Importance of the locus coeruleus-norepinephrine system in sleep- wake regulation: Implications for aging and Alzheimer's disease

Five decades ago, seminal studies positioned the brainstem locus coeruleus (LC) norepinephrine (NE) system as a key substrate for the regulation of wakefulness and sleep, and this picture has recently been elaborated thanks to methodological advances in the precise investigation and experimental modulation of LC structure and functions. This review presents and discusses findings that support the major role of the LC-NE system at different levels of sleep-wake organization, ranging from its involvement in the overall architecture of the sleep-wake cycle to its associations with sleep microstructure, while accounting for the intricate neuroanatomy surrounding the LC. Given the particular position held by the LC NE system by being at the intersection of sleep-wake dysregulation and initial pathophysiological processes of Alzheimer's disease (AD), we conclude by examining emerging opportunities to investigate LC NE mediated relationships between sleep-wake alteration and AD in human aging. We further propose several research perspectives that could support the LC-NE system as a promising target for the identification of at-risk individuals in the preclinical stages of AD, and for the development of novel preventive interventions. ?? 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Automated summary

This article reviews the seminal studies from five decades ago that identified the brainstem locus coeruleus norepinephrine system as a key regulator of wakefulness and sleep. It discusses the various roles of this system in the organization of sleep-wake cycles and sleep microstructure, and explores the potential links between sleep-wake alterations and Alzheimer's disease. The article concludes by proposing research perspectives and opportunities for using the locus coeruleus norepinephrine system as a target for identifying individuals at risk of Alzheimer's disease and developing preventive interventions.