The prelimbic cortex arbitrates memory-guided conflict resolution

Balancing reward and avoidance to produce an adaptive behavior is a critical aspect of conflict resolution. Here, we investigated how mice balance reward-seeking and avoidance during memory-guided conflict resolution. Mice were trained to combine the drive to approach a reward and avoid a foot shock without compromising either goal. During training, mice learn that a light cue signals the availability of reward and an auditory cue signals the onset of a foot shock which they can avoid by stepping onto a platform. During testing, the light and auditory cues are delivered simultaneously, creating a conflict between reward-seeking and punishment avoidance. Our results demonstrate that mice learn to flexibly accommodate behavioral drives to maximize rewards while avoiding the foot shock. We then leveraged a whole-brain tissue clearing approach to identify sex-specific whole-brain activity profiles, and specifically identified the PL as a central hub. Using calcium imaging, we found PL activity signals task variables and predicts successful conflict resolution. Finally, silencing PL engrams disrupts the balance between reward seeking and avoidance behaviors. These findings reveal the PL's mechanistic role in guiding behavioral flexibility in a sex-specific manner.