Women experience major depressive disorder (MDD) nearly twice as often as men, but the neurophysiology of this sex difference in prevalence is not fully understood. In preclinical animal models of depression utilizing male mice, activity of glutamatergic afferents from ventral hippocampus (vHPC) to nucleus accumbens (NAc) regulates mood-related behavioral responses to stress, but the circuit-level mechanisms underlying stress responses in female mice are not as clear. Female mice, however, uniquely exhibit susceptibility to anhedonia, a common symptom of depression, following subchronic variable stress (SCVS). Using whole-cell patch clamp electrophysiology, we identify a lower excitability of male vHPC-NAc projections compared to those in female mice. We demonstrate that the lower excitability in male projections is adult testosterone-dependent, and that this accompanies resilience to anhedonia in males following stress: orchidectomy induces increased vHPC-NAc excitability and susceptibility to SCVS in male mice, and exogenous testosterone levels vHPC-NAc excitability and mitigates anhedonia susceptibility in ovariectomized female mice. We further demonstrate a causal link between vHPC-NAc excitability and SCVS susceptibility using designer receptors exclusively activated by designer drugs (DREADDs), with circuit activity inversely correlated to anhedonia resilience in both sexes. We also find that anhedonia following SCVS requires an extended increase in vHPC-NAc activity, as activation of vHPC-NAc only during behavioral assessment does not result in decreased sucrose preference in male mice. Using translating ribosome affinity purification (TRAP), we interrogate male and female vHPC-NAc circuit-specific gene expression and uncover differential expression of genes in multiple pathways that may regulate differing circuit excitability between the sexes, and ultimately may explain sex differences in SCVS susceptibility. Lastly, we investigate the role of ΔFosB, a transcription factor known to reduce HPC excitability, in vHPC-NAc neurons in male and female mice, and demonstrate that this molecule is a key influencer of chronic social defeat stress (CSDS) responses in male mice. This study highlights hormone-dependent differences in vHPC-NAc circuit excitability in adult mice, which are directly causative of resilience to SCVS-induced anhedonia, and identifies sex differences in vHPC-NAc gene transcription that may mediate sex-specific responses to stress and depression pathogenesis.
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