Dual anterior insula-prefrontal cortex circuits mediate chronic stress-induced social interaction deficits

Chronic emotional stress (CES) impairs social behavior, but the underlying neural mechanisms remain unclear. Using a CES mouse model, we identified susceptible (SUS) individuals with social fear and diminished novelty preference. We further identified two distinct subpopulations of projection neurons within the dorsal part (AID) and the ventral part (AIV) of insular cortex-AID^CaMKIIα and AIV^CaMKIIα-that encode social fear and social novelty preference by targeting the frontal association (FrA) and prelimbic (PrL) cortex, respectively. Moreover, hyperactivation of AID^CaMKIIα→FrA drives social avoidance, while hypoactivity of AIV^CaMKIIα→PrL underlies social novelty preference deficits. Mechanistically, these changes are mediated by increased local inhibition from parvalbumin-positive (PV⁺) interneurons and reduced oxytocin receptor (OXTR) signaling in PrL gamma-aminobutyric acidergic (GABAergic) interneurons. Restoring AIV^CaMKIIα→PrL activity or enhancing OXTR signaling rescues social novelty preference. Our study reveals segregated insula-prefrontal circuits that differentially regulate social fear and novelty motivation, providing circuit-specific targets for treating stress-induced social impairments.