Locus-coeruleus norepinephrine activity gates sensory-evoked awakenings from sleep

Abstract

<jats:title>Abstract</jats:title><jats:p>A defining feature of sleep is reduced responsiveness to external stimuli, but the mechanisms gating sensory-evoked arousal remain unclear. We hypothesized that reduced locus-coeruleus norepinephrine (LC-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 of 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. Importantly, liminal 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.</jats:p>

Sleep Differentially Affects Early and Late Neuronal Responses to Sounds in Auditory and Perirhinal Cortices

“…propose that the degree of response attenuation in high-order cortex mirrors the depth of sleep as defined behaviorally. Indeed, arousal thresholds in the rat are higher in NREM sleep (compared with REM sleep) and with increased slow-wave activity (Neckelmann and Ursin, 1993;Hayat et al, 2019). Along this line, light NREM sleep is associated with a lower arousal threshold (Ermis et al, 2010;Hayat et al, 2019), and we find it exhibits a more modest response attenuation than both NREM sleep and REM sleep.…”

Sleep differentially affects early and late neuronal responses to sounds in auditory and perirhinal cortices

“…We propose that the degree of response attenuation in high-order cortex mirrors the depth of sleep as defined behaviorally. Indeed, in the rat arousal thresholds are higher in NREM sleep (compared with REM sleep) and with increased slow wave activity (Neckelmann and Ursin, 1993;Hayat et al, 2019). Along this line, light NREM sleep is associated with a lower arousal threshold (Emris et al, 2010;Hayat et al, 2019) and we find it exhibits a more modest response attenuation than both NREM sleep and REM sleep.…”

Redefining Noradrenergic Neuromodulation of Behavior: Impacts of a Modular Locus Coeruleus Architecture

“…A central question that LC research has oft considered is how a broadly projecting nucleus could affect any singular function without affecting them all. For example, LC activation triggers awakening and arousal (Carter et al, 2010;Hayat et al, 2019), which is associated with enhanced sensory discrimination (Aston- Martins and Froemke, 2015) and lowered sensory neuron response thresholds (Waterhouse et al, 1990(Waterhouse et al, , 1998Edeline, 1998, 2004;Bouret and Sara, 2002;Devilbiss and Waterhouse, 2004;Devilbiss et al, 2006;Edeline et al, 2011;Navarra et al, 2013), but this sits at odds with the observation that LC activation is also associated with suppression of nociceptive sensory inputs (analgesia). This apparent paradox is readily demonstrable in attentional analgesia paradigms in humans where LC activity is associated with the interaction between attention (increased visual sensory discrimination) and analgesia (diminished nociceptive percept) (Brooks et al, 2017).…”