Infraslow locus coeruleus activity coordinates spindle rhythms and heart rate to gate fluctuating non-REM sleep substates

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 1- and {beta}-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.