Infraslow noradrenergic locus coeruleus activity fluctuations are gatekeepers of the NREM-REM sleep cycle

The noradrenergic locus coeruleus (LC) regulates arousal levels during wakefulness, but its role in sleep remains unclear. Here, we show in mice that fluctuating LC neuronal activity partitions non-rapid-eye-movement sleep (NREMS) into two brain-autonomic states that govern the NREMS-REMS cycle over ~50-s periods; high LC activity induces a subcortical-autonomic arousal state that facilitates cortical microarousals, whereas low LC activity is required for NREMS-to-REMS transitions. This functional alternation regulates the duration of the NREMS-REMS cycle by setting permissive windows for REMS entries during undisturbed sleep while limiting these entries to maximally one per ~50-s period during REMS restriction. A stimulus-enriched, stress-promoting wakefulness was associated with longer and shorter levels of high and low LC activity, respectively, during subsequent NREMS, resulting in more microarousal-induced NREMS fragmentation and delayed REMS onset. We conclude that LC activity fluctuations are gatekeepers of the NREMS-REMS cycle and that this role is influenced by adverse wake experiences.