Elevated dopamine signaling from ventral tegmental area to prefrontal cortical parvalbumin neurons drives conditioned inhibition.

Conditioned inhibition is an important process to suppress learned responses for optimal adaptation, but its underlying biological mechanism is poorly understood. Here we used safety learning (SL)/fear discrimination after fear conditioning as a conditioned inhibition model because it demonstrates the essential properties of summation and retardation. Activity of the dorsomedial prefrontal cortex (dmPFC) parvalbumin (PV) neurons bidirectionally regulates spiking levels of dmPFC excitatory neurons and fear states. Responses to safety cues are increased in dopaminergic (DA) neurons in the ventral tegmental area (VTA) and in PV neurons in dmPFC after SL. Plasticity in the VTA is implicated, since SL requires activation of N-methyl-d-aspartate receptors. Furthermore, in a posttraumatic stress disorder model, impaired SL is associated with impaired potentiation of VTA DA neuron activity. Our results demonstrate a DA-dependent learning process that targets prefrontal inhibitory neurons for suppression of learned responses, and have implications for the pathogenesis and treatment of various psychiatric diseases.