Elsevier

Sleep Medicine

Volume 8, Issue 4, June 2007, Pages 302-330
Sleep Medicine

Neurobiology of REM and NREM sleep

https://doi.org/10.1016/j.sleep.2007.03.005Get rights and content

Abstract

This paper presents an overview of the current knowledge of the neurophysiology and cellular pharmacology of sleep mechanisms. It is written from the perspective that recent years have seen a remarkable development of knowledge about sleep mechanisms, due to the capability of current cellular neurophysiological, pharmacological and molecular techniques to provide focused, detailed, and replicable studies that have enriched and informed the knowledge of sleep phenomenology and pathology derived from electroencephalographic (EEG) analysis. This chapter has a cellular and neurophysiological/neuropharmacological focus, with an emphasis on rapid eye movement (REM) sleep mechanisms and non-REM (NREM) sleep phenomena attributable to adenosine. The survey of neuronal and neurotransmitter-related brainstem mechanisms of REM includes monoamines, acetylcholine, the reticular formation, a new emphasis on GABAergic mechanisms and a discussion of the role of orexin/hypcretin in diurnal consolidation of REM sleep. The focus of the NREM sleep discussion is on the basal forebrain and adenosine as a mediator of homeostatic control. Control is through basal forebrain extracellular adenosine accumulation during wakefulness and inhibition of wakefulness-active neurons. Over longer periods of sleep loss, there is a second mechanism of homeostatic control through transcriptional modification. Adenosine acting at the A1 receptor produces an up-regulation of A1 receptors, which increases inhibition for a given level of adenosine, effectively increasing the gain of the sleep homeostat. This second mechanism likely occurs in widespread cortical areas as well as in the basal forebrain. Finally, the results of a new series of experimental paradigms in rodents to measure the neurocognitive effects of sleep loss and sleep interruption (modeling sleep apnea) provide animal model data congruent with those in humans.

Introduction

This paper presents an overview of the current knowledge of the neurophysiology and cellular pharmacology of sleep mechanisms. It is written from the perspective that recent years have seen a remarkable development of knowledge about sleep mechanisms, due to the capability of current cellular neurophysiological, pharmacological and molecular techniques to provide focused, detailed, and replicable studies that have enriched and informed the knowledge of sleep phenomenology and pathology derived from electroencephalographic (EEG) analysis. This chapter has a cellular and neurophysiological/ neuropharmacological focus, with an emphasis on rapid eye movement (REM) sleep mechanisms and non-REM (NREM) sleep phenomena attributable to adenosine. A detailed historical introduction to the topics of this chapter is available in the Steriade and McCarley book [1]. For the reader interested in an update on the terminology and techniques of cellular physiology, one of the standard neurobiology texts can be consulted (e.g., [2]). Overviews of REM sleep physiology are also available [1], [3], as well as an overview of adenosine and NREM sleep [4]. The present paper draws on these accounts for the text, and we begin with brief and elementary overviews of sleep architecture and phylogeny/ontogeny to provide a basis for the later mechanistic discussions. Part I treats REM sleep and the relevant anatomy and physiology, and then comments very briefly on the role of hypocretin/orexin in REM sleep control. Part II discusses NREM sleep in the context of adenosinergic mechanisms.

Sleep may be divided into two phases. REM sleep is most often associated with vivid dreaming and a high level of brain activity. The other phase of sleep, NREM sleep or slow wave sleep (SWS), is usually associated with reduced neuronal activity; thought content during this state in humans is, unlike dreams, usually nonvisual and consists of ruminative thoughts. As one goes to sleep, the low voltage fast EEG of waking gradually gives way to a slowing of frequency and, as sleep moves toward the deepest stages, there is an abundance of delta waves, EEG waves with a frequency of 0.5 to <4 Hz and of high amplitude. The first REM period usually occurs about 70 min after the onset of sleep. REM sleep in humans is defined by the presence of low voltage fast EEG activity, suppression of muscle tone (usually measured in the chin muscles) and the presence, of course, of rapid eye movements. The first REM sleep episode in humans is short. After the first REM sleep episode, the sleep cycle repeats itself with the appearance of NREM sleep, and then about 90 min after the start of the first REM period, another REM sleep episode occurs. This rhythmic cycling persists throughout the night. The REM sleep cycle length is 90 min in humans and the duration of each REM sleep episode after the first is approximately 30 min. While EEG staging of REM sleep in humans usually shows a fairly abrupt transition from NREM to REM sleep, recording of neuronal activity in animals presents quite a different picture. Neuronal activity begins to change long before the EEG signs of REM sleep are present. To introduce this concept, Fig. 1 shows a schematic of the time course of neuronal activity relative to EEG definitions of REM sleep. Later portions of this chapter will elaborate on the activity depicted in this figure. Over the course of the night, delta wave activity tends to diminish and NREM sleep has waves of higher frequencies and lower amplitude.

Section snippets

REM sleep

REM sleep is present in all mammals, and recent data suggest that this includes the egg-laying mammals (monotremes), such as the echidna (spiny anteater) and the duckbill platypus. Birds have very brief bouts of REM sleep. REM sleep cycles vary in duration according to the size of the animal, with elephants having the longest cycle and smaller animals having shorter cycles. For example, the cat has a sleep cycle of approximately 22 min, while the rat cycle is about 12 min. In utero, mammals spend

NREM sleep and adenosine

This section focuses on nonrapid eye movement (NREM) sleep and adenosine, with a special focus on the basal forebrain. Another chapter in this volume discusses hypothalamic sleep mechanisms.

References (202)

  • H.H. Webster et al.

    Neurotoxic lesions of the dorsolateral pontomesencephalic tegmentum-cholinergic area in the cat. II. Effects upon sleep–waking states

    Brain Res

    (1988)
  • M. Thakkar et al.

    Chronic low amplitude electrical stimulation of the laterodorsal tegmental nucleus of freely moving cats increases REM sleep

    Brain Res

    (1996)
  • Y. Kayama et al.

    Firing of ’possibly’ cholinergic neurons in the rat laterodorsal tegmental nucleus during sleep and wakefulness

    Brain Res

    (1992)
  • H. Merchant-Nancy et al.

    Brain distribution of c-fos expression as a result of prolonged rapid eye movement(REM) sleep period duration

    Brain Res

    (1995)
  • J.C. Hendricks et al.

    Different behaviors during paradoxical sleep without atonia depend on pontine lesion site

    Brain Res

    (1982)
  • M.F. Trulson et al.

    Raphe unit activity in freely moving cats: correlation with level of behavioral arousal

    Brain Res

    (1979)
  • K. Rasmussen et al.

    Activity of serotonin containing neurons in nucleus centralis superior of freely moving cats

    Exp Neurol

    (1984)
  • R. Cespuglio et al.

    Single unit recordings in the nuclei raphe dorsalis and magnus during the sleep–waking cycle of semi-chronic prepared cats

    Neurosci Lett

    (1981)
  • C. Fornal et al.

    Activity of serotonin containing neurons in nucleus raphe magnus in freely moving cats

    Exp Neurol

    (1985)
  • G.f. Steinfels et al.

    Behavioral correlates of dopaminergic unit activity in freely moving cats

    Brain Res

    (1983)
  • D.C. Brooks et al.

    Brain stem serotonin depletion and ponto-geniculo-occipital wave activity in the cat treated with reserpine

    Neuropharmacology

    (1972)
  • D.J. McGinty et al.

    Dorsal raphe neurons: depression of firing during sleep in cats

    Brain Res

    (1976)
  • R. Lydic et al.

    The time-course of dorsal raphe discharge, PGO waves, and muscle tone averaged across multiple sleep cycles

    Brain Res

    (1983)
  • M.A. Ruch-Monachon et al.

    Drugs and PGO waves in the lateral geniculate body of the curarized rat

    Archives Internationales de Pharmacodynamie et Thérapie

    (1976)
  • T. Honda et al.

    An ultrastructural study of cholinergic and non-cholinergic neurons in the laterodorsal and pedunculopontine tegmental nuclei in the rat

    Neuroscience

    (1995)
  • K. Semba

    Multiple output pathways of the basal forebrain: organization, chemical heterogeneity and roles in vigilance

    Behav Brain Res

    (2000)
  • T.L. Steininger et al.

    Serotonergic dorsal raphe nucleus projections to the cholinergic and noncholinergic neurons of the pedunculopontine tegmental region: a light and electron microscopic anterograde tracing and immunohistochemical study

    J Comp Neurosci

    (1997)
  • J.I. Luebke et al.

    Serotonin hyperpolarizes cholinergic low-threshold burst neurons in the rat laterodorsal tegmental nucleus in vitro

    Proc Natl Acad Sci USA

    (1992)
  • C.M. Portas et al.

    Behavioral state-related changes of extracellular serotonin concentration in the dorsal raphe nucleus: a microdialysis study in the freely moving cat

    Brain Res

    (1994)
  • S.B. Auerbach et al.

    Extracellular serotonin and 5-hydroxyindoleacetic acid in hypothalamus of the unanesthetized rat measured by in vivo dialysis coupled to high-performance liquid chromatography with electrochemical detection: dialysate serotonin reflects neuronal release

    Brain Res

    (1989)
  • L. Imeri et al.

    Changes in the serotonergic system during the sleep–wake cycle: simultaneous polygraphic and voltammetric recordings in hypothalamus using a telemetry system

    Neuroscience

    (1994)
  • L.O. Wilkinson et al.

    Extracellular serotonin levels change with behavioral state but not with pyrogen-induced hyperthermia

    J Neurosci

    (1991)
  • K. Sakai et al.

    Role of dorsal raphe neurons in paradoxical sleep generation in the cat: no evidence for a serotonergic mechanism

    Eur J Neurosci

    (2001)
  • M.M. Thakkar et al.

    Behavioral state control through differential serotonergic inhibition in the mesopontine cholinergic nuclei: a simultaneous unit recording and microdyalisis study

    J Neurosci

    (1998)
  • A. Caballero et al.

    Unilateral lesions in locus coeruleus area enhance paradoxical sleep

    Electroencephalogr Clin Neurophysiol

    (1986)
  • R. Cespuglio et al.

    Alterations in the sleep–waking cycle induced by cooling of the locus coeruleus area

    Electroencephalogr Clin Neurophysiol

    (1982)
  • D.A. Nitz et al.

    GABA release in the locus coeruleus as a function of sleep/wake state

    Neuroscience

    (1997)
  • E.S. Levine et al.

    Neurochemical afferents controlling the activity of serotonergic neurons in the dorsal raphe nucleus: microiontophoretic studies in the awake cat

    J Neurosci

    (1992)
  • X. Li et al.

    Presynaptic nicotinic receptors facilitate monoaminergic transmission

    J Neurosci

    (1998)
  • F. Petitjean et al.

    Hypersomnia by isthmic lesion in cat. II. Neurophysiological and pharmacological study

    Brain Res

    (1975)
  • J.P. Sastre et al.

    Importance of the ventrolateral region of the periaqueductal gray and adjacent tegmentum in the control of paradoxical sleep as studied by muscimol microinjections in the cat

    Neuroscience

    (1996)
  • M. Thakkar et al.

    Phasic but not tonic REM selective discharge of periaqueductal gray neurons in freely behaving animals: Relevance to postulates of GABAergic inhibition of monoaminergic neurons

    Brain Res

    (2002)
  • R.E. Brown et al.

    Electrophysiological recordings from brainstem GABAergic neurons in GAD67-GFP knock-in mice and REM sleep control by cholinergic and orexigenic mechanisms

    Sleep

    (2006)
  • M. Steriade et al.

    Brain control of sleep and wakefulness

    (2005)
  • R.W. McCarley

    Mechanisms and models of REM sleep control

    Archives Ital de Biol

    (2004)
  • S. Deurveilher et al.

    Pontine microinjection of carbachol does not reliably enhance paradoxical sleep in rats

    Sleep

    (1997)
  • P. Bourgin et al.

    Induction of rapid eye movement sleep by carbachol infusion into the pontine reticular formation in the rat

    NeuroReport

    (1995)
  • M.D. Pollack et al.

    Microinjection of neostigmine into the pontine reticular formation of the mouse: further evaluation of a proposed REM sleep enhancement technique

    Brain Res

    (2005)
  • R. Goutagny et al.

    Paradoxical sleep in mice lacking M3 and M2/M4 muscarinic receptors

    Neuropsychobiology

    (2005)
  • Cited by (0)

    This work was supported by grants from the Department of Veterans Affairs, Medical Research Service and NIMH (R37 MH39,683 and R01 MH40,799).

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