SEX-DEPENDENT TAC2–NK3R SIGNALING IN THE LATERAL HYPOTHALAMIC AREA REGULATES FEAR MEMORY

Recent findings indicate that neural circuits underlying memory formation may be sex specific. In rodents, Tac2 projections from the central medial amygdala (CeM) to the posterior part of the bed nucleus of the stria terminalis (BNST) are required for fear memory consolidation in males but not in females. Consistently, pharmacological blockade of its receptor, Neurokinin 3 (Nk3R), impairs fear memory consolidation in male mice while enhancing it in females. Notably, the lateral hypothalamic area (LHA) represents the major downstream target of Tac2 projections from both the CeM and BNST. Dissection of the LHA tachykinergic system reveals a finely tuned organization comprising two distinct neuronal populations: (I) GABAergic Tac2-expressing neurons co-expressing Serpin1, and (II) glutamatergic neurons expressing Nk3R and co-expressing Pmch and Cartpt, with no Tac2 expression. To investigate the role of this circuitry in fear memory processing, calcium dynamics in the LHA were recorded using miniscope imaging in male and female mice following administration of an Nk3R antagonist 30 minutes after fear acquisition (FA). This manipulation elicited sex-dependent patterns of LHA neuronal activity. We next examined whether these effects could be recapitulated by inhibiting BNST Tac2 inputs to the LHA. Using a Cre/Flp-dependent chemogenetic strategy to selectively inhibit BNST-to-LHA Tac2 projections after fear acquisition, we found that pathway inhibition impaired fear memory retrieval in males while enhancing it in females. Together, these results suggest that interactions between BNST-derived Tac2 GABAergic projections and Nk3R-expressing glutamatergic neurons in the LHA may contribute to the sex-specific regulation of fear memory.