The multifaceted involvement of subregions of the rat prefrontal cortex in the formation of enduring associative olfactory memory

Enduring memory engrams initially depend on the hippocampus but progressively shift toward cortical networks during systems consolidation. How these extrahippocampal regions cooperate to establish remote, corticalized memories remains poorly understood. Using a socially transmitted food preference paradigm combined with c-fos activity mapping, we identified distinct contributions of rat prefrontal subregions-including the orbitofrontal (OFC), medial prefrontal (mPFC), anterior cingulate (ACC), and posterior cingulate (PCC) cortices-to recent and remote olfactory associative memory retrieval. Activity patterns revealed a time-dependent reorganization of cortical circuits: the OFC and ACC were preferentially recruited during remote memory retrieval, whereas the PCC was more active for recent memory. Fos imaging and chemogenetic manipulations further demonstrated that the mPFC supports both encoding and retrieval of recent and remote memory, indicating a dual role compared with other prefrontal areas. Despite widespread neuronal activation, cortical engram formation follows a rostral-caudal functional gradient, where discrete prefrontal subregions exhibit distinct activation kinetics. These findings reveal that enduring memory consolidation involves coordinated, region-specific reorganization within the prefrontal cortex, with the mPFC acting as a central hub ensuring the integration and persistence of olfactory associative memories across time.