∆FosB: A transcriptional regulator of stress and antidepressant responses

Abstract

ΔFosB is a member of the Fos family of transcription factors. While other family members are induced rapidly but transiently in response to a host of acute stimuli, ΔFosB is unique in that it accumulates in response to repeated stimulation due to its unusual protein stability. Such prolonged induction of ΔFosB, within nucleus accumbens (NAc), a key brain reward region, has been most studied in animal models of drug addiction, with considerable evidence indicating that ΔFosB promotes reward and motivation and serves as a mechanism of drug sensitization and increased drug self-administration. In more recent years, prolonged induction of ΔFosB has also been observed within NAc in response to chronic administration of certain forms of stress. Increasing evidence indicates that this induction represents a positive, homeostatic adaptation to chronic stress, since overexpression of ΔFosB in this brain region promotes resilience to stress, whereas blockade of its activity promotes stress susceptibility. Chronic administration of several antidepressant medications also induces ΔFosB in the NAc, and this induction is required for the therapeutic-like actions of these drugs in mouse models. Validation of these rodent findings is the demonstration that depressed humans, examined at autopsy, display reduced levels of ΔFosB within the NAc. As a transcription factor, ΔFosB produces this behavioral phenotype by regulating the expression of specific target genes, which are under current investigation. These studies of ΔFosB are providing new insight into the molecular basis of depression and antidepressant action, which is defining a host of new targets for possible therapeutic development.

Treatment-resistant depression: are animal models of depression fit for purpose?

“…Viral-mediated overexpression of GluA2 in the same structure also induced resilience to social defeat (Nestler 2015). The effects of chronic fluoxetine were abolished in mice with a viral-induced overexpression of deltafosB or CaMKII within the accumbens (Nestler 2015). However, in this model, antidepressant resistance is not associated with increased stress sensitivity.…”

“…Overexpression of DeltaFos within the nucleus accumbens (achieved either using bitransgenic mice or by viral injection) promotes resilience to chronic social defeat, whereas increased expression of deltaJun in the same area has the opposite effects (Nestler 2015). Viral-mediated overexpression of GluA2 in the same structure also induced resilience to social defeat (Nestler 2015).…”

Brain activation induced by chronic psychosocial stress in mice

“…While the parent isoform FOSB is rapidly induced and degraded, the ∆FOSB form accumulates through repeated stimuli during a course of a chronic treatment, with each acute stimulus inducing a low level of ΔFOSB, and the repeated stress exposure causing the gradual increase in its total levels 20 . Since the estimated half-life of ΔFOSB is 8 days it is a useful marker for repeatedly activated neurons [20][21][22] . In contrast to MEMRI that enables brain-wide mapping of neural activation and activity-dependent connectivity, ∆FOSB immunohistochemistry detects nuclear activation with high cellular resolution.…”

The role of chromatin repressive marks in cognition and disease: A focus on the repressive complex GLP/G9a

“…Using microarrays the authors found two interesting aspects; (a) repeated cocaine exposure led to enhanced gene expression compared to animals that were acutely treated with cocaine and (b) overexpression of G9a (HSV-G9a) in the NAc was sufficient to block the cocainedependent increase in gene expression (Maze et al, 2010). Amongst others, FosB and Bdnf expression were increased by chronic cocaine consumption (Nestler, 2014a(Nestler, , 2014b. G9a and H3K9me2 enrichment in FosB/DFosB and Bdnf VI promoters was reduced when animals were chronically treated with cocaine (Maze et al, 2010) (I.…”