Locus coeruleus activity fluctuations set a non-reducible timeframe for mammalian NREM-REM sleep cycles

The noradrenergic locus coeruleus (LC) is vital for brain states underlying wakefulness, whereas its roles for sleep remain uncertain. Combining mouse sleep-wake monitoring, behavioral manipulations, LC fiber photometry and closed-loop optogenetics, we found that LC neuronal activity partitioned non-rapid-eye-movement sleep (NREMS) into alternating brain and autonomic states that rule the NREMS-REMS cycle. High LC activity levels generated an autonomic-subcortical arousal state that facilitated cortical microarousals, while low levels were obligatory for REMS entries. Timed optogenetic LC inhibition revealed that this functional alternation set the duration of the NREMS-REMS cycle by ruling REMS entries during undisturbed sleep and when pressure for REMS was high. A stimulus-enriched, stress-promoting wakefulness increased high LC activity levels at the expense of low ones in subsequent NREMS, fragmenting NREMS through microarousals and delaying REMS onset. We conclude that LC activity fluctuations gatekeep the NREM-REMS cycle over recurrent infraslow intervals, but they also convey vulnerability to adverse wake experiences.