The Neurobiology of Sleep and Wakefulness

Abstract

SYNOPSIS Since the discovery of Rapid Eye Movement (REM) sleep in the late 1950s, identification of the neural circuitry underlying wakefulness, sleep onset and the alternation between REM and non-REM (NREM) sleep has been an active area of investigation. Synchronization and desynchronization of cortical activity as detected in the electroencephalogram (EEG) is due to a corticothalamocortical loop, intrinsic cortical oscillators, monoaminergic and cholinergic afferent input to the thalamus, and the basal forebrain cholinergic input directly to the cortex. The monoaminergic and cholinergic systems are largely wake-promoting; the brainstem cholinergic nuclei are also involved in REM sleep regulation. These wake-promoting systems receive excitatory input from the hypothalamic hypocretin/orexin system. Sleep-promoting nuclei are GABAergic in nature and found in the preoptic area, brainstem and lateral hypothalamus. Although the pons is critical for the expression of REM sleep, recent research has suggested that melanin-concentrating hormone/GABAergic cells in the lateral hypothalamus "gate" REM sleep. The temporal distribution of sleep and wakefulness is due to interaction between the circadian system and the sleep homeostatic system. Although the hypothalamic suprachiasmatic nuclei contain the circadian pacemaker, the neural circuitry underlying the sleep homeostat is less clear. Prolonged wakefulness results in the accumulation of extracellular adenosine, possibly from glial sources, which is an important feedback molecule for the sleep homeostatic system. Cortical neuronal nitric oxide (nNOS) neurons may also play a role in propagating slow waves through the cortex in NREM sleep. Several neuropeptides and other neurochemicals likely play important roles in sleep/wake control. Although the control of sleep and wakefulness seemingly involves multiple redundant systems, each of these systems provides a vulnerability that can result in sleep/wake dysfunction that may predispose to physical and/or neuropsychiatric disorders.

Genetic Pathways to Insomnia

“…The serotonin neurotransmitter system is particularly relevant to depression [48] in addition to having a role in sleep-wake regulation [49], making it a logical candidate gene target. Multiple studies have examined the classic 5-HTTLPR polymorphism (short or long allele) (e.g., [50,51]), as well as polymorphisms in monoamine oxidase A (MAO-A) (e.g., [52]), which is an enzyme that breaks down serotonin, thus contributing to its availability in the brain [48].…”

Revealing the role of the endocannabinoid system modulators, SR141716A, URB597 and VDM-11, in sleep homeostasis

“…In the last decades, accumulating reports have suggested that the sleep-wake cycle is under control of a complex neurobiological network which includes neuroanatomical, neurochemical and molecular components (Murillo-Rodrı´guez et al, 2012;Zeitzer, 2013;Saper, 2013;Fernandes et al, 2015;Schwartz and Kilduff, 2015). In parallel, further complicatedness in the understanding of sleep mechanism has been pointed-out due to that circadian and homeostatic factors influence sleep processes (Curie et al, 2013Houben et al, 2014;Borbely et al, 2016).…”

Neurobiological Role of Hypocretin in Regulation of Psychiatric Disorders

“…For example, waking is modulated by the activity of diverse neurotransmitter systems such as noradrenaline, dopamine, serotonin, acetylcholine, histamine and hypocretin [3,[15][16][17][18][19][20][21][22][23][24] (Fig. 2).…”