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: 10.26). 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, Sep 28, 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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    • "Nuclear protein isolation was done following a published protocol [76]. Please refer to Additional file 7 for details. "
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    ABSTRACT: Increasing evidence supports a role for altered gene expression in mediating the lasting effects of cocaine on the brain, and recent work has demonstrated the involvement of chromatin modifications in these alterations. However, all such studies to date have been restricted by their reliance on microarray technologies that have intrinsic limitations. We use next generation sequencing methods, RNA-seq and ChIP-seq for RNA polymerase II and several histone methylation marks, to obtain a more complete view of cocaine-induced changes in gene expression and associated adaptations in numerous modes of chromatin regulation in the mouse nucleus accumbens, a key brain reward region. We demonstrate an unexpectedly large number of pre-mRNA splicing alterations in response to repeated cocaine treatment. In addition, we identify combinations of chromatin changes, or signatures, that correlate with cocaine-dependent regulation of gene expression, including those involving pre-mRNA alternative splicing. Through bioinformatic prediction and biological validation, we identify one particular splicing factor, A2BP1(Rbfox1/Fox-1), which is enriched at genes that display certain chromatin signatures and contributes to drug-induced behavioral abnormalities. Together, this delineation of the cocaine-induced epigenome in the nucleus accumbens reveals several novel modes of regulation by which cocaine alters the brain. We establish combinatorial chromatin and transcriptional profiles in mouse nucleus accumbens after repeated cocaine treatment. These results serve as an important resource for the field and provide a template for the analysis of other systems to reveal new transcriptional and epigenetic mechanisms of neuronal regulation.
    Genome biology 04/2014; 15(4):R65. DOI:10.1186/gb-2014-15-4-r65 · 10.81 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 · 2.78 Impact Factor
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