Hyperexcitability of female serotonin neurons underlies sex-specific anxiety responses

Mood disorders display robust sex differences in prevalence, symptom profile, and treatment outcomes, with women nearly twice as likely as men to be diagnosed. However, the neural substrates mediating sex-specific regulation of mood and related disorders remain incompletely understood. Here, we identify a neural circuit mechanism involving serotonergic (5-HT) projections from the median raphe region (MRR) to the ventral hippocampus (vHP) responsible for sex-specific regulation of anxiety-like behavior in mice. Using a multimodal approach combining electrophysiology, fiber photometry, and optogenetics, we show that 5-HT neurons targeting the vHP (5-HTvHP neurons) display heightened intrinsic excitability and delayed deactivation in female mice during exposure to aversive environments. Optogenetic activation of this pathway enhanced anxiety-like behavior, and decreased risk-assessment behavior in females, but not in males. Collectively, our findings establish 5-HTvHP neurons as a critical circuit for the regulation of anxiety and provide a mechanistic framework for understanding how serotonergic modulation contributes to sex-specific vulnerability to mood disorders.