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Brain Circuitry Controlling Sleep and Wakefulness

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Brain Circuitry Controlling Sleep and Wakefulness Review Article Address correspondence to Dr John H. Peever, Brain Circuitry Department of Cell and Systems Biology, University of Toronto, 25 Harbord St, Controlling Sleep and Toronto, ON M5S 3G5, Canada, [email protected]. Relationship Disclosure: Wakefulness Dr Horner has received personal compensation for serving as a consultant for Richard L. Horner, PhD; John H. Peever, PhD Dairy Farmers of Canada and Viord Inc and receives royalties from BookBaby for his book, The Universal ABSTRACT Pastime: Sleep and Rest Purpose of Review: This article outlines the fundamental brain mechanisms that Explained. Dr Horner has control sleep-wake patterns and reviews how pathologic changes in these control received grants from Canada Research Chair (950-229813), mechanisms contribute to common sleep disorders. the Canadian Institutes of Recent Findings: Discrete but interconnected clusters of cells located within the Health Research (MT-15563), brainstem and hypothalamus comprise the circuits that generate wakefulness, nonYrapid and the National Sanitarium Association Innovative eye movement (non-REM) sleep, and REM sleep. These clusters of cells use specific Research Program (00144051). neurotransmitters, or collections of neurotransmitters, to inhibitorexcitetheirrespective Dr Peever has received grant sleep- and wake-promoting target sites. These excitatory and inhibitory connections support from the Canadian Institutes of Health Research. modulate not only the presence of wakefulness or sleep, but also the levels of arousal Unlabeled Use of within those states, including the depth of sleep, degree of vigilance, and motor activity. Products/Investigational Dysfunction or degeneration of wake- and sleep-promoting circuits is associated with Use Disclosure: narcolepsy, REM sleep behavior disorder, and age-related sleep disturbances. Drs Horner and Peever report no disclosures. Summary: Research has made significant headway in identifying the brain circuits that * 2017 American Academy control wakefulness, non-REM, and REM sleep and has led to a deeper understanding of Neurology. of common sleep disorders and disturbances. Continuum (Minneap Minn) 2017;23(4):955–972. INTRODUCTION sleep, the other being sleep intensity. From birth until death, the human Sleep intensity, or depth, is commonly brain spends one or more periods of measured as the difficulty in waking each 24-hour day in wakefulness and someone up from sleep in response to the remaining hours in sleep. Differ- a given stimulus, such as an auditory ent people sleep different amounts tone. Such an index of sleep depth is (typically 7 to 9 hours per day) to correlated with the prominence of equip them with optimal alertness, high-voltage slow waves in the EEG. attention, performance, and executive Based on the distribution of sleep function. Figure 1-1 summarizes the stages throughout the night, normal recommendations for sleep time du- sleep is typically characterized by: rations across the life span based on (1) deep nonYrapid eye movement an extensive literature review by a (non-REM) sleep predominating at panel of scientists and clinicians.1 the beginning of the night, (2) lighter The physiologic and neurobiological non-REM sleep and increasing in- mechanisms that influence the timing trusions of wakefulness toward the of sleep onset and offset are intro- end of the night, and (3) increasing duced in this article. REM sleep amounts and intensity Sleep duration is one of the two throughout the night. The brain mech- major components underlying optimal anisms that generate these states of Continuum (Minneap Minn) 2017;23(4):955–972 ContinuumJournal.com 955 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Sleep and Wakefulness FIGURE 1-1 Sleep amounts across the human life span. According to a report by the National Sleep Foundation, recommended amounts (hours) of sleep are shown for each age range and are arranged in the following categories: recommended, may be appropriate, and not recommended. Data from Hirshkowitz M, et al, Sleep Health.1 sleephealthjournal.org/article/S2352-7218%252815%252900015-7/fulltext. KEY POINTS wakefulness, non-REM, and REM sleep influence specific components of sleep h Different people sleep are the major focus of this article, behavior. Examples of such drugs and different amounts, but which serves as a key to understanding their mode of action on aspects of the normal healthy adults where the breakdown or pathophysio- sleep-wake circuitry will be discussed generally sleep between logic changes occur in the different in appropriate sections of this review. 7 and 9 hours per day. However, daily sleep sleep disorders. Individuals experience what would times vary among be classified as normal sleep behavior BRAIN MECHANISMS OF people and across their when the activity of these cell clusters life spans. WAKEFULNESS AND SLEEP andcircuitschangeinanormally h Cell groups located Several discrete clusters of cells exist coordinated sequence in time and primarily in the in distinct regions of the brain that place within the brain. However, sleep 2,3 brainstem and together comprise the interconnected disorders are common and varied. hypothalamus function circuits generating the states we recog- Suboptimal timing or quality of sleep to drive the individual nize as wakefulness, non-REM sleep, can occur as a result of two major behavioral states of and REM sleep. These interconnecting factors that are not mutually exclusive: sleep and wakefulness. clusters of brain cells use individual (1) a primary sleep disorder (eg, insom- These cell groups are neurotransmitters, or collections of nia, narcolepsy, restless legs syndrome, mutually connected neurotransmitters, to inhibit or excite sleep-related breathing problems, and and use specific their target sites. These excitatory and circadian rhythm sleep-wake disor- neurotransmitters to inhibitory connections modulate not ders) or (2) lifestyle influences (eg, promote each brain only the presence of wakefulness or phase shifts due to occupational or state by either inhibiting or activating their sleep per se, but also the levels of recreational activities such as shift work, respective target sites. arousal within those states, including lack of exposure to direct sunlight, or the depth of sleep, degree of vigilance, extended nocturnal exposure to artifi- and motor activity. Some commonly cial light). used drugs modulate these excitatory Each of these sleep disorders is intro- and inhibitory connections and thus duced and explained in subsequent exert alerting or sedating properties or articles in this issue. However, two 956 ContinuumJournal.com August 2017 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS important overarching principles are cordingly, this article first introduces h Sleep is optimized when outlined in this introductory discussion the brain mechanisms that generate the sleep period is on sleep neurobiology and physiology the states of wakefulness and sleep. The aligned with an that relate to sleep disorders: article then focuses on sleep disorders individual’s circadian 1. Sleep is best optimized when the (narcolepsy and RBD) to highlight how body clock. sleep period is appropriately current research findings are identifying h Diffuse circuits located aligned with an individual’s the pathophysiologic underpinnings of in the brainstem, circadian body clock (ie, when the mechanisms and management of hypothalamus, and the sleep type is aligned with such disorders. basal forebrain chronotype). Misalignment or contain glutamate, mismanagement of this optimal Wakefulness-Generating norepinephrine, relationship can result in Circuits histamine, serotonin, experiences of poor sleep quality, Several neuronal groups contribute to dopamine, and orexin, inappropriate sleepiness, and the brain activation of wakefulness, which serve to promote wakefulness. sleep initiation or maintenance which is characterized by low-voltage insomnia. Such misalignment and fast-wave EEG activity and rest- occurs in shift work sleep ing postural motor tone in the EMG. disorder, advanced or delayed Lesions or degeneration of the ascend- sleep-wake phase disorders, ing projections of the arousal circuits and irregular sleep-wake can produce excessive sleepiness and phase disorder.2 are thought to underlie the outbreak of 2. Sleep parasomnias are best encephalitis lethargica in the 1920s.7,8 explained by the basic premise Drug-induced modulation of these that sleep and wakefulness are circuits facilitates sedation and sleep. not mutually exclusive states and Of significance to the initial discus- can dissociate. Such dissociation sion of wakefulness-generating systems can result in components of are the neuronal groups containing behaviors that are normally norepinephrine, histamine, serotonin, associated with wakefulness and dopamine (Figure 1-2A). Because temporarily overlapping with of commonalities in the chemical sleep.4,5 Such overlap causes a structure of these neuromodulators, class of sleep disorders that are they are collectively grouped under classified as the parasomnias the term monoamines.Othercell and defined as behaviors or groups also contribute to the activated experiences intruding into brain state of wakefulness. Accordingly, sleep.2,6 This overlap of waking orexin (hypocretin), acetylcholine, and and sleep behaviors/experiences glutamate-containing cell groups are produces identifiable and
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