Intercalated amygdala dysfunction drives extinction deficits in theSapap3mouse model of obsessive-compulsive disorder

Abstract

ABSTRACTBackgroundThe avoidance of aversive stimuli due to negative reinforcement learning is critical for survival in real-world environments, which demand dynamic responding to both positive and negative stimuli that often conflict with each other. Individuals with obsessive-compulsive disorder (OCD) commonly exhibit impaired negative reinforcement and extinction, perhaps involving deficits in amygdala functioning. An amygdala subregion of particular interest is the intercalated nuclei of the amygdala (ITC) which has been linked to negative reinforcement and extinction, with distinct clusters mediating separate aspects of behavior. This study focuses on the dorsal ITC cluster (ITCd) and its role in negative reinforcement during a complex behavior that models real-world dynamic decision making.MethodsWe investigated the impact of ITCdfunction 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 OCD-like behavior: theSapap3-null mouse.ResultsWe find impaired neural activity in the ITCdof male and femaleSapap3-null mice to the encoding of negative stimuli during platform-mediated avoidance.Sapap3-null mice also exhibit deficits in extinction of avoidant behavior, which is modulated by ITCdneural activity.ConclusionsSapap3-null mice fail to extinguish avoidant behavior in platform-mediated avoidance, due to heightened ITCdactivity. This deficit can be rescued by optogenetically inhibiting ITCdduring extinction. Together, our results provide insight into the neural mechanisms underpinning negative reinforcement deficits in the context of OCD, emphasizing the necessity of ITCdin responding to negative stimuli in complex environments.