LIGHTING UP THE LATERAL HABENULA: SEX-SPECIFIC 5-HT2C PATHWAYS IN STRESS AND DEPRESSION

Preclinical and clinical evidence indicates that hyperactivity of the lateral habenula (LHb) plays a central role in the onset and persistence of major depressive disorder (MDD), with emerging data suggesting sex-specific differences in LHb function. A potential mechanism involves modulation by the 5-HT2C receptor (5-HT2CR). Previous studies report sex-dependent differences in 5-HT2CR expression and function, and selective activation of this receptor in the LHb is sufficient to induce depression-like behaviour in rodents. Here, we investigate the contribution of LHb 5-HT2CR to sex-specific vulnerability to depression using a transgenic mouse model. Male and female 5-HT2CR-deficient mice and wild-type littermates were exposed to Chronic Unpredictable Mild Stress (CUMS), an established paradigm to induce depression-like phenotypes. Behaviour was assessed using a testing battery targeting core MDD-related domains, including anhedonia, self-care and motivation, anxiety-like behaviour, social interaction, and coping under acute stress. Neuronal activation in the LHb was quantified by immunohistochemical detection of c-Fos. Preliminary results reveal marked sex differences in behavioural profiles across genotypes and stress conditions, with both sex and 5-HT2CR deficiency modulating CUMS-induced outcomes. Notably, CUMS reliably induced a classic depression-like phenotype in wild-type males, accompanied by robust increases in LHb c-Fos expression. While the spatial distribution of c-Fos–positive cells within the LHb was similar across groups, the overall magnitude of LHb activation differed substantially as a function of sex, genotype, and CUMS exposure. Together, these findings highlight sex-specific and receptor-dependent regulation of LHb activity in stress-induced depression and support a critical role for LHb 5-HT2CR in MDD pathophysiology.