SEX DIVERGENCE OF BASOLATERAL AMYGDALA CIRCUIT IN A MOUSE MODEL OF DEPRESSION

Depression is a leading cause of disability worldwide, with women being twice as likely as men to be affected. Beyond reduced activity and motivation, depression is associated with a negative hedonic bias: patients perceive sensory stimuli as less pleasant. However, the neurobiological foundations of disrupted emotional processing and whether they differ between sexes remain poorly understood. In rodents, basolateral amygdala (BLA) circuits play a major role in valence assignment, with pathways responding to positive or negative stimuli. Specifically, BLA-to-Nucleus-Accumbens (NAc) neurons encode emotional valence thereby shaping learning, motivation and action selection. Our objective was thus to elucidate the role of BLA-to-NAc neurons in driving depressive-like phenotype in both sexes. In the Unpredictable Chronic Mild Stress (UCMS) mouse model of depression, we first confirm a negative hedonic bias, using an olfactory preference test. We also demonstrate that UCMS induces a sex-specific depressive-like phenotype across multiple behavioral domains. Notably, we showed reduced BLA-to-NAc activity in UCMS males. In contrast, this pathway exhibits higher activity in females. Consistently, chemogenetic activation of BLA-to-NAc neurons exerted positive antidepressant-like effects in UCMS males, while exacerbating the depressive-like behavior in UCMS females. In parallel with these opposite activity changes, and despite the absence of sex differences in BLA-to-NAc input/output connectivity in controls, we uncovered sex-specific alterations in presynaptic connectivity following UCMS. Overall, our findings suggest that a sex divergence in BLA circuitry might support disrupted emotional processing in depressive states and provide new avenues for translational research to understand the sex-dependent mechanisms underlying depression and treatment efficacy.