Transcriptional determinants of goal-directed learning and representational drift in the parahippocampal cortex

Task learning involves learning associations between stimuli and outcomes and storing these relationships in memory. While this information can be reliably decoded from population activity, individual neurons encoding this representation can drift over time. The circuit or molecular mechanisms underlying this drift and its role in learning are unclear. We performed two-photon calcium imaging in the perirhinal cortex during task training. Using post hoc spatial transcriptomics, we measured immediate-early gene (IEG) expression and assigned monitored neurons to excitatory or inhibitory subtypes. We discovered an IEG-defined network spanning multiple subtypes that form stimulus-outcome associations. Targeted deletion of brain-derived neurotrophic factor in the perirhinal cortex disrupted IEG expression and impaired task learning. Representational drift slowed with prolonged training. Pre-existing representations were strengthened while stimulus-reward associations failed to form. Our findings reveal the cell types and molecules regulating long-term network stability that is permissive for task learning and memory allocation.