Prefrontal control of hippocampal map reorganization during sleep

During wakefulness, encountering unfamiliar experiences triggers hippocampal remapping, a process wherein place cell ensembles reorganize to develop unique representations of the novel information. Classical theories of systems consolidation suggest that subsequent sleep allows these wake-formed representations to stabilize and gradually transfer to medial prefrontal cortex (mPFC) networks, primarily through bottom-up hippocampal reactivations.

To investigate this, researchers employed miniscope Ca2+ imaging of CA1 place cells to monitor hippocampal activity as mice navigated both a familiar and a novel environment. As anticipated, place cells remapped in the novel context. However, a single episode of post-encoding sleep unexpectedly reversed remapping dynamics by favoring the reinstatement of familiar place cell representations in the novel environment, a phenomenon that did not occur during the wake condition.

This neural reinstatement was associated with behavioral indicators of familiarity, such as decreased exploration and rearing. Chemogenetic inactivation of the mPFC during post-encoding sleep disrupted this generalization effect, instead maintaining the novel hippocampal map. Consequently, the findings suggest that sleep does not merely consolidate wake-established hippocampal patterns, but actively shapes hippocampal maps through prefrontal control, thereby facilitating memory generalization.