Oxytocin attenuates fear learning by enhancing local GABAergic inhibition in prelimbic cortex

Acute stress exposure is a primary trigger for Post-Traumatic Stress Disorder (PTSD), a debilitating condition with limited prophylactic options. Enhancing psychological resilience against fear learning, a core component of PTSD, is a critical therapeutic gap, especially for individuals in high-risk occupations. Oxytocin, a neuropeptide known for its roles in social bonding and anxiety reduction, has emerged as a promising candidate due to its neuromodulatory effects on brain regions involved in fear processing, such as the prelimbic cortex (PL).

Researchers investigated oxytocin's role in fear learning using a preclinical model. They administered intranasal oxytocin pretreatment and also performed local PL oxytocin infusion to assess its impact on fear learning. The study further explored the mechanism by selectively activating OxtR+ neurons within the PL and specifically OxtR+ SST interneurons. They used genetic ablation of Oxtr in GABA neurons and silencing of SST interneurons to confirm the necessity of these pathways. Electrophysiological techniques were employed to measure GABAergic synaptic transmission.

Pretreating with intranasal oxytocin exerted a prolonged, yet reversible, attenuation of fear learning. This effect was recapitulated by both local PL oxytocin infusion and selective activation of PL OxtR+ neurons, confirming the prelimbic cortex as a key site of action. While OxtRs are expressed on both pyramidal and somatostatin (SST) neurons, SST interneurons exhibited higher Oxtr expression. Both fear conditioning and oxytocin application preferentially excited PL OxtR+ SST interneurons. Crucially, preactivating OxtR+ SST neurons, but not OxtR+ pyramidal neurons, elicited the fear reduction effect. Ablating Oxtr in GABA neurons or silencing SST interneurons abolished oxytocin's fear-attenuating effects. Mechanistically, OxtR+ SST interneuron activation or oxytocin application potentiated GABAergic synaptic transmission onto PL pyramidal neurons.

Oxytocin attenuates fear learning by enhancing local inhibitory circuits in the prelimbic cortex via OxtR+ SST interneurons, which then potentiate GABAergic input to pyramidal neurons.