Handbook of Sleep Research

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• Publisher: Academic Press
• Year: 2019
• Print ISBN: 9780128137437
• eBook ISBN: 9780128137444
• Topic: Biological Sciences
• Subtopic: Neuroscience
• Index: Biological Sciences

Handbook of Sleep Research, Volume 30, provides a comprehensive review of the current status of the neuroscience of sleep research. It begins with an overview of the neural, hormonal and genetic mechanisms of sleep and wake regulation before outlining the various proposed functions of sleep and the role it plays in plasticity, and in learning and memory. Finally, the book discusses disorders of sleep and waking, covering both lifestyle factors that cause disrupted sleep and psychiatric and neurological conditions that contribute to disorders.- Emphasizes a comparative and multidisciplinary approach to the topic of sleep- Covers the neurobiology and physiology of sleep stages, mechanisms of waking, and dreaming- Discusses in detail the proposed functions of sleep, from health and rest, to memory consolidation and synaptic plasticity- Examines the current state of research in mammalian and non-mammalian species, ranging from primates to invertebrates

Part B

Regulation Of Waking And Sleeping

Chapter 5

The Circuit, Cellular, and Synaptic Bases of Sleep-Wake Regulation

Elda Arrigoni; Patrick M. Fuller Department of Neurology and Division of Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States

Abstract

While considerable progress has been made in our understanding of how the brain regulates sleep and wakefulness, including the transitions between sleep and wakefulness, important knowledge gaps persist. In this chapter, we review the experimental work undertaken by scientist over the past 100 years that has informed our modern-day understanding of sleep-wake neurobiology. We now know, for example, that sleep and wake are actively regulated processes and that they are subserved by discrete cell populations, circuit pathways, and transmitters, which we discuss herein. A particularly prominent role for the brain's fast neurotransmitters, glutamate and GABA, in the regulation of wake and sleep has recently emerged, in turn informing the revision of long-standing models of the neurochemical basis of wake and sleep. It is expected that newer and more efficacious drugs for treating disorders of sleep and arousal will be one important product of our revised understanding of the neurochemical milieu of sleep-wake. Perhaps most importantly, however, the experimental work directed at the “how” of sleep and wake has provided several important clues as to the “why” of sleep, which is widely considered to be one of the greatest mysteries in the neurosciences.

Keywords

EEG; Circadian; REM sleep; NREM sleep; Basal forebrain; Narcolepsy; Hypothalamus; Brain stem; ARAS

I Introduction

The “why” of sleep is considered by many scientists to be one of the most enduring mysteries and important questions in the neurosciences. Sleep appears to be as vital to our existence as water and food, we spend ~ 1/3 of our lives sleeping, and all animals sleep, yet we still do not understand, at least not fully, the why of sleep. Underscoring our fascination with sleep, it has been the topic of writings since the beginning of the recorded history. For example, the ancient Hindu textbook Upanishad (~ 1000 BC) described four states of “vigilance,” two of which correspond to the sleeping state, that is, non-rapid eye movement sleep and rapid eye movement sleep. The ancient philosopher Aristotle wrote an entire essay on sleep that he titled “On sleep and sleeplessness” in 350 BC. And Hippocrates, the famous ancient physician, was the first to emphasize the importance of sleep to health, as he writes in aphorism that “bad sleep and insomnolence, when immoderate, are bad.” And as one prominent sleep scientist, Allan Rechtschaffen, remarked, “If sleep doesn’t serve an absolutely vital function, it is the biggest mistake evolution ever made.” In short, the adaptive advantage of having our brains go “off-line” for any extended period of time remains unclear. After all, the time spent in the sleep state is a time of heightened vulnerability and represents “downtime” with respect to pursuing biological imperatives like eating and drinking and, certainly from the standpoint of ones’ genes, procreating. On the flip side of this, if an animal, be that a human or a mouse, could go without sleep, this would appear highly adaptive, in particular given that there would be more time to find food, mate, exploit the environment, conquer territory, learn, and so forth. Our present understanding is that sleep does many things, which may include synaptic remodeling, clearing out wake-accumulated toxins from the brain, and ensuring that memories are formed, but these processes, even collectively, are likely only a partial and somewhat unsatisfactory answer.

With respect to the “how” of sleep, more the ostensible focus of this chapter, the first true “theory of sleep” is likely credited to Lucretius who in the first century BC hypothesized that sleep was a passive phenomenon and reflected only the cessation of wake. Lucretius's theory became the predecessor to the “deafferentation theory,” which persisted for many years and held that sleep is initiated passively when sensory inputs fall below a threshold necessary to maintain cortical arousal. Interestingly, implicit in these theories of sleep is that wakefulness is the default and actively regulated state of our existence. Contemporary models of sleep-wake regulation, which are discussed herein, reflect a deeper understanding of the circuit, cellular, and synaptic substrates underlying different states of vigilance and, in particular, hold both sleep and wakefulness to be active processes requiring the participation of specific sleep- and wake-promoting neurons. We may not yet fully understand the “why” and “how” of sleep, but as described herein, scientists are closing in on answers to these important knowledge gaps.

II The Phenomenology of Sleep, Wake and the Sleep-Wake Cycle

Over the course of a typical 24 hour day, the brain cycles through three behavioral states, each of which is operationally defined by the level of behavioral arousal and electrocortical activity. Sleep, for example, is a behavioral state characterized by a decreased sensitivity to stimuli, stereotypic posture, a reduction in motor activity (as measured by the electromyogram, EMG), and a distinctive cortical electroencephalogram (EEG; see Fig. 5.1). The rapid reversibility and self-regulating aspect of sleep are two key features that differentiate the sleep state from other states of altered consciousness, such as coma and anesthesia (Rechtschaffen & Kales, 1968). On the other hand, the behavioral state of wake is characterized by a high level of alertness or vigilance, often occurring concurrently with motor behaviors, and a more “active” cortical EEG.

Fig. 5.1 The EEG characterizing the waking state contains desynchronized high-frequency, low-amplitude waves. The “quiet wake/drowsy” EEG with the eyes closed contains waves in the 8–13 Hz range that are termed alpha waves. During stage N1 of NREM sleep, the EEG becomes slower, and theta waves (4–7 Hz and “sawtooth” in appearance) emerge. During stage N2 of NREM sleep, both “sleep spindles” (phasic burst of 11–16 Hz) and “K-complexes” (a well-delineated negative sharp wave followed immediately by a positive component) appear in the EEG. During stages 3 and 4 (now combined into stage N3 in the 2007 AASM manual, see text) of NREM sleep, high-amplitude slow waves (also called delta waves) in the 1–4 Hz range appear. Finally, during REM sleep (stage R), the EEG transitions to a high-frequency, low-amplitude activity that resembles stage N1 of NREM sleep and, also, conjugate saccades are seen in the EOG (not shown) that reflect the rapid eye movements that occur and give this behavioral state its name.

During the earliest stage of the transition from wake to sleep, commonly referred to as “quiet wakefulness” or “quiet rest,” EEG oscillations predominate in the 8–13 Hz range and are referred to as alpha rhythm. At the onset of non-rapid eye movement (NREM) sleep, EEG frequency slows, and waves become larger in amplitude reflecting increased cortical synchrony. In humans, NREM sleep has been classically described as being composed of four stages; however, the American Academy of Sleep Medicine (AASM) has recently published an updated set of rules used for the staging of human sleep. In the updated AASM manual, the three behavioral states of wake, NREM sleep, and REM sleep are still conceptualized on the basis of the EEG, electrooculogram (EOG), and EMG; however, stages 3 and 4 of NREM sleep are now combined into a single stage (N3) that is characterized by epochs consisting of 20% or more slow-wave activity of frequency 0.5–2 Hz and amplitude > 75 μV as measured over the frontal regions (Iber, Ancoli-Israel, Chesson, & Quan, 2007).

During stage 1 (N1) of NREM sleep, conscious awareness of the external environment disappears, and the EEG slows further, with oscillations predominating in the 4–7 Hz theta range. Stage 2 (N2) is typified by a complete loss of conscious awareness and the appearance of “sleep spind...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• Preface: Sleep Research in the 21st Century—Advances and Challenges
• Part A: Brain Activity During Sleep and Waking
• Part B: Regulation Of Waking And Sleeping
• Part C: Rem Sleep And Dreaming
• Part D: Evolution, Cross-Cultural and Comparative Approaches, and Novel Model Systems
• Part E: Sleep, Plasticity, and Memory
• Part F: Sleep, Emotion, and Motivation
• Part G: Disturbed Sleep
• Part H: Sleep In Aging and Disease
• Index