Induction of ΔFosB in Reward-Related Brain Structures after Chronic Stress

Abstract

Acute and chronic stress differentially regulate immediate-early gene (IEG) expression in the brain. Although acute stress induces c-Fos and FosB, repeated exposure to stress desensitizes the c-Fos response, but FosB-like immunoreactivity remains high. Several other treatments differentially regulate IEG expression in a similar manner after acute versus chronic exposure. The form of FosB that persists after these chronic treatments has been identified as ⌬FosB, a splice variant of the fosB gene. This study was designed to determine whether the FosB form induced after chronic stress is also ⌬FosB and to map the brain regions and identify the cell populations that exhibit this effect. Western blotting, using an antibody that recognizes all Fos family members, revealed that acute restraint stress caused robust induction of c-Fos and full-length FosB, as well as a small induction of ⌬FosB, in the frontal cortex (fCTX) and nucleus accumbens (NAc). The induction of c-Fos (and to some extent full-length FosB) was desensitized after 10 d of restraint stress, at which point levels of ⌬FosB were high. A similar pattern was observed after chronic unpredictable stress. By use of immunohistochemistry, we found that chronic restraint stress induced ⌬FosB expression predominantly in the fCTX, NAc, and basolateral amygdala, with lower levels of induction seen elsewhere. These findings establish that chronic stress induces ⌬FosB in several discrete regions of the brain. Such induction could contribute to the long-term effects of stress on the brain.

Neonatal Ventral Hippocampal Lesions Produce an Elevation of ΔFosB-Like Protein(s) in the Rodent Neocortex

“…It is thought that the VH modulates the hypothalamic-pituitary-adrenal axis, producing an inhibition of this pathway following stress (Herman et al, 1998;Mitchell and Goldman, 2004). Interestingly, it has recently been shown that chronic stress increases the expression of DFosB in several of the brain regions in which we observed an increase in DFosB following neonatal VH lesions, such as the mPFC, caudate putamen, and nucleus accumbens (Perrotti et al, 2004). It is therefore possible that VH lesions produce a state of enhanced responsiveness to stress resulting in comparable alterations in the activity or neuroendocrine and neuronal pathways that mediate stress-induced increase in DFosB expression.…”

Repeated Unpredictable Stress and Antidepressants Differentially Regulate Expression of the Bcl-2 Family of Apoptotic Genes in Rat Cortical, Hippocampal, and Limbic Brain Structures

“…The stressors, which varied from day to day for a period of 10 days, were administered according to an established paradigm (Willner et al, 1992;Ortiz et al, 1996;Perrotti et al, 2004). This stress paradigm has been previously shown to produce profound effects on a number of cellular, biochemical, and neurochemical end points (Willner et al, 1992;Ortiz et al, 1996;Perrotti et al, 2004).…”

“…The primary goals of this study were: (1) to examine the influence of a 10-day repeated unpredictable stress (RUS) paradigm (Willner et al, 1992;Ortiz et al, 1996;Perrotti et al, 2004) on expression of Bcl-2, Bcl-xl, and Bax mRNAs and (2) to investigate whether treatment with clinically effective antidepressants from distinct pharmacological classes, as well as repeated electroconvulsive seizures (ECS), regulates expression of the apoptotic genes. We extend our analyses from cortex and hippocampus to include previously uncharacterized hypothalamic-limbic brain regions.…”

ΔFosB in the Nucleus Accumbens Regulates Food-Reinforced Instrumental Behavior and Motivation

“…Viral-mediated gene transfer was performed as previously described (Carlezon et al, 1998;Perrotti et al, 2004). In short, cDNAs encoding the specific proteins were inserted into the herpes simplex virus (HSV) amplicon HSV-PrPUC and packaged into the virus using the helper 5dl1.2.…”