Acute social defeat induces cannabinoid type 1 receptor-dependent synaptic depression in the anterior ventral subiculum to anterior hypothalamic nucleus pathway to drive social avoidance in male mice

BACKGROUND: Social avoidance is a protective response that limits exposure to harmful social stimuli. Although avoidance is a characteristic stress phenotype, its circuit-level regulation remains unclear. The ventral subiculum (vSUB), a major hippocampal output, projects to the anterior hypothalamic nucleus (AHN), a key region for stress responses. METHODS: Male mice underwent acute social defeat stress (ASDS) or subthreshold social defeat stress. We combined social interaction, open field, and elevated plus maze testing with optogenetic-assisted slice recording, pharmacology, pathway-specific chemogenetics and optogenetics, retrograde and anterograde transsynaptic tracing, and in situ hybridization. RESULTS: ASDS induced presynaptic depression at anterior vSUB (avSUB) → AHN synapses through a glucocorticoid- and cannabinoid type 1 receptor (CB1R)-dependent mechanism, while posterior vSUB (pvSUB) → AHN synapses were unaffected. Infusing a CB1R antagonist into the AHN before ASDS attenuated both the synaptic depression and the social avoidance. Chemogenetic activation of the avSUB → AHN pathway during ASDS attenuated social avoidance, whereas its inhibition induced avoidance under subthreshold stress. Optogenetic activation of the avSUB → AHN pathway produced an immediate increase in social approach. Anterograde tracing revealed that anterior and posterior vSUB neurons project to largely separate AHN populations. The pvSUB → AHN pathway modulates anxiety-like behavior without altering social approach. CONCLUSIONS: These findings reveal specialized roles for vSUB subregions in social and emotional responses, and identify presynaptic gating of the avSUB → AHN synapse as a control point for stress-induced social withdrawal.