Hippocampus consolidates memory in the upstate of cortical sleep slow oscillations

Cortical slow oscillations (SOs), a hallmark of non-rapid eye movement (NonREM) sleep, have been proposed to support systems memory consolidation by organizing hippocampal-cortical communication. However, whether consolidation requires hippocampal memory processing during SO-defined windows is unclear. Here, we used closed-loop optogenetics to transiently inhibit dorsal hippocampal activity in adult rats (N = 12) during NonREM sleep following object-place association learning, either during cortical SO upstates or outside SOs, compared with a no-stimulation control. Inhibition during SO upstates completely abolished expression of memory at retrieval, despite preserved sleep architecture and intact cortical SO and spindle dynamics. By contrast, inhibition outside SOs preserved memory and only slightly reduced performance compared to the no-stimulation control. Memory impairment from hippocampal inhibition was largely mediated by SO upstates nesting spindles. Our findings provide novel evidence that sleep-dependent systems consolidation requires precisely timed hippocampal-neocortical dialogue.