The Periaqueductal Gray Selectively Supports Reversal Learning During a Flexible Discrimination Task in Mice

Flexible, goal-directed behavior depends on the ability to update value representations in response to changing contingencies. This ability depends on distributed brain networks, calling for use of whole-brain imaging. Widely used in human research, the challenge of functional fMRI in rodents has only recently been properly addressed, opening the door to whole-brain imaging of behaving mice. Here, we used functional MRI in mice performing a go/no-go odor discrimination task, we compared neural activity during initial cue-reward learning (acquisition) and subsequent contingency reversal. Trial-by-trial estimates of state-action values from a model-free reinforcement-learning algorithm allowed us to dissociate acquisition from reversal-related signals, revealing that ventral striatal responses tracked expected value during acquisition, whereas reversal learning additionally recruited the periaqueductal gray (PAG), a midbrain structure classically linked to threat processing and aversive learning. PAG activity closely followed model-derived signatures of reversal learning, implicating it in the suppression of previously rewarded actions and in updating behavior in the absence of explicit punishment. These findings reveal a previously unrecognized computational role for the PAG in value-based decision-making and cognitive flexibility, and substantiate task-fMRI as a powerful tool to study the rodent brain at a mesoscale resolution.