Abstract
To understand what makes sleep vulnerable in disease, it is useful to look at how wake-promoting mechanisms affect healthy sleep. Wake-promoting neuronal activity is inhibited during non-rapid-eye-movement sleep (NREMS). However, sensory vigilance persists in NREMS in animals and humans, suggesting that wake promotion could remain functional. Here, we demonstrate that consolidated mouse NREMS is a brain state with recurrent fluctuations of the wake-promoting neurotransmitter noradrenaline on the ∼50-s timescale in the thalamus. These fluctuations occurred around mean noradrenaline levels greater than the ones of quiet wakefulness, while noradrenaline (NA) levels declined steeply in REMS. They coincided with a clustering of sleep spindle rhythms in the forebrain and with heart-rate variations, both of which are correlates of sensory arousability. We addressed the origins of these fluctuations by using closed-loop optogenetic locus coeruleus (LC) activation or inhibition timed to moments of low and high spindle activity during NREMS. We could suppress, lock, or entrain sleep-spindle clustering and heart-rate variations, suggesting that both fore- and hindbrain-projecting LC neurons show coordinated infraslow activity variations in natural NREMS. Noradrenergic modulation of thalamic, but not cortical, circuits was required for sleep-spindle clustering and involved NA release into primary sensory and reticular thalamic nuclei that activated both α1- and β-adrenergic receptors to cause slowly decaying membrane depolarizations. Noradrenergic signaling by LC constitutes a vigilance-promoting mechanism that renders mammalian NREMS vulnerable to disruption on the close-to-minute timescale through sustaining thalamocortical and autonomic sensory arousability. VIDEO ABSTRACT.
Highlights
The restorative and beneficial effects of sleep arise from its continuity.[1]
Wake-promoting neuronal activity is inhibited during non-rapid-eye-movement sleep (NREMS)
We demonstrate that consolidated mouse NREMS is a brain state with recurrent fluctuations of the wake-promoting neurotransmitter noradrenaline on the $50-s timescale in the thalamus
Summary
The restorative and beneficial effects of sleep arise from its continuity.[1] This requires that behavioral interactions with the sensory environment are suppressed. Birds would crash and dolphins would drown if switching off from the sensory environment were not supplemented by vigilance.[2] Because natural dangers and predators pose a risk to all animals, irrespective of whether they are asleep or awake, it is natural to hypothesize that sleep evolution must have been tightly coupled to vigilance-promoting mechanisms. Neurological and psychiatric conditions underlying sleep disorders are highly diverse, yet identifying their origins remains challenging.[3,4,5] For these reasons, a better estimate of sleep’s vulnerability in the healthy animal and of its neuronal basis is desirable
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