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. Within medial prefrontal cortex, inhibitory neurons expressing parvalbumin are important for updating strategies in a rule shift task. 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, 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behavioral strategies by synchronizing callosal communication and preventing it from inappropriately maintaining outdated neural representations.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, and identify long-range projections from prefrontal parvalbumin neurons as a key circuit locus for understanding and treating these deficits.

Cell type-specific dynamics of prefrontal gamma synchrony during flexible behavior

“…We first show that γ-Synchrony emerges in PVI rapidly following outcomes on trials which involve a decision conflict between the old and new rules, specifically when mice are in the process of adopting a new strategy (Fig 2). This was a surprising result as previous work from our lab has primarily seen increases in γ-Synchrony following error trials 16,22 . However, this difference is likely due to the modified task used here.…”

Acute psilocybin enhances cognitive flexibility in rats

“…At the level of neuronal networks, psilocybin may impact set-shifting by modulating neuronal activity in mPFC both directly, via activation of 5HT receptors, as well as indirectly via its effects on neuromodulatory regions that project to frontal cortex. Recent results that show a preeminent role of inhibitory interneurons in mediating strategy switching [55,56] and increased expression of activity-dependent genes in inhibitory neurons in the mPFC following psilocybin administration [57] support this notion. Psilocybin also impacts the activity in the dorsal raphe nucleus (DRN) and the locus coeruleus (LC) [58–62].…”

Acute psilocybin enhances cognitive flexibility in rats

“…At the level of neuronal networks, psilocybin may impact setshifting by modulating neuronal activity in mPFC both directly, via activation of 5HT receptors, as well as indirectly via its effects on neuromodulatory regions that project to frontal cortex. Recent results that show a preeminent role of inhibitory interneurons in mediating strategy switching [53,54] and increased expression of activity-dependent genes in inhibitory neurons in the mPFC following psilocybin administration [55] support this notion. Psilocybin also impacts the activity in the dorsal raphe nucleus (DRN) and the locus coeruleus (LC) [56][57][58][59][60].…”