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DOI: 10.1101/2023.05.20.541586

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

A.Osorio-Forero G. Foustoukos R. Cardis ...+3 A. Luthi
The noradrenergic locus coeruleus (LC) supports vital brain functions during wakefulness. In contrast, the LC has been associated with sleep-promotion and -disruption, leaving its functions for sleep uncertain. Here, we show that the LC is essential for the progression of natural, undisturbed sleep because it creates a non-reducible timeframe for the non-rapid-eye-movement (NREM) sleep-REM sleep cycle. Fiber-photometric jGCaMP8s-based LC activity measures, closed-loop optogenetics and mouse sleep-wake monitoring revealed that LC showed ~50-s-activity fluctuations, during which high activity levels promoted a NREMS with high arousability, while low levels a NREMS with the opportunity for transitions to REMS. The NREMS-REMS cycle was shortened by LC inhibition due to precocious REMS onset. Supporting LC's pivotal role as a gatekeeper of the NREMS-REMS cycle, REMS entries occurred on intervals no shorter than ~50 s during REMS-restriction. A stimulus-enriched wake experience strengthened LC fluctuations, which contributed to subsequent NREMS fragmentation and delayed REMS. The LC fluctuations are hence indispensable for the NREMS-REMS cycle but they can become sleep-disruptive as a result of prior wake experience.