SEROTONERGIC MODULATION OF IDENTIFIED VENTRAL HIPPOCAMPUS OUTPUT PATHWAYS IN ANXIETY

The hippocampus functions as a cognitive hub, with the ventral hippocampus (vHP) encoding and relaying distinct behavior-contingent information to selective downstream targets. Moreover, the vHP receives dense serotonergic input from the raphe nuclei and expresses a diverse repertoire of inhibitory and excitatory serotonin (5-HT) receptors. Our laboratory has shown that optogenetic activation of 5-HT neurons projecting to the vHP (5-HT^vHP) selectively increases anxiety-like behavior in female mice, revealing a sex-specific role for this pathway. However, the neural mechanisms underlying these differences remain unclear. We hypothesize that sex-specific emotional responses arise from physiological differences in serotonergic modulation at both presynaptic and postsynaptic levels. To address presynaptic mechanisms, we investigated the electrophysiological properties of 5-HT^vHP neurons by performing in vitro whole-cell patch-clamp recordings on 5-HT^vHP neurons of adult male and female mice. Female median raphe region 5-HT^vHP neurons shown a uniquely hyperexcitability compared to males and other raphe subregions, suggesting their key role in the sex-specific modulation of anxiety. To address postsynaptic mechanisms, we combined retrograde AAV labeling and fluorescent in situ hybridization to map the expression of key 5-HT receptors (Htr1a, Htr2a, Htr2c, Htr4, Htr5b) across vHP projections to PFC, NAc, LS, LH, and BLA. We hypothesize that 5-HT release in the vHP selectively activates and suppresses distinct pathways, fine-tuning emotional behavior. Our work revealed pathway- and sex-specific differences in the expression pattern of excitatory and inhibitory Htrs. Together, this project defines how serotonergic signaling engages distinct vHP circuits to shape emotion-related behaviors differently in male and female mice.