Role of Nuclear Factor κB in Ovarian Hormone-Mediated Stress Hypersensitivity in Female Mice

Background: The molecular mechanisms of stress-induced depressive behaviors have been characterized extensively in male rodents; however, much less is known about female subjects, despite the fact that human depression is far more prevalent in women. Methods: To gain insight into these mechanisms, we performed microarray analysis in nucleus accumbens (NAc), a key brain reward region implicated in depression, in ovariectomized (OVX) and gonadally intact female mice after chronic unpredictable stress and measured stress-induced depression-like behavior in the forced swim test (FST). Male mice were studied in the FST for comparison. Results: We find that stress regulation of genes in NAc of gonadally intact female mice is blunted in OVX mice. This pattern of gene regulation is consistent with behavioral findings on the FST: the pro-depression-like effect of stress in intact female mice is absent in OVX female and gonadally intact male mice. We identified, among many genes regulated by stress, several nuclear factor κB (NFκB) subunits-a pro-survival transcription factor involved in cellular responses to stress-as being highly upregulated in NAc of OVX mice. Given the role of NFκB during stress, we hypothesized that upregulation of NFκB by OVX decreases susceptibility to stress. Indeed, we show that inhibition of NFκB in NAc of OVX animals increases susceptibility to stress-induced depressive behaviors, whereas activation of NFκB in NAc of intact female subjects blocks susceptibility. Conclusions: These results suggest a hormonal mechanism of NFκB regulation that contributes to stress-induced depressive behaviors in female subjects and might represent a mechanism for gender differences in prevalence rates of these disorders in humans.