Cognitive flexibility, the ability to alter strategy according to changing stimulus-response-
reward relationships, is critical for updating learned behavior. Attentional set-shifting, a test
of cognitive flexibility, depends on the activity of prefrontal cortex (PFC). It remains unclear,
however, what role PFC neurons play to support set-shifting. Using optogenetics and two-
photon calcium imaging, we demonstrate that medial PFC activity does not bias
sensorimotor responses during set-shifting, but rather enables set-shifting by encoding trial …

Cognitive flexibility, the ability to alter one's strategy in light of changing stimulus-response-
reward relationships, is critical for acquiring and updating learned behavior by trial and
error. Successful performance of attentional set-shifting, a test of cognitive flexibility, has
been shown to critically involve the prefrontal cortex (PFC). It is unclear, however, whether
PFC neurons support set-shifting behavior by guiding action selection or by monitoring
feedback from completed actions. Using optogenetics and 2-photon calcium imaging, we …