthermore, distinct patterns of FosB/DeltaFosB expression detected in sensitized and non-sensitized mice seem to be more related to withdrawal period rather than to chronic drug exposure. Finally, increases in FosB/DeltaFosB expression during withdrawal period could be considered as being due to both functional and pathological plasticity.
    Pharmacology Biochemistry and Behavior 12/2013; 117. DOI:10.1016/j.pbb.2013.12.007 · 2.82 Impact Factor
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    • "DFosB is a stable transcription factor that has an essential role in long-term adaptive changes in the brain associated with diverse conditions, including stress resilience and antidepressant treatment. For example, its induction in nucleus accumbens (NAc), a brain reward region, after chronic social defeat stress occurs preferentially in resilient mice and contributes to a state of resilience (Ohnishi et al, 2011; Vialou et al, 2010). Likewise, its induction in NAc by antidepressants is required for the therapeutic-like effects of these drugs (Vialou et al, 2010). "
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    ABSTRACT: Chronic social defeat stress in mice produces a susceptible phenotype characterized by several behavioral abnormalities consistent with human depression, that are reversed by chronic but not acute exposure to antidepressant medications. Recent work in addiction models demonstrates that the transcription factor ?FosB and protein kinase CaMKII are co-regulated in nucleus accumbens (NAc), a brain reward region implicated in both addiction and depression models including social defeat. Previous work has also demonstrated that ?FosB is induced in NAc after chronic social defeat stress or after chronic antidepressant treatment, where it mediates a pro-resilience or antidepressant-like phenotype. Here, using chromatin immunoprecipitation (ChIP) assays, we found that ?FosB binds the CaMKIIα gene promoter in NAc, and that this binding increases after mice are exposed to chronic social defeat stress. Paradoxically, chronic exposure to the antidepressant fluoxetine reduces binding of ?FosB to the CaMKIIα promoter, and reduces CaMKII expression in NAc, despite the fact that ?FosB is induced under these conditions. These data suggest a novel epigenetic mechanism of antidepressant action, whereby fluoxetine induces some chromatin change at the CaMKIIα promoter which blocks ?FosB binding. Indeed, chronic fluoxetine reduces acetylation and increases lysine 9 dimethylation of histone H3 at the CaMKIIα promoter in NAc, effects also seen in depressed humans exposed to antidepressants. Overexpression of CaMKII in NAc blocks fluoxetine's antidepressant effects in the chronic social defeat paradigm, while inhibition of CaMKII activity in NAc mimics fluoxetine exposure. These findings suggest that epigenetic suppression of CaMKIIα expression in NAc is behaviorally relevant and offer a novel pathway for possible therapeutic intervention in depression and related syndromes.Neuropsychopharmacology accepted article preview online, 15 November 2013. doi:10.1038/npp.2013.319.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 11/2013; 39(5). DOI:10.1038/npp.2013.319 · 7.83 Impact Factor
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