Differences between males and females in how fear memories are formed and extinguished may help explain certain neuropsychiatric conditions like Post-Traumatic Stress Disorder (PTSD). In male mice, we found that silencing specific fibers from the centromedial amygdala (CeM) to the bed nucleus of the stria terminalis (BNSTpl) using chemogenetics impaired their fear memory while stimulating those fibers optogenetically enhanced inhibitory synaptic responses. Imaging calcium activity in freely moving mice showed that fear memory circuits in the BNSTpl differ between sexes. In humans, the TAC3R gene variant (rs2765) was associated with reduced connectivity between the CeM and BNST, impairing fear memory in men but not women. In another study, female mice exposed to acute stress presented impaired fear extinction, linked to increased Pacap and Pac1R expression in the hypothalamus. Similarly, women with PTSD who carried the PAC1R variant (rs2267735) showed similar impairments in fear extinction. These findings highlight how sex-specific neural circuits involved in fear memory may contribute to differences in PTSD susceptibility.

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