Oxytocin receptor Gαi signaling drives valence reassignment to facilitate reversal of social trauma-induced avoidance

Abstract Traumatic social experiences often generate social deficits that form the core symptom of psychopathologies like social anxiety disorder (SAD). The failure to overwrite these aversive social associations is a fundamental barrier to recovery from SAD. Using the mouse social fear conditioning (SFC) paradigm, we identify a discrete population of oxytocin receptor (OXTR)-expressing neurons in the caudal lateral septum (LSc OXTR ) that act as a critical hub for adaptive learning during social fear extinction. Using calcium imaging in mice undergoing extinction training, we show that successful valence reassignment is best predicted by the precise temporal inhibition of LSc OXTR neurons during the contact phase of social investigation. This contact-associated suppression of LSc OXTR neurons was absent in mice that failed to extinguish fear. Notably, successful extinction was also associated with enhanced oxitocinerg innervation within the LSc. Chemogenetic silencing of LSc OXTR neurons prior to extinction impaired extinction, indicating that a specific temporal activity pattern of LSc OXTR neurons is necessary for adaptive learning. Pharmacological dissection of downstream OXTR signaling revealed that selective activation of Gαi-coupled, but not Gαq-coupled, signaling accelerated extinction and promoted social approach. Our findings establish that extinction success is governed by the temporally precise, Gαi-mediated silencing of LSc OXTR neurons during social contact, revealing a novel mechanism for adaptive social valence processing with direct implications for treatment-resistant SAD.