Sleep-modulated disinhibition enables replay for memory consolidation, accelerated by ripples

Memory consolidation involves elusive neural mechanisms. Here, we develop a biophysically detailed model of the entorhinal-hippocampal-cortical network to reveal that disinhibition drives synaptic and systems consolidation. Transitioning to slow-wave sleep via neuromodulatory dampening of inhibition generates up-down states and spontaneous, time-compressed replays of spatial sequences encoded with phase precession. Lateral inhibition levels unify physiological and pathological ripple diversity. Cortical disinhibition enables memory transfer from hippocampus. Weakened afferent CA1 synapses eliminate ripples but spare replays, proposing strategies to mitigate ripple disruptions. Replays sustain systems consolidation even without ripples, albeit slower; excessive weakening halts it, rescuable by enhanced hippocampal-to-cortical connectivity. Medial entorhinal cortex (MEC)-mediated CA1 disinhibition compensates for attenuated neuromodulatory CA1 disinhibition, mimicking MEC-input-dependent quiet wakefulness replay; under this configuration during wakefulness, artificially inducing disinhibition triggers replays and ripples that drive consolidation, underscoring disinhibitions state-agnostic role. These insights elucidate disinhibitions centrality in engraining memories and fostering hippocampal independence, reconciling empirical observations, yielding testable predictions, and identifying therapeutic avenues for memory disorders.