New advances in molecular and neural mechanisms of sleep regulation

Sleep exists ubiquitously among invertebrate and vertebrate animals. While sleep survives millions of years of evolution, it is unclear exactly what essential functions that sleep provides to animals. Sleep and wakefulness are mainly regulated by circadian and homeostatic mechanisms [1, 2]. However, the molecular and neural mechanisms of sleep regulation, especially in mammals, remain unclear. This special issue consisted of four review articles cover some of the new exciting advances in sleep research.

In recent years, there has been a rapid expansion of our knowledge on the neural pathways that control wakefulness, rapid eye movement (REM) sleep and non-REM (NREMS) sleep [3– 5]. The paraventricular nucleus of the hypothalamus (PVH) is an important hub for regulating neuroendocrine and autonomic functions, complex behaviors and negative emotions after stress [6]. Jiang et al. provide a focused and thorough review of emerging anatomical and neuroscience research supporting a critical role of PVH in the promotion and maintenance of wakefulness [7].

The core molecular pathways and biochemical mechanisms that govern mammalian sleep regulation remain to be elucidated. Funato and Yanagisawa wrote a nice review of forward and reverse mouse genetics studies in search for mammalian sleep regulatory genes [8]. Notably, their previous studies of orexin knockout mice uncover the mechanistic link between orexin deficiency and human sleep disorder–narcolepsy [9]. A tour-de-force forward genetic screen of randomly mutagenized mice has identified Sik3 and Nalcn as key regulators of NREM and REM sleep, respectively [10]. Moreover, the advent of new genome-editing tools, such as CRISPR/Cas9, has greatly expedited identification of new sleep regulatory genes by reverse mouse genetics [11– 13].

Although most human adults sleep on average 8 hours per day, there are natural short sleepers (NSS) who need only 4 to 6.5-h sleep per day without any obvious negative health consequences. Zheng and Zhang reviewed human genetic studies that identified the causative mutations in a series of NSS families in the last decade [14]. Understanding the genetic basis of NSS provides an opportunity to study not only the genetic mechanism of human sleep, but also relationship between sleep and physiological function [14].

Apart from genetic factors, environmental factors also exert major influences on sleep quantity and quality. Public health measures to prevent the spread of COVID-19, have caused unprecedented social isolation on a global scale since 2020. Social isolation is a major risk factor for sleep disturbances and other adverse health outcomes. Vora et al. reviewed the impact of social isolation on sleep and other behaviors in the fruit flies, and implications of these research to studies of social isolation in humans [15].

It is an exciting time for sleep research. We envision that genetic studies of the worm, fly, fish, mouse and human will solve the fundamental questions of why do we sleep and how is sleep regulated in the foreseeable future. Deep understanding of the molecular and neural mechanisms of sleep regulation will facilitate the development of new and mechanism-based sleep medicines for treatment of many sleep disorders.