Locus coeruleus norepinephrine activity mediates sensory-evoked awakenings from sleep

Abstract

A defining feature of sleep is reduced responsiveness to external stimuli, but the mechanisms mediating sensory-evoked arousal remain unclear. We hypothesized that reduced locus coeruleus (LC) norepinephrine (NE) activity during sleep mediates unresponsiveness, and its action promotes sensory-evoked awakenings. We tested this using electrophysiological, behavioral, pharmacological, and optogenetic techniques alongside auditory stimulation in freely behaving rats. We found that systemic reduction in NE signaling lowered probability of sound-evoked awakenings (SEAs). The level of tonic LC activity during sleep anticipated SEAs. Optogenetic LC activation promoted arousal as evident in sleep-wake transitions, EEG desynchronization, and pupil dilation. Minimal LC excitation before sound presentation increased SEA probability. Optogenetic LC silencing using a soma-targeted anion-conducting channelrhodopsin (stGtACR2) suppressed LC spiking and constricted pupils. Brief periods of LC opto-silencing reduced the probability of SEAs. Thus, LC-NE activity determines the likelihood of sensory-evoked awakenings, and its reduction during sleep constitutes a key factor mediating behavioral unresponsiveness.This work was supported by the Israel Science Foundation (ISF) grants 1326/15 and 51/11 (I-CORE cognitive sciences) and the Adelis Foundation (to Y.N.). E.J.K. is an INSERM fellow. O.Y. is supported by the European Research Council (ERC-2013-StG OptoNeuromod 337637) and the Adelis Foundation. CAV2 vector production was supported by CNRS BioCampus (Montpellier). A.S. is a Wellcome Trust-funded PhD student on the Neural Dynamics program. A.J.K. is supported by the ISF grant 762/16 and the European Society of Anaesthesiology young investigator startup gran