For decades, numerous seminal studies have built our understanding of the locus coeruleus (LC), the vertebrate brain’s principal noradrenergic system. Containing a numerically small but broadly efferent cell population, the LC provides brain-wide noradrenergic modulation that optimizes network function in the context of attentive and flexible interaction with the sensory environment. This review turns attention to the LC’s roles during sleep. We show that these roles go beyond down-scaled versions of the ones in wakefulness. Novel dynamic assessments of noradrenaline signaling and LC activity uncover a rich diversity of activity patterns that establish the LC as an integral portion of sleep regulation and function. The LC could be involved in beneficial functions for the sleeping brain, and even minute alterations in its functionality may prove quintessential in sleep disorders.

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.