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.