CIRCUIT-SPECIFIC REGULATION OF SOCIAL AVOIDANCE BY THE VENTRAL SUBICULUM-TO-ANTERIOR HYPOTHALAMIC PATHWAYS AFTER STRESS

Social avoidance serves as a protective mechanism to mitigate distress by limiting exposure to harmful social stimuli. While avoidance behavior is a characteristics phenotype of stress responses, the underlying circuit-level modulation remain unclear. The ventral subiculum (vSUB), a major hippocampal output integrating emotional information, projects extensively to the anterior hypothalamus (AHA), a key region for orchestrating stress responses. This study investigated how acute social defeat stress (ASDS) modulates the vSUB-AHA pathway to drive social avoidance behaviors. It was observed that the vSUB-AHA pathway undergoes presynaptic depression during ASDS via a CB1 receptor-dependent mechanism. Through chemogenetic and optogenetic modulation, the vSUB-AHA circuit was shown to selectively regulate social avoidance under various stress conditions. Specifically, chemogenetic activation of the vSUB-AHA pathway during ASDS attenuated social avoidance, whereas its inhibition exacerbated avoidance behavior during subthreshold social defeat stress. Furthermore, optogenetic activation of vSUB terminals in the AHA produced an immediate increase in social approach behaviors. Interestingly, social avoidance and anxiety-like behaviors were found to be differentially regulated along the anterior-posterior (A-P) axis of the vSUB. The anterior vSUB-AHA pathway was implicated in social avoidance, while the posterior vSUB-AHA pathway was associated with anxiety regulation. Notably, anterograde tracing revealed that neurons from the anterior and posterior vSUB project to distinct neuronal populations within the AHA. These findings reveal specialized roles for A-P vSUB subregions in orchestrating social and emotional responses, highlighting the topographical complexity of the vSUB-AHA circuit in stress-related behaviors.