Theta-band phase locking during encoding leads to coordinated entorhinal-hippocampal replay

Precisely timed interactions between hippocampal and cortical neurons during replay epochs are thought to support learning. Indeed, research has shown that replay is associated with heightened hippocampal-cortical synchrony. Yet many caveats remain in our understanding. Namely, it remains unclear how this offline synchrony comes about, whether it is specific to particular behavioral states, and how—if at all—it relates to learning. In this study, we sought to address these questions by analyzing coordination between CA1 cells and neurons of the deep layers of the medial entorhinal cortex (dMEC) while rats learned a novel spatial task. During movement, we found a subset of dMEC cells that were particularly locked to hippocampal LFP theta-band oscillations and that were preferentially coordinated with hippocampal replay during offline periods. Further, dMEC synchrony with CA1 replay peaked ∼10 ms after replay initiation in CA1, suggesting that the distributed replay reflects extra-hippocampal information propagation and is specific to “offline” periods. Finally, theta-modulated dMEC cells showed a striking experience-dependent increase in synchronization with hippocampal replay trajectories, mirroring the animals’ acquisition of the novel task and coupling to the hippocampal local field. Together, these findings provide strong support for the hypothesis that synergistic hippocampal-cortical replay supports learning and highlights phase locking to hippocampal theta oscillations as a potential mechanism by which such cross-structural synchrony comes about.