Circuit-specific androgen receptor regulation of hippocampal neuronal excitability

Project Summary Major depressive disorder (MDD) is a highly prevalent psychiatric disorder that has a complex multifactorial etiology, with stress vulnerability emerging as a critical risk factor. MDD disproportionately affects women, with female prevalence almost double that of men, but the biological basis of this sex difference is not understood. Additionally, roughly half of MDD patients do not respond to existing treatments, and therefore there is an urgent need to understand MDD’s biological etiology and the molecular mechanisms underlying sex differences to develop new therapeutic strategies. MDD is associated with abnormalities of the brain’s reward circuitry, and studies have implicated the ventral hippocampal (vHPC) projections to the nucleus accumbens (NAc; vHPC- NAc) in stress-induced susceptibility to anhedonia, the reduced motivation from pleasurable stimuli, in male mice. However, despite the higher prevalence rates of MDD in females, studies that include both male and female subjects are lacking. Our lab used subchronic variable stress (SCVS), which shows an anhedonia phenotype in female mice but not males, to investigate the sex differences in stress-induced anhedonia. We found that female mice are susceptible to SCVS-induced anhedonia and have increased basal vHPC-NAc circuit excitability compared to males. Moreover, vHPC-NAc circuit excitability is reduced by adult testosterone, and I now show that AR on vHPC-NAc neurons are necessary for testosterone-mediated reduction in circuit excitability, but the mechanisms by which androgen receptors (AR) regulate this excitability remain unknown. Here, I will test the hypothesis that ARs reduce excitability of vHPC-NAc neurons by directly changing gene expression in the nucleus. In Aim 1, I will use novel mouse lines to conditionally knockout cytosolic or nuclear AR signaling in male and female mice to determine effects on vHPC-NAc excitability using whole-cell slice electrophysiology. This experiment will reveal the signaling mechanisms by which ARs reduce vHPC-NAc excitability in both sexes and pave the way for investigation of downstream gene targets or signaling mechanisms that could represent novel targets for therapeutic MDD strategies. In Aim 2, I will identify the ion channels mediating the basal sex difference of vHPC-NAc circuit excitability by using pharmacology to selectively isolate channels while using whole-cell slice electrophysiology on male and female control mice. These experiments will elucidate the underpinning of sex differences in this circuit and may lead to specific pharmacological targets that could be used to treat females for MDD. Overall, this research plan will determine the AR signaling pathways involved and the molecular mechanisms underlying vHPC-NAc circuit excitability in both sexes. The knowledge gained from these studies will elucidate how adult testosterone regulates vHPC-NAc circuit function to drive sex-specific behaviors and vulnerability to stress. Critically, this project will also provide me with world-class training in electrophysiology, neuropharmacology, and circuit manipulations in mouse models, propelling my independent career.