Neuropeptidergic transmission shapes emergent properties of prefrontal cortical circuits underlying learning

The prefrontal cortex (PFC) is essential for top-down control of affect and its dysfunction is implicated in many psychiatric disorders. Inhibitory interneurons expressing somatostatin have been implicated in cognition, affect, and disease. However, somatostatin's function as a neuropeptide transmitter remains unclear. Here, we investigated the contribution of somatostatin neurotransmission in differentiating between salient (rewarding or aversive) and neutral outcomes. Monitoring somatostatin release and somatostatin receptor antagonism revealed time-dependent regulation of outcome-specific associative learning during acquisition. We found that somatostatin transmission enables configural representations incorporating a salient, aversive outcome in prefrontal cortical neurons, and a threat-driven shift in population-level network activity in-vivo. These findings show a novel role for somatostatin, an interneuron "cellular marker", signaling in shaping learning and emergent network dynamics. Further this framework revealed that reduced somatostatin neuropeptidergic transmission may impair top-down control of affective behaviors observed in mental health disorders, suggesting potential new avenues for therapeutic intervention.