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

Abstract Precisely timed interactions between hippocampal and cortical neurons during replay epochs are thought to support memory consolidation. Indeed, research has shown 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 behavioural states and how - if at all - it relates to learning. In this study, we sought to address these questions by analysing 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 cell which were particularly locked to hippocampal LFP theta-band oscillations and which were preferentially coordinated with hippocampal replay during offline periods. Further, dMEC synchrony with CA1 replay peaked ∼10ms after replay initiation in CA1, suggesting the distributed replay reflects extra-hippocampal information propagation, and was specific to ‘offline’ periods. Finally, theta-modulated dMEC cells only became coordinated with replay after an animal’s first encounter with a novel spatial environment and then showed a striking experience-dependent increase in synchronisation 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 the consolidation of new memories and highlights phase locking to hippocampal theta oscillations as a potential mechanism by which such cross-structural synchrony comes about. Importantly, as CA1 phase-locking to theta is implicated in the generation of theta sequences, thought to be required for replay expression, we speculate the dMEC theta phase-locking reflects the emergence of distributed hippocampal-dMEC theta sequences and that these may support the commission of memories to long-term cortical storage.