Androgen Regulation of CRF Receptor 1 as a mediator of stress responses

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Project Summary There are striking sex differences in stress/mood associated disorders, such as anxiety and depression with women showing 2-3 fold greater prevalence than men. These differences are believed to be regulated by sex- specific patterns of gonadal hormone exposure and their subsequent effects on brain circuitry. In particular, androgen actions through the cognate androgen receptor (AR) have been shown by our lab and others to suppress the release of stress hormones and decrease stress-related behaviors associated with anxiety and depression. However, the specific neural mechanisms through which androgens act to produce these effects remain largely unknown. Recent studies in our laboratory and others have demonstrated that cells expressing corticotropin releasing factor receptor 1 (CRFR1) are likely critical for androgen regulation of stress responses. CRF signaling through CRFR1 is widely known to regulate anxiety- and depressive-like behaviors as well as activation of the hypothalamic pituitary adrenal (HPA) axis which controls stress hormone (e.g. glucocorticoid) secretion. Our laboratory has demonstrated high levels of AR within CRFR1 neurons in key stress regulating brain regions in the mouse that have previously been implicated as sites for androgen regulation of stress functions ((paraventricular hypothalamus (PVN) and ventral bed nucleus of the stria terminalis (BSTv)). We propose to determine the role of AR, specifically within CRFR1 neurons of the PVN and BSTv, in regulating stress-associated behaviors and the HPA axis. This will be accomplished using a Cre mouse line and viruses designed to knockdown or overexpress AR within Cre-expressing neurons. Overall, we expect these studies will identify critical cell groups that regulate stress-related functions, thus aiding in our understanding of the neurobiological roots of related human disorders, including depression and anxiety.