Modulation of Neuronal Ensembles Switches Memory Flexibility via Hippocampal Network Resynchronization

Engram cells are formed during learning and store memory information. However, little is known about the modulation of engram cells on time-dependent memory flexibility. Employing a male mouse model, we demonstrated that a temporal factor dictates the memory state, driving either pattern separation or pattern completion. Reengagement of engram cells in the dentate gyrus (DG) during memory retrieval in altered contexts was higher during pattern separation than during pattern completion, concomitant with a time-dependent reduction in synaptic transmission. Specific activation of DG engrams promoted pattern separation, whereas their inhibition accelerated pattern completion. Furthermore, activating DG engrams not only prolonged sharp-wave ripple (SWR) duration and enhanced theta-gamma phase-amplitude coupling (PAC) in CA1, but also strengthened cross-regional theta (DG) -gamma (CA1) PAC and gamma (DG-CA1) coherence. Conversely, their inhibition resulted in diminished SWR durations, attenuated these PACs, and reduced DG-CA1 gamma coherence. Finally, elevated Rac1 activity within DG engrams accelerated pattern completion, while reduced activity facilitated pattern separation. These findings show that engram cells drive time-dependent memory flexibility via neural network resynchronization. Significance Statement Memories are not static; they evolve from precise discrimination (pattern separation) to generalization (pattern completion) over time. However, the neural mechanisms linking cellular memory traces to this behavioral shift remain unclear. We demonstrate that the reactivation level of specific "engram cells" in the dentate gyrus acts as a master switch for this transition. Maintaining high engram engagement preserves memory precision by driving synchronized network oscillations, whereas their inhibition accelerates generalization. These findings bridge the gap between cellular engram dynamics and system-level network synchrony, revealing a fundamental mechanism by which the brain regulates memory flexibility.