BookR: School of Health Core Facilities Booking

Adaptive behavior depends on a dynamic balance between acquisition and extinction memories. Male and female rodents differ in extinction learning rates, suggestion potential sex-based differences in this balance. In males, deletion of extinction-recruited neurons in the central nucleus (CN) of the amygdala impairs extinction retrieval, shifting behavior toward acquisition (Lay et al., 2023). Here, we tested whether this mechanism also operates in females. In contrast to previously reported findings in males, deleting extinction-recruited CN neurons after single or extended extinction training had no effect on extinction retrieval in female rats. This lack of behavioral impact was not due to sex differences in CN activation during extinction. However, during early extinction, females showed greater activity in the basolateral amygdala (BLA) than males. Deletion of this BLA ensemble produced a more substantial reduction in conditioned approach than in non-deletion controls. These findings uncover a potential interplay between the CN and BLA in regulating conditioned approach in females. While ablation of extinction-recruited CN neurons do not modulate extinction retrieval in females, targeted BLA neuronal ablation during early extinction shifts behavior toward low, extinction-level responding. Thus heightened BLA activation during early extinction may prevent the emergence of extinction-like behavior in females. These findings, taken together with those reported by Lay et al. (2023) offer new insights into potential sex-based differences in the neural mechanisms underlying extinction and may inform the development of sex-based treatments for cue-triggered appetitive behaviors.Significance Statement This manuscript uncovers a neural mechanism that explains why females take longer to inhibit previously learned behavior. Together with findings reported in Lay et al. (2023), we uncover that the BLA and CN play complementary roles in balancing acquisition and extinction memories-BLA supports acquisition-based responses, which dominate during the early stages of extinction in females, while CN facilitates extinction-based responding, which develops faster in males. The CN-dependent extinction process, however, was not obtained in the females. This novel mechanism may account for the observed sex differences in disorders where competing memories influence behavior, such as drug abuse versus abstinence or anxiety versus cue-exposure therapy.