Chemogenetic activation of an infralimbic cortex to basolateral amygdala projection promotes resistance to acute social defeat stress.

Tremendous individual differences exist in stress responsivity and social defeat stress is a key approach for identifying cellular mechanisms of stress susceptibility and resilience. Syrian hamsters show reliable territorial aggression, but after social defeat they exhibit a conditioned defeat (CD) response characterized by increased submission and an absence of aggression in future social interactions. Hamsters that achieve social dominance prior to social defeat exhibit greater defeat-induced neural activity in infralimbic (IL) cortex neurons that project to the basolateral amygdala (BLA) and reduced CD response compared to subordinate hamsters. Here, we hypothesize that chemogenetic activation of an IL-to-BLA neural projection during acute social defeat will reduce the CD response in subordinate hamsters and thereby produce dominant-like behavior. We confirmed that clozapine-N-oxide (CNO) itself did not alter the CD response and validated a dual-virus, Cre-dependent, chemogenetic approach by showing that CNO treatment increased c-Fos expression in the IL and decreased it in the BLA. We found that CNO treatment during social defeat reduced the acquisition of CD in subordinate, but not dominant, hamsters. This project extends our understanding of the neural circuits underlying resistance to acute social stress, which is an important step toward delineating circuit-based approaches for the treatment of stress-related psychopathologies.