Semin Neurol 2004; 24(3): 211-223
DOI: 10.1055/s-2004-835067
Published 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Neurophysiological Mechanisms of Sleep and Wakefulness: A Question of Balance

Christopher M. Sinton1 , Robert W. McCarley2
  • 1Lecturer, Department of Psychiatry, Harvard Medical School, Brockton VA Medical Center, Brockton, Massachusetts
  • 2Professor, Department of Psychiatry, Harvard Medical School, Brockton VA Medical Center, Brockton, Massachusetts
Further Information

Publication History

Publication Date:
27 September 2004 (online)

Following a summary of the stages of sleep and wakefulness as monitored with the electroencephalogram and electromyogram, important aspects of the neurophysiology and neuroanatomy of the circuits of vigilance state control are reviewed. A homeostatic drive for sleep and a circadian influence work in concert to determine sleepiness. These processes influence sleep-promoting and central arousing neuronal systems, the former dependent on a group of neurons in the hypothalamic ventrolateral preoptic area and the latter governed by neurons in the pons and basal forebrain. The interactive neuronal circuit that is formed by these cell groups ensures the balance between sleep and wakefulness and the rapid transition to and from sleep. As sleep deepens, the switch to rapid eye movement (REM) sleep occurs. This transition can also be viewed as a balance between one group of pontine neurons that discharge only during REM sleep and another group that cease to discharge during REM sleep. This article concludes with future perspectives based on the recent discovery of the orexin cell group. Orexinergic neurons may be critical both for promoting wakefulness at certain times in the daily cycle and for controlling the switch into REM sleep.

REFERENCES

  • 1 Chatrian GE, Lairy GC The EEG of the waking adult. In: Rémond A Handbook of Electroencephalography and Clinical Neurophysiology. Vol. 6A Amsterdam; Elsevier 1976: 7-28
  • 2 Jankel W R, Niedermeyer E. Sleep spindles.  J Clin Neurophysiol. 1985;  2 1-35
  • 3 Niedermeyer E. Sleep and EEG. In: Niedermeyer E, Lopes da Silva F Electroencephalography: Basic Principles, Clinical Applications, and Related Fields. 3rd Ed Baltimore; Williams & Wilkins 1993: 153-166
  • 4 Amzica F, Steriade M. Cellular substrates and laminar profile of sleep K-complex.  Neuroscience. 1998;  82 671-686
  • 5 Steriade M, McCarley R W. Brainstem Control of Wakefulness and Sleep. New York; Plenum Press 1990
  • 6 Nicholls J G, Martin A R, Wallace B G, Fuchs P A. From Neuron to Brain. 4th Ed. Sunderland, MA; Sinauer Associates 2000
  • 7 Kandel E R, Schwartz J H, Jessell T M. Principles of Neural Science. 4th ed. New York; McGraw-Hill 2000
  • 8 Steriade M, Curró Dossi R, Nuñez A. Network modulation of a slow intrinsic oscillation of cat thalamocortical neurons implicated in sleep delta waves: cortically induced synchronization and brainstem cholinergic suppression.  J Neurosci. 1991;  11 3200-3217
  • 9 Steriade M, Amzica F. Coalescence of sleep rhythms and their chronology in corticothalamic networks.  Sleep Res Online. 1998;  1 1-10
  • 10 McCormick D A. Cholinergic and noradrenergic modulation of thalamocortical processing.  Trends Neurosci. 1989;  12 215-221
  • 11 von Krosigk M, Bal T, McCormick D A. Cellular mechanisms of a synchronized oscillation in the thalamus.  Science. 1993;  261 361-364
  • 12 Buzsaki G, Bickford R G, Ponomareff G, Thal L G, Mandel R, Gage F H. Nucleus basalis and thalamic control of neocortical activity in the freely moving rat.  J Neurosci. 1988;  8 4007-4026
  • 13 Amzica F, Steriade M. Electrophysiological correlates of sleep delta waves.  Electroencephalogr Clin Neurophysiol. 1998;  107 69-83
  • 14 von Economo C. Sleep as a problem of localization.  J Nerv Ment Dis. 1930;  71 249-259
  • 15 von Economo C. Encephalitis Lethargica: Its Sequelae and Treatment. London; Oxford University Press 1931
  • 16 Moruzzi G, Magoun H W. Brain stem reticular formation and activation of the EEG.  Electroencephalogr Clin Neurophysiol. 1949;  1 455-473
  • 17 Steriade M, Datta S, Paré D, Oakson G, Curro Dossi R C. Neuronal activities in brain-stem cholinergic nuclei related to tonic activation processes in thalamocortical systems.  J Neurosci. 1990;  10 2541-2559
  • 18 McGinty D J, Harper R M. Dorsal raphe neurons: depression of firing during sleep in cats.  Brain Res. 1976;  101 569-575
  • 19 Aston-Jones G, Bloom F E. Activity of norepinephrine containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle.  J Neurosci. 1981;  1 876-886
  • 20 Vanni-Mercier G, Sakai K, Jouvet M. “Waking-state specific” neurons in the caudal hypothalamus of the cat.  C R Acad Sci III. 1984;  298 195-200
  • 21 Snyder S H, Brown B, Kuhar J. The subsynaptosomal localization of histamine, histadine decarboxylase and histamine methyltransferase in rat hypothalamus.  J Neurochem. 1974;  23 37-45
  • 22 Sherin J E, Elmquist J K, Torrealba F, Saper C B. Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat.  J Neurosci. 1998;  18 4705-4721
  • 23 McCormick D A, Bal T. Sleep and arousal: thalamocortical mechanisms.  Annu Rev Neurosci. 1997;  20 185-215
  • 24 Sterman M B, Clemente C. Forebrain inhibitory mechanisms: sleep patterns induced by basal forebrain stimulation in the behaving cat.  Exp Neurol. 1962;  6 103-117
  • 25 Szymusiak R. Magnocellular nuclei of the basal forebrain: substrates of sleep and arousal regulation.  Sleep. 1995;  18 478-500
  • 26 Sherin J E, Shiromani P J, McCarley R W, Saper C B. Activation of ventrolateral preoptic neurons during sleep.  Science. 1996;  271 216-219
  • 27 Lu J, Greco M A, Shiromani P, Saper C B. Effect of lesions of the ventrolateral preoptic nucleus on NREM and REM sleep.  J Neurosci. 2000;  20 3830-3842
  • 28 Steininger T L, Gong H, McGinty D, Szymusiak R. Subregional organization of preoptic area/anterior hypothalamus projections to arousal-related monoaminergic cell groups.  J Comp Neurol. 2001;  429 638-653
  • 29 Chou T C, Bjorkum A A, Gaus S E, Lu J, Scammell T E, Saper C B. Afferents to the ventrolateral preoptic nucleus.  J Neurosci. 2002;  22 977-990
  • 30 Schmidt M H, Gervasoni D, Luppi P H, Fort P. Quantitative analysis of cholinergic afferents to the ventrolateral preoptic area: role in waking mechanisms.  Sleep. 2003;  26 A37
  • 31 Chou T C, Scammell T E, Gooley J J, Gaus S E, Saper C B, Lu J. Critical role of the dorsomedial hypothalamic nucleus in a wide range of behavioral circadian rhythms.  J Neurosci. 2003;  23 10691-10702
  • 32 McCarley R W, Strecker R E, Thakkar M M, Porkka-Heiskanen T. Adenosine and 5-HT as regulators of behavioural state. In: Borbély AA, Hayaishi O, Sejnowski TJ, Altman JS The Regulation of Sleep Strasbourg; Human Frontier Science Program 2000: 103-112
  • 33 Strecker R E, Moriarty S, Thakkar M et al.. Adenosinergic modulation of basal forebrain and preoptic/anterior hypothalamic neuronal activity in the control of behavioral state.  Behav Brain Res. 2000;  115 183-204
  • 34 Porkka-Heiskanen T, Strecker R E, McCarley R W. Brain site-specificity of extracellular adenosine concentration changes during sleep deprivation and spontaneous sleep: an in vivo microdialysis study.  Neuroscience. 2000;  99 507-517
  • 35 Rainnie D G, Grunze H C, McCarley R W, Greene R W. Adenosine inhibition of mesopontine cholinergic neurons: implications for EEG arousal.  Science. 1994;  263 689-692
  • 36 Kirillov A B, Myre C D, Woodward D J. Bistability, switches and working memory in a two-neuron inhibitory-feedback model.  Biol Cybern. 1993;  68 441-449
  • 37 McCarley R W. Sleep neurophysiology: basic mechanisms underlying control of wakefulness and sleep. In: Chokroverty S Sleep Disorders Medicine: Basic Science, Technical Considerations, and Clinical aspects. 2nd ed Woburn, MA; Butterworth-Heinemann 1999: 21-50
  • 38 Greene R W, McCarley R W. Cholinergic neurotransmission in the brainstem: implications for behavioral state control. In: Steriade M, Biesold D Brain Cholinergic Systems New York; Oxford University Press 1990: 224-235
  • 39 McCarley R W, Greene R W, Rainnie D, Portas C M. Brain stem neuromodulation and REM sleep.  Semin Neurosci. 1995;  7 341-354
  • 40 Siegel J M. Brainstem mechanisms generating REM sleep. In: Kryger MH, Roth T, Dement WC Principles and Practice of Sleep Medicine. 3rd ed Philadelphia; Saunders 2000: 112-133
  • 41 Jouvet M. What does a cat dream about?.  Trends Neurosci. 1979;  2 15-16
  • 42 Mitani A, Ito K, Hallanger A H, Wainer B H, Kataoka K, McCarley R W. Cholinergic projections from the laterodorsal and pedunculopontine tegmental nuclei to the pontine gigantocellular tegmental field in the cat.  Brain Res. 1988;  451 397-402
  • 43 Webster H H, Jones B E. Neurotoxic lesions of the dorsolateral pontomesencephalic tegmentum-cholinergic area in the cat. II. Effects upon sleep-waking states.  Brain Res. 1988;  458 285-302
  • 44 Thakkar M, Portas C M, McCarley R W. Chronic low amplitude electrical stimulation of the laterodorsal tegmental nucleus of freely moving cats increases REM sleep.  Brain Res. 1996;  723 223-227
  • 45 Kodama T, Lai Y Y, Siegel J M. Enhancement of acetylcholine release during REM sleep in the caudomedial medulla as measured by in vivo microdialysis.  Brain Res. 1992;  580 348-350
  • 46 Leonard T O, Lydic R. Pontine nitric oxide modulates acetylcholine release, rapid eye movement sleep generation, and respiratory rate.  J Neurosci. 1997;  17 774-785
  • 47 McCarley R W, Hobson J A. Neuronal excitability modulation over the sleep cycle: a structural and mathematical model.  Science. 1975;  189 58-60
  • 48 McCarley R W, Massaquoi S G. Neurobiological structure of the revised limit cycle reciprocal interaction model of REM sleep cycle control.  J Sleep Res. 1992;  1 132-137
  • 49 Mühlethaler M, Khateb A, Serafin M. Effects of monoamines and opiates on pedunculopontine neurones. In: Mancia M, Marini G The Diencephalon and Sleep New York; Raven Press 1990: 367-378
  • 50 Luebke J I, Greene R W, Semba K, Kamondi A, McCarley R W, Reiner P B. Serotonin hyperpolarizes cholinergic low-threshold burst neurons in the rat laterodorsal tegmental nucleus in vitro.  Proc Natl Acad Sci USA. 1992;  89 743-747
  • 51 Leonard C S, Llinás R. Serotonergic and cholinergic inhibition of mesopontine cholinergic neurons controlling REM sleep: an in vitro electrophysiological study.  Neuroscience. 1994;  59 309-330
  • 52 Cespuglio R, Gomez M E, Walker E, Jouvet M. Effect of cooling and electrical stimulation of nuclei of raphe system on status of alertness in cat [in French].  Electroencephalogr Clin Neurophysiol. 1979;  47 289-308
  • 53 Portas C M, Thakkar M, Rainnie D, McCarley R W. Microdialysis perfusion of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) in the dorsal raphe nucleus decreases serotonin release and increases rapid eye movement sleep in the freely moving cat.  J Neurosci. 1996;  16 2820-2828
  • 54 Sanford L D, Ross R J, Seggos A E, Morrison A R, Ball W A, Mann G L. Central administration of two 5-HT receptor agonists: effect on REM sleep initiation and PGO waves.  Pharmacol Biochem Behav. 1994;  49 93-100
  • 55 Horner R L, Sanford L D, Annis D, Pack A I, Morrison A R. Serotonin at the laterodorsal tegmental nucleus suppresses rapid-eye-movement sleep in freely behaving rats.  J Neurosci. 1997;  17 7541-7552
  • 56 Williams J A, Reiner P B. Noradrenaline hyperpolarizes identified rat mesopontine cholinergic neurons in vitro .  J Neurosci. 1993;  13 3878-3883
  • 57 Monti J M. Involvement of histamine in the control of the waking state.  Life Sci. 1993;  53 1331-1338
  • 58 de Lecea L, Kilduff T S, Peyron C et al.. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity.  Proc Natl Acad Sci USA. 1998;  95 322-327
  • 59 Sakurai T, Amemiya A, Ishii M et al.. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior.  Cell. 1998;  92 573-585
  • 60 Elias C F, Saper C B, Maratos-Flier E et al.. Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area.  J Comp Neurol. 1998;  402 442-459
  • 61 Peyron C, Tighe D, van den Pol A et al.. Neurons containing hypocretin (orexin) project to multiple neuronal systems.  J Neurosci. 1998;  18 9996-10015
  • 62 Date Y, Ueta Y, Yamashita H et al.. Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems.  Proc Natl Acad Sci USA. 1999;  96 748-753
  • 63 Horvath T L, Peyron C, Diano S et al.. Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system.  J Comp Neurol. 1999;  415 145-159
  • 64 Nambu T, Sakurai T, Mizukami K, Hosoya Y, Yanagisawa M, Goto K. Distribution of orexin neurons in the adult rat brain.  Brain Res. 1999;  827 243-260
  • 65 Siegel J M. Narcolepsy: a key role for hypocretins.  Cell. 1999;  98 409-412
  • 66 Lin L, Faraco J, Li R et al.. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene.  Cell. 1999;  98 365-376
  • 67 Chemelli R M, Willie J T, Sinton C M et al.. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation.  Cell. 1999;  98 437-451
  • 68 Nishino S, Ripley B, Overeem S, Lammers G J, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy.  Lancet. 2000;  355 39-40
  • 69 Nishino S, Ripley B, Overeem S et al.. Low cerebrospinal fluid hypocretin (orexin) and altered energy homeostasis in human narcolepsy.  Ann Neurol. 2001;  50 381-388
  • 70 Mignot E, Lammers G J, Ripley B et al.. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias.  Arch Neurol. 2002;  59 1553-1562
  • 71 Ripley B, Overeem S, Fujiki N et al.. CSF hypocretin/orexin levels in narcolepsy and other neurological conditions.  Neurology. 2001;  57 2253-2258
  • 72 Peyron C, Faraco J, Rogers W et al.. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains.  Nat Med. 2000;  6 991-997
  • 73 Thannickal T C, Moore R Y, Nienhuis R et al.. Reduced number of hypocretin neurons in human narcolepsy.  Neuron. 2000;  27 469-474
  • 74 Choo K L, Guilleminault C. Narcolepsy and idiopathic hypersomnolence.  Clin Chest Med. 1998;  19 169-181
  • 75 Hagan J J, Leslie R A, Patel S et al.. Orexin A activates locus coeruleus cell firing and increases arousal in the rat.  Proc Natl Acad Sci USA. 1999;  96 10911-10916
  • 76 Brown R E, Sergeeva O, Eriksson K S, Haas H L. Orexin A excites serotoninergic neurons in the dorsal raphe nucleus of the rat.  Neuropharmacology. 2001;  40 457-459
  • 77 Burlet S, Tyler C J, Leonard C S. Direct and indirect excitation of laterodorsal tegmental neurons by hypocretin/orexin peptides: implications for wakefulness and narcolepsy.  J Neurosci. 2002;  22 2862-2872
  • 78 Thakkar M M, Ramesh V, Cape E G, Winston S, Strecker R E, McCarley R W. REM sleep enhancement and behavioral cataplexy following orexin (hypocretin) II receptor antisense perfusion in the pontine reticular formation.  Sleep Res Online. 1999;  2 112-120
  • 79 Xi M C, Morales F R, Chase M H. Effects on sleep and wakefulness of the injection of hypocretin-1 (orexin-A) into the laterodorsal tegmental nucleus of the cat.  Brain Res. 2001;  901 259-264
  • 80 Beuckmann C T, Sinton C M, Williams S C et al.. Expression of a poly-glutamine-ataxin-3 transgene in orexin neurons induces narcolepsy-cataplexy in the rat.  J Neurosci. 2004;  24 4469-4477
  • 81 Sutcliffe J G, de Lecea L. The hypocretins: setting the arousal threshold.  Nat Rev Neurosci. 2002;  3 339-349
  • 82 Kiyashchenko L I, Mileykovskiy B Y, Maidment N et al.. Release of hypocretin (orexin) during waking and sleep states.  J Neurosci. 2002;  22 5282-5286
  • 83 Dijk D J, Czeisler C A. Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans.  J Neurosci. 1995;  15 3526-3538
  • 84 Dijk D J, Czeisler C A. Paradoxical timing of the circadian rhythm of sleep propensity serves to consolidate sleep and wakefulness in humans.  Neurosci Lett. 1994;  166 63-68
  • 85 Dijk D-J, Duffy J F. A circadian perspective on human sleep-wake regulation and ageing. In: Borbély AA, Hayaishi O, Sejnowski TJ, Altman JS The Regulation of Sleep Strasbourg; Human Frontier Science Program 2000: 212-222
  • 86 Dantz B, Edgar D M, Dement W C. Circadian rhythms in narcolepsy: studies on a 90 minute day.  Electroencephalogr Clin Neurophysiol. 1994;  90 24-35
  • 87 Taheri S, Sunter D, Dakin C et al.. Diurnal variation in orexin A immunoreactivity and prepro-orexin mRNA in the rat central nervous system.  Neurosci Lett. 2000;  279 109-112
  • 88 Fujiki N, Yoshida Y, Ripley B, Honda K, Mignot E, Nishino S. Changes in CSF hypocretin-1 (orexin A) levels in rats across 24 hours and in response to food deprivation.  Neuroreport. 2001;  12 993-997
  • 89 Yoshida Y, Fujiki N, Nakajima T et al.. Fluctuation of extracellular hypocretin-1 (orexin A) levels in the rat in relation to the light-dark cycle and sleep-wake activities.  Eur J Neurosci. 2001;  14 1075-1081
  • 90 Zeitzer J M, Buckmaster C L, Parker K J, Hauck C M, Lyons D M, Mignot E. Circadian and homeostatic regulation of hypocretin in a primate model: implications for the consolidation of wakefulness.  J Neurosci. 2003;  23 3555-3560
  • 91 Kleitman N. Sleep and Wakefulness. Chicago; University Chicago Press 1963

Robert W McCarleyM.D. 

Department of Psychiatry, Harvard Medical School, Brockton VA Medical Center 116A

940 Belmont Street, Brockton

MA 02401

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