Transformations in prefrontal ensemble activity underlying rapid threat avoidance learning

To survive, animals must rapidly learn to avoid aversive outcomes by predicting threats and taking preemptive actions to avoid them. Often, this involves identifying locations that are safe in the context of specific, impending threats and remaining in those locations until the threat passes. Thus, animals quickly learn how threat-predicting cues alter the implications of entering or leaving a safe location. The prelimbic subregion (PL) of the medial prefrontal cortex (mPFC) integrates learned associations to influence threat avoidance strategies.^{1,2,3,4,5,6,7,8,9,10,11,12} These processes become dysfunctional in mood and anxiety disorders, which are characterized by excessive avoidance.^13,14 Prior work largely focused on the role of PL activity in avoidance behaviors that are fully established,^12,15,16,17 leaving the prefrontal mechanisms driving avoidance learning poorly understood. To determine when and how learning-related changes emerge, we recorded PL neural activity using miniscope Ca²⁺ imaging^18,19 as mice rapidly learned to avoid a cued threat by accessing a safe location. Early in learning, PL population dynamics accurately predicted trial outcomes and tracked individual learning rates. Once behavioral performance stabilized, neurons that encoded avoidance behaviors or risky exploration were strongly modulated by the conditioned tone. Our findings reveal that, during avoidance learning, the PL rapidly generates novel representations of whether mice will take avoidance or exploratory actions during an impending threat. We reveal the sequence of transformations that unfold in the PL and how they relate to individual learning rates.