Adolescent stress impairs postpartum social behavior via anterior insula-prelimbic pathway in mice

Adolescent stress can be a risk factor for abnormal social behavior in the postpartum period, which critically affects an individual social functioning. Nonetheless, the underlying mechanisms remain unclear. Using a mouse model with optogenetics and in vivo calcium imaging, we found that adolescent psychosocial stress, combined with pregnancy and delivery, caused hypofunction of the glutamatergic pathway from the anterior insula to prelimbic cortex (AI-PrL pathway), which altered PrL neuronal activity, and in turn led to abnormal social behavior. Specifically, the AI-PrL pathway played a crucial role during recognizing the novelty of other mice by modulating "stable neurons" in PrL, which were constantly activated or inhibited by novel mice. We also observed that glucocorticoid receptor signaling in the AI-PrL pathway had a causal role in stress-induced postpartum changes. Our findings provide functional insights into a cortico-cortical pathway underlying adolescent stress-induced postpartum social behavioral deficits.