SEX-DEPENDENT MODULATION OF FEAR MEMORY BY TAC2-POSITIVE NEURONS IN THE LATERAL HYPOTHALAMUS

The Tac2 gene encodes the neuropeptide neurokinin B (NkB), which primarily binds with the neurokinin 3 receptor (Nk3R). Notably, recent studies have shown opposite sex-dependent effects on fear memory consolidation following pharmacological blockade of this pathway, suggesting sex-specific mechanisms of Tac2 signaling. However, the neural circuits through which Tac2 regulates fear memory, and how they differ between sexes, remain incomplete. To address this gap, we first quantified protein levels of NkB and Nk3R in female and male mice across fear-related brain regions. Among the studied areas, the lateral hypothalamus (LH) revealed a consistently higher basal NkB expression in females compared to males. The LH is a highly enriched NK3R region that has been shown to play a critical role in modulating autonomic defensive behaviors. Based on these observations, we next explored the involvement of Tac2-positive neurons in LH in fear memory processing. Tac2-cre mice were injected with AAV-hSyn-DIO-hM4Di-mCherry in LH, and neuronal activity was inhibited via deschloroclozapine or vehicle administration 30 minutes after fear acquisition. Interestingly, this manipulation resulted in sex-divergent effects by promoting impairment in fear memory consolidation in males, meanwhile increasing it in female mice. Altogether, these findings suggest LH Tac2-positive neurons as a key, sex-dependent regulator of fear memory consolidation and provide new insights into the Tac2 neural circuit mediating sex-differences in fear-related behaviors.