Noradrenergic circuit control of non-REM sleep substates

Curr Biol. 2021 Nov 22;31(22):5009-5023.e7. doi: 10.1016/j.cub.2021.09.041. Epub 2021 Oct 13.


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.

Keywords: GRAB sensors; adrenergic receptors; arousability; autonomic nervous system; dopamine-β-hydroxylase; heart rate; noradrenaline; quiet wakefulness; sleep spindles; thalamus.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Animals
  • Electroencephalography
  • Mammals
  • Mice
  • Norepinephrine
  • Prosencephalon
  • Sleep* / physiology
  • Thalamus
  • Wakefulness* / physiology


  • Norepinephrine