Prelimbic cortex ensembles promote appetitive learning-associated behavior

Memories of prior rewards bias our actions and future decisions. To determine the neural correlates of an appetitive associative learning task, we trained male mice to discriminate a reward-predicting cue over the course of 7 d. Encoding, recent recall, and remote recall were investigated to determine the areas of the brain recruited at each stage of learning. Using cFos as a proxy for neuronal activity, we found unique brain-wide patterns of activity across days that seem to correlate with distinct stages of learning. In particular, the prelimbic (PL) cortex was significantly recruited during the encoding of a novel association presentation, but its activity decreases as learning continues. To causally dissect the role of the PL in a reward memory across days, we chemogenetically inhibited first the PL entirely and then only tagged memory-bearing cells that were active during encoding in two stages of learning: early and late. Both nonspecific and specific PL inhibition experiments indicate that the PL drives behavior during late stages of learning to facilitate appropriate cue-driven behavior. Overall, our work underscores memory's role in discriminative reward seeking, and points to the PL as a target for modulating disorders in which impaired reward processing is a core component.