Oxytocin attenuates fear learning via enhancing somatostatin interneuron-mediated local GABAergic inhibition in the prelimbic cortex.

Acute stress exposure can trigger post-traumatic stress disorder (PTSD). Prophylactic interventions may enhance psychological resilience against PTSD in high-risk occupations. Here, we demonstrate that pretreating with intranasal oxytocin exerts prolonged yet reversible attenuation of fear learning via oxytocin receptors (OxtRs) expressed in prelimbic cortex (PL). Crucially, both local PL oxytocin infusion and selective activation of PL OxtR+ neurons recapitulate this fear reduction. Although OxtRs are expressed on pyramidal and somatostatin (SST) neurons, SST interneurons exhibit higher Oxtr expression. Both fear conditioning and oxytocin application preferentially excite PL OxtR+ SST interneurons. Accordingly, preactivating OxtR+ SST neurons, but not OxtR+ pyramidal neurons, elicits the reduction effect on fear learning. Ablating Oxtr in γ-aminobutyric acid (GABA) neurons or silencing SST interneurons abolishes oxytocin's fear-attenuating effects. Mechanistically, OxtR+ SST interneuron activation or oxytocin application potentiates GABAergic synaptic transmission onto PL pyramidal neurons. Collectively, these findings establish that oxytocin attenuates fear learning by enhancing local inhibitory circuits in PL, revealing a potential therapeutic approach for reducing PTSD risk.