Intercalated Amygdala Dysfunction Drives Avoidance Extinction Deficits in the Sapap3 Mouse Model of Obsessive-Compulsive Disorder

Background: The avoidance of aversive stimuli through negative reinforcement learning, which demands dynamic responding to both positive and negative stimuli that often conflict with each other, is critical for survival in real-world environments. Individuals with obsessive-compulsive disorder commonly exhibit impaired negative reinforcement and extinction, perhaps involving deficits in amygdala functioning. The intercalated nuclei of the amygdala (ITC) is an amygdala subregion of particular interest that has been linked to negative reinforcement and extinction, with distinct clusters mediating separate aspects of behavior. This study focuses on the dorsal ITC cluster (ITC_d) and its role in negative reinforcement during a complex behavior that models real-world dynamic decision making.

Methods: We investigated the impact of ITC_d function on negative reinforcement and extinction by applying fiber photometry measurement of GCaMP6f signals and optogenetic manipulations during a platform-mediated avoidance task in a mouse model of obsessive-compulsive disorder-like behavior, the Sapap3-null mouse.

Results: We found impaired neural activity in the ITC_d of male and female Sapap3-null mice to the encoding of negative stimuli during platform-mediated avoidance. Sapap3-null mice also exhibited deficits in extinction of avoidant behavior, which were modulated by ITC_d neural activity.

Conclusions: Sapap3-null mice failed to extinguish avoidant behavior in platform-mediated avoidance due to heightened ITC_d activity. This deficit was rescued by optogenetically inhibiting ITC_d during extinction. Together, our results provide insight into the neural mechanisms that underlie negative reinforcement deficits in the context of obsessive-compulsive disorder and emphasize the necessity of ITC_d in responding to negative stimuli in complex environments.