Long-range inhibition synchronizes and updates prefrontal task activity

Abstract Changes in patterns of activity within the medial prefrontal cortex enable rodents, non-human primates, and humans to update their behavior to adapt to changes in the environment, e.g., during cognitive tasks 1–5 . Within medial prefrontal cortex, inhibitory neurons expressing parvalbumin are important for updating strategies in a rule shift task 6–8 . Nevertheless, causal mechanisms through which parvalbumin neurons recruit specific circuits to produce prefrontal network dynamics that switch from maintaining to updating task-related patterns of activity remain unknown. Here we identify a new long-range inhibitory projection from prefrontal parvalbumin neurons to the contralateral cortex that mediates this process. Whereas nonspecifically inhibiting all callosal projections does not prevent mice from learning rule shifts, selectively inhibiting these callosal parvalbumin projections disrupts rule shift learning, desynchronizes gamma-frequency activity that is necessary for learning 8 , and suppresses changes in prefrontal activity patterns that normally accompany rule shifts. Thus, callosal parvalbumin projections switch prefrontal circuits from maintaining to updating behavioral strategies by synchronizing callosal communication and preventing it from inappropriately maintaining outdated neural representations. These findings may explain how deficits in prefrontal parvalbumin neurons and gamma synchrony cause impaired behavioral flexibility in schizophrenia 9–10 , and identify long-range projections from prefrontal parvalbumin neurons as a key circuit locus for understanding and treating these deficits.