Medial prefrontal cortex activity precedes dorsomedial striatum in need for change during history-based flexible...

Being cognitively flexible is vital for survival, and its impairment is central to many psychiatric and neurodegenerative disorders. Both the medial prefrontal cortex (mPFC) and dorsomedial striatum (DMS) are essential for cognitive flexibility, but their specific roles-particularly which region first detects and encodes environmental changes-remain debated. Using head-restrained mice in a choice task based on action-outcome history, we show that many mPFC and DMS neurons represent the difference in reward history between options, a decision variable guiding advantageous choices. Crucially, mPFC encodes this variable earlier and more rapidly than DMS. Temporally targeted optogenetic interference with mPFC representation impairs decision-making. Moreover, functional connectivity between mPFC and DMS strengthens as the overall reward proportion declines. Our results support a framework in which the prefrontal cortex acts as the initial detector of inferred environmental changes, enhancing communication with the striatum to promote adaptive and flexible behavior.