Noradrenergic circuit control of non-REM sleep substates

Abstract

The continuity of non-rapid-eye-movement sleep (NREMS) is essential for its functions. However, many mammalian species, including humans, show NREMS fragility to maintain environmental vigilance. The neural substrates balancing NREMS continuity and fragility substates are unexplored. We show that the locus coeruleus (LC) is necessary and sufficient to generate infraslow (~50 s) continuity-fragility fluctuations in mouse NREMS. Through machine-learning-guided closed-loop optogenetic LC interrogation, we suppressed, locked, or entrained continuity-fragility fluctuations, as evident by LC-mediated regulation of sleep spindle clustering and heart rate variability. Noradrenergic modulation of thalamic but not cortical circuits was required for infraslow sleep spindle clustering and involved rapid noradrenaline increases that activated both α1- and β-adrenergic receptors to cause slowly decaying membrane depolarizations. The LC thus coordinates brain and bodily states during NREMS to engender continuity-fragility, accentuating its role in the physiology of sleep-related sensory uncoupling and as target in sleep disorders showing abnormal cortical and/or autonomic arousability.

Hypothalamic control of noradrenergic neurons stabilizes sleep

“…We then performed in vivo calcium imaging of LC NA neurons in freely behaving knockout (Hcrt KO/KO xDbh-Cre) and control (Dbh-Cre) mice, combined with EEG/EMG recordings. We found that LC NA neurons are periodically reactivated during NREMS, as reported recently 13,14 , in both genotypes (Fig. 2a).…”

“…LC NA neuronal activity increased prior to NREMS to wake transitions in both knockout and control mice (Fig. 2b), consistent with the role of LC NA reactivations in providing a fragility window for transitions 13,14 . However, we found that LC NA reactivations during NREMS are significantly more frequent in hypocretin knockout mice compared to controls (p = 0.0005, unpaired t-test), which resulted from a shorter refractory period (p < 0.0001, unpaired t-test; Fig.…”

“…2e). As LC NA activity is detrimental for the generation of thalamocortical sleep spindles 13 , we also quantified spindles and found a significant reduction in the NREMS spindle density and alternations in spindle characterizations (p < 0.0001, unpaired t-test; Fig. 2f and Supp.…”

“…Locus coeruleus noradrenergic (LC NA ) neurons, which receive the densest projections of hypocretin cells 9 , show periodic reactivations during non-rapid eye movement sleep (NREMS) and can gate sleep to wake transitions 13,14 . Optogenetic activation of LH HCRT or LC NA neurons induces rapid awaking from both NREMS and REMS 15,16 .…”

“…Deletion of hypocretin gene resulted in more frequent LC NA reactivations during NREMS. As these reactivations are a window of sleep fragility and possible awakenings 13,14 , the fragmented NREMS in Hcrt KO/KO mice could be explained by a mediatory role for the hypocretin system that suppresses the LC NA reactivations during sleep. Moreover, a shorter silent period of LC NA neurons required prior to REMS onset can explain more frequent NREMS-REMS transitions in Hcrt KO/KO mice, and a similar mechanism could cause "sleep onset REM period" in human narcolepsy.…”