Transformations in prefrontal ensemble activity underlying rapid threat avoidance learning.

The capacity to learn cues that predict aversive outcomes, and understand how to avoid those outcomes, is critical for adaptive behavior. Naturalistic avoidance often means accessing a safe location, but whether a location is safe depends on the nature of the impending threat. These relationships must be rapidly learned if animals are to survive. The prelimbic subregion (PL) of the medial prefrontal cortex (mPFC) integrates learned associations to influence these threat avoidance strategies. Prior work has focused on the role of PL activity in avoidance behaviors that are fully established, leaving the prefrontal mechanisms that drive rapid avoidance learning poorly understood. To determine when and how these learning-related changes emerge, we recorded PL neural activity using miniscope calcium imaging as mice rapidly learned to avoid a threatening cue by accessing a safe location. Over the course of learning, we observed enhanced modulation of PL activity representing intersections of a threatening cue with safe or risky locations and movements between them. We observed rapid changes in PL population dynamics that preceded changes observable in the encoding of individual neurons. Successful avoidance could be predicted from cue-related population dynamics during early learning. Population dynamics during specific epochs of the conditioned tone period correlated with the modeled learning rates of individual animals. In contrast, changes in single-neuron encoding occurred later, once an avoidance strategy had stabilized. Together, our findings reveal the sequence of PL changes that characterize rapid threat avoidance learning.