The Neurobiology of Sleep

ABSTRACT

The neurobiology of sleep and narcolepsy is reviewed. Non-rapid eye movement (NREM) sleep is generated by neurons in the preoptic region of the hypothalamus and adjacent basal forebrain. Lesions in these regions cause insomnia. Stimulation of these regions rapidly produces sleep onset. The key brain structure for generating REM sleep is the pons and adjacent portions of the midbrain. Damage to the pons and/or caudal midbrain can cause abnormalities in REM sleep. The persistent sleepiness of narcolepsy is a result of a loss of hypocretin function.

KEYWORDS

REM sleep - brainstem - pons - midbrain - glutamate - acetylcholine - norepinephrine - serotonin - hypocretin - orexin

REFERENCES

• 1 von-Economo C. Sleep as a problem of localization.  J Nerv Ment Dis. 1930;  71 249-259
• 2 von-Economo C. Die encephalitis lethargica. Wien Deuticke 1918
• 3 Nauta W JH. Hypothalamic regulation of sleep in rats: an experimental study.  J Neurophysiol. 1946;  9 285-316
• 4 Szymusiak R, McGinty D. Sleep suppression following kainic acid-induced lesions of the basal forebrain.  Exp Neurol. 1986;  94(3) 598-614
• 5 Sterman M B, Clemente C D. Forebrain inhibitory mechanisms: sleep patterns induced by basal forebrain stimulation in the behaving cat.  Exp Neurol. 1962;  6 103-117
• 6 Sagar S M, Sharp F R, Curran T. Expression of c-fos protein in brain: metabolic mapping at the cellular level.  Science. 1988;  240(4857) 1328-1331
• 7 Basheer R, Sherin J E, Saper C B et al.. Effects of sleep on wake-induced c-fos expression.  J Neurosci. 1997;  17 9746-9750
• 8 Gvilia I, Xu F, McGinty D, Szymusiak R. Homeostatic regulation of sleep: a role for preoptic area neurons.  J Neurosci. 2006;  26(37) 9426-9433
• 9 Sherin J E, Shiromani P J, McCarley R W, Saper C B. Activation of ventrolateral preoptic neurons during sleep.  Science. 1996;  271(5246) 216-219
• 10 Suntsova N, Szymusiak R, Alam M N, Guzman-Marin R, McGinty D. Sleep-waking discharge patterns of median preoptic nucleus neurons in rats.  J Physiol. 2002;  543(Pt 2) 665-677
• 11 Findlay A LR, Hayward J N. Spontaneous activity of single neurones in the hypothalamus of rabbits during sleep and waking.  J Physiol. 1969;  201(1) 237-258
• 12 Kaitin K I. Preoptic area unit activity during sleep and wakefulness in the cat.  Exp Neurol. 1984;  83(2) 347-357
• 13 Szymusiak R, McGinty D J. Sleep-related neuronal discharge in the basal forebrain of cats.  Brain Res. 1986;  370(1) 82-92
• 14 Alam M N, McGinty D, Szymusiak R. Thermosensitive neurons of the diagonal band in rats: relation to wakefulness and non-rapid eye movement sleep.  Brain Res. 1997;  752(1–2) 81-89
• 15 Szymusiak R, Gvilia I, McGinty D. Hypothalamic control of sleep.  Sleep Med. 2007;  8(4) 291-301
• 16 Szymusiak R, McGinty D. Hypothalamic regulation of sleep and arousal.  Ann N Y Acad Sci. 2008;  1129(1) 275-286
• 17 McCormick D A, Pape H C. Properties of a hyperpolarization-activated cation current and its role in rhythmic oscillation in thalamic relay neurones.  J Physiol. 1990;  431 291-318
• 18 McCormick D A. Cholinergic and noradrenergic modulation of thalamocortical processing.  Trends Neurosci. 1989;  12(6) 215-221
• 19 Steriade M, Gloor P, Llinás R R, Lopes de Silva F H, Mesulam M M. Report of IFCN Committee on Basic Mechanisms. Basic mechanisms of cerebral rhythmic activities.  Electroencephalogr Clin Neurophysiol. 1990;  76(6) 481-508
• 20 Steriade M, McCormick D A, Sejnowski T J. Thalamocortical oscillations in the sleeping and aroused brain.  Science. 1993;  262(5134) 679-685
• 21 Steriade M. Brain electrical activity and sensory processing during waking and sleep. In: Kryger MH, Roth T, Dement WC Principles and Practice of Sleep Medicine. 4th ed. Philadelphia; Elsevier Saunders 2005: 101-119
• 22 Steriade M. Sleep, epilepsy and thalamic reticular inhibitory neurons.  Trends Neurosci. 2005;  28(6) 317-324
• 23 Jacobs B L, Fornal C A. Activity of serotonergic neurons in behaving animals.  Neuropsychopharmacology. 1999;  21(2, Suppl) 9S-15S
• 24 John J, Wu M F, Boehmer L N, Siegel J M. Cataplexy-active neurons in the posterior hypothalamus: implications for the role of histamine in sleep and waking behavior.  Neuron. 2004;  42(4) 619-634
• 25 Steininger T L, Alam M N, Gong H, Szymusiak R, McGinty D. Sleep-waking discharge of neurons in the posterior lateral hypothalamus of the albino rat.  Brain Res. 1999;  840(1–2) 138-147
• 26 Mileykovskiy B Y, Kiyashchenko L I, Siegel J M. Behavioral correlates of activity in identified hypocretin/orexin neurons.  Neuron. 2005;  46(5) 787-798
• 27 Nitz D, Siegel J M. GABA release in the posterior hypothalamus of the cat as a function of sleep/wake state.  Am J Physiol. 1996;  271 R1707-R1712
• 28 Nitz D, Siegel J M. GABA release in the dorsal raphe nucleus: role in the control of REM sleep.  Am J Physiol. 1997;  273(1 Pt 2) R451-R455
• 29 Nitz D, Siegel J M. GABA release in the locus coeruleus as a function of sleep/wake state.  Neuroscience. 1997;  78 795-801
• 30 Blanco-Centurion C, Gerashchenko D, Shiromani P J. Effects of saporin-induced lesions of three arousal populations on daily levels of sleep and wake.  J Neurosci. 2007;  27(51) 14041-14048
• 31 Lai Y Y, Siegel J M. Pontomedullary glutamate receptors mediating locomotion and muscle tone suppression.  J Neurosci. 1991;  11(9) 2931-2937
• 32 Siegel J M. The neurotransmitters of sleep.  J Clin Psychiatry. 2004;  65(Suppl 16) 4-7
• 33 Siegel J M. REM sleep. In: Kryger MH, Roth T, Dement WC Principles and Practice of Sleep Medicine. 4th ed. Philadelphia; Elsevier Saunders 2005: 120-135
• 34 Lu J, Sherman D, Devor M, Saper C B. A putative flip-flop switch for control of REM sleep.  Nature. 2006;  441(7093) 589-594
• 35 Luppi P H, Gervasoni D, Verret L et al.. Paradoxical (REM) sleep genesis: the switch from an aminergic-cholinergic to a GABAergic-glutamatergic hypothesis.  J Physiol (Paris). 2006;  100(5-6) 271-283
• 36 Hirshkowitz M, Schmidt M H. Sleep-related erections: clinical perspectives and neural mechanisms.  Sleep Med Rev. 2005;  9(4) 311-329
• 37 Parmeggiani P L. Thermoregulation and sleep.  Front Biosci. 2003;  8 s557-s567
• 38 Villablanca J. Behavioral and polygraphic study of “sleep” and “wakefulness” in chronic decerebrate cats.  Electroencephalogr Clin Neurophysiol. 1966;  21(6) 562-577
• 39 Morrison A R, Bowker R M. The biological significance of PGO spikes in the sleeping cat.  Acta Neurobiol Exp (Warsz). 1975;  35(5-6) 821-840
• 40 De Gennaro L, Ferrara M. Sleep deprivation and phasic activity of REM sleep: independence of middle-ear muscle activity from rapid eye movements.  Sleep. 2000;  23(1) 81-85
• 41 Siegel J M, Tomaszewski K S. Behavioral organization of reticular formation: studies in the unrestrained cat. I. Cells related to axial, limb, eye, and other movements.  J Neurophysiol. 1983;  50(3) 696-716
• 42 Siegel J M, Tomaszewski K S, Wheeler R L. Behavioral organization of reticular formation: studies in the unrestrained cat. II. Cells related to facial movements.  J Neurophysiol. 1983;  50(3) 717-723
• 43 Siegel J M, Nienhuis R, Fahringer H M et al.. Activity of medial mesopontine units during cataplexy and sleep-waking states in the narcoleptic dog.  J Neurosci. 1992;  12(5) 1640-1646
• 44 Bard P, Macht M B. The behavior of chronically decerebrate cats. In: Wolstenholme GEW, O'Conner CMO Neurological Basis of Behavior. London; Churchill 1958: 55-75
• 45 Dement W C. The occurrence of low voltage, fast, electroencephalogram patterns during behavioral sleep in the cat.  Electroencephalogr Clin Neurophysiol. 1958;  10(2) 291-296
• 46 Jouvet M. Research on the neural structures and responsible mechanisms in different phases of physiological sleep.  Arch Ital Biol. 1962;  100 125-206
• 47 Adey W R, Bors E, Porter R W. EEG sleep patterns after high cervical lesions in man.  Arch Neurol. 1968;  19(4) 377-383
• 48 Lai Y Y, Siegel J M. Medullary regions mediating atonia.  J Neurosci. 1988;  8(12) 4790-4796
• 49 Siegel J M, Tomaszewski K S, Nienhuis R. Behavioral states in the chronic medullary and midpontine cat.  Electroencephalogr Clin Neurophysiol. 1986;  63(3) 274-288
• 50 Siegel J M, Nienhuis R, Tomaszewski K S. REM sleep signs rostral to chronic transections at the pontomedullary junction.  Neurosci Lett. 1984;  45(3) 241-246
• 51 Siegel J M. Pontomedullary interactions in the generation of REM sleep. In: McGinty DJ, Drucker-Colin R, Morrison A, Parmeggiani PL Brain Mechanisms of Sleep. New York; Raven Press 1985: 157-174
• 52 Matsuzaki M. Differential effects of sodium butyrate and physostigmine upon the activities of para-sleep in acute brain stem preparations.  Brain Res. 1969;  13(2) 247-265
• 53 Schenkel E, Siegel J M. REM sleep without atonia after lesions of the medial medulla.  Neurosci Lett. 1989;  98(2) 159-165
• 54 Mileykovskiy B Y, Kiyashchenko L I, Kodama T, Lai Y Y, Siegel J M. Activation of pontine and medullary motor inhibitory regions reduces discharge in neurons located in the locus coeruleus and the anatomical equivalent of the midbrain locomotor region.  J Neurosci. 2000;  20(22) 8551-8558
• 55 Gadea-Ciria M. Tele-encephalic versus cerebellar control upon ponto-geniculo-occipital waves during paradoxical sleep in the cat.  Experientia. 1976;  32(7) 889-890
• 56 Mahowald M W, Schenck C H, Bornemann M A. Pathophysiologic mechanisms in REM sleep behavior disorder.  Curr Neurol Neurosci Rep. 2007;  7(2) 167-172
• 57 Siegel J M, McGinty D J. Pontine reticular formation neurons: relationship of discharge to motor activity.  Science. 1977;  196(4290) 678-680
• 58 Siegel J M, McGinty D J, Breedlove S M. Sleep and waking activity of pontine gigantocellular field neurons.  Exp Neurol. 1977;  56(3) 553-573
• 59 Sastre J P, Sakai K, Jouvet M. Are the gigantocellular tegmental field neurons responsible for paradoxical sleep?.  Brain Res. 1981;  229(1) 147-161
• 60 Drucker-Colín R, Pedraza J GB. Kainic acid lesions of gigantocellular tegmental field (FTG) neurons does not abolish REM sleep.  Brain Res. 1983;  272(2) 387-391
• 61 Webster H H, Jones B E. Neurotoxic lesions of the dorsolateral pontomesencephalic tegmentum-cholinergic cell area in the cat. II. Effects upon sleep-waking states.  Brain Res. 1988;  458(2) 285-302
• 62 Swanson L W. Brain Maps: Structure of the Rat Brain. Elsevier 1992
• 63 Shouse M N, Siegel J M. Pontine regulation of REM sleep components in cats: integrity of the pedunculopontine tegmentum (PPT) is important for phasic events but unnecessary for atonia during REM sleep.  Brain Res. 1992;  571(1) 50-63
• 64 Hendricks J C, Morrison A R, Mann G L. Different behaviors during paradoxical sleep without atonia depend on pontine lesion site.  Brain Res. 1982;  239(1) 81-105
• 65 Jouvet M, Delorme F. Locus coeruleus et sommeil paradoxal.  Comptes Rendus de l' Academie des Sciences. 1965;  159 895-899
• 66 Lai Y Y, Shalita T, Hajnik T et al.. Neurotoxic N-methyl-D-aspartate lesion of the ventral midbrain and mesopontine junction alters sleep-wake organization.  Neuroscience. 1999;  90(2) 469-483
• 67 Lai Y Y, Hsieh K C, Nguyen D, Shalita T, Peever J, Siegel J M. Neurotoxic lesions at the ventral mesopontine junction change in sleep time and muscle activity during sleep: an animal model of motor disorders in sleep.  Neuroscience. 2008;  154(2) 431-443
• 68 Holmes C J, Mainville L S, Jones B E. Distribution of cholinergic, GABAergic and serotonergic neurons in the medial medullary reticular formation and their projections studied by cytotoxic lesions in the cat.  Neuroscience. 1994;  62(4) 1155-1178
• 69 Lai Y Y, Siegel J M. Cardiovascular and muscle tone changes produced by microinjection of cholinergic and glutamatergic agonists in dorsolateral pons and medial medulla.  Brain Res. 1990;  514(1) 27-36
• 70 Crochet S, Onoe H, Sakai K. A potent non-monoaminergic paradoxical sleep inhibitory system: a reverse microdialysis and single-unit recording study.  Eur J Neurosci. 2006;  24(5) 1404-1412
• 71 Vanini G, Torterolo P, McGregor R, Chase M H, Morales F R. GABAergic processes in the mesencephalic tegmentum modulate the occurrence of active (rapid eye movement) sleep in guinea pigs.  Neuroscience. 2007;  145(3) 1157-1167
• 72 Xi M C, Morales F R, Chase M H. Interactions between GABAergic and cholinergic processes in the nucleus pontis oralis: neuronal mechanisms controlling active (rapid eye movement) sleep and wakefulness.  J Neurosci. 2004;  24(47) 10670-10678
• 73 Watson C J, Soto-Calderon H, Lydic R, Baghdoyan H A. Pontine reticular formation (PnO) administration of hypocretin-1 increases PnO GABA levels and wakefulness.  Sleep. 2008;  31(4) 453-464
• 74 Xi M C, Morales F R, Chase M H. Interactions between GABAergic and cholinergic processes in the nucleus pontis oralis: neuronal mechanisms controlling active (rapid eye movement) sleep and wakefulness.  J Neurosci. 2004;  24(47) 10670-10678
• 75 George R, Haslett W L, Jenden D J. A cholinergic mechanism in the brainstem reticular formation: induction of paradoxical sleep.  Int J Neuropharmacol. 1964;  3 541-552
• 76 Vanni-Mercier G, Sakai K, Lin J S, Jouvet M. Mapping of cholinoceptive brainstem structures responsible for the generation of paradoxical sleep in the cat.  Arch Ital Biol. 1989;  127(3) 133-164
• 77 Katayama Y, DeWitt D S, Becker D P, Hayes R L. Behavioral evidence for a cholinoceptive pontine inhibitory area: descending control of spinal motor output and sensory input.  Brain Res. 1984;  296(2) 241-262
• 78 Mitler M M, Dement W C. Cataplectic-like behavior in cats after micro-injections of carbachol in pontine reticular formation.  Brain Res. 1974;  68(2) 335-343
• 79 Gnadt J W, Pegram G V. Cholinergic brainstem mechanisms of REM sleep in the rat.  Brain Res. 1986;  384(1) 29-41
• 80 Shiromani P J, Fishbein W. Continuous pontine cholinergic microinfusion via mini-pump induces sustained alterations in rapid eye movement (REM) sleep.  Pharmacol Biochem Behav. 1986;  25(6) 1253-1261
• 81 Velazquez-Moctezuma J, Gillin J C, Shiromani P J. Effect of specific M1, M2 muscarinic receptor agonists on REM sleep generation.  Brain Res. 1989;  503(1) 128-131
• 82 Deurveilher S, Hars B, Hennevin E. Pontine microinjection of carbachol does not reliably enhance paradoxical sleep in rats.  Sleep. 1997;  20(8) 593-607
• 83 Verret L, Fort P, Gervasoni D, Léger L, Luppi P H. Localization of the neurons active during paradoxical (REM) sleep and projecting to the locus coeruleus noradrenergic neurons in the rat.  J Comp Neurol. 2006;  495(5) 573-586
• 84 Lai Y Y, Siegel J M. Muscle tone suppression and stepping produced by stimulation of midbrain and rostral pontine reticular formation.  J Neurosci. 1990;  10(8) 2727-2734
• 85 Lai Y Y, Clements J R, Siegel J M. Glutamatergic and cholinergic projections to the pontine inhibitory area identified with horseradish peroxidase retrograde transport and immunohistochemistry.  J Comp Neurol. 1993;  336(3) 321-330
• 86 Lai Y Y, Clements J R, Wu X Y et al.. Brainstem projections to the ventromedial medulla in cat: retrograde transport horseradish peroxidase and immunohistochemical studies.  J Comp Neurol. 1999;  408(3) 419-436
• 87 Boissard R, Gervasoni D, Schmidt M H, Barbagli B, Fort P, Luppi P H. The rat ponto-medullary network responsible for paradoxical sleep onset and maintenance: a combined microinjection and functional neuroanatomical study.  Eur J Neurosci. 2002;  16(10) 1959-1973
• 88 Onoe H, Sakai K. Kainate receptors: a novel mechanism in paradoxical (REM) sleep generation.  Neuroreport. 1995;  6(2) 353-356
• 89 Siegel J M. Behavioral functions of the reticular formation.  Brain Res. 1979;  180 69-105
• 90 Siegel J M, Wheeler R L, McGinty D J. Activity of medullary reticular formation neurons in the unrestrained cat during waking and sleep.  Brain Res. 1979;  179(1) 49-60
• 91 Drucker-Colin R R, Pedraza J GB. Kainic acid lesions of gigantocellular tegmental field (FTG) neurons does not abolish REM sleep.  Brain Res. 1983;  272 387-391
• 92 Suzuki S S, Siegel J M, Wu M F. Role of pontomedullary reticular formation neurons in horizontal head movements: an ibotenic acid lesion study in the cat.  Brain Res. 1989;  484(1–2) 78-93
• 93 Kodama T, Takahashi Y, Honda Y. Enhancement of acetylcholine release during paradoxical sleep in the dorsal tegmental field of the cat brain stem.  Neurosci Lett. 1990;  114(3) 277-282
• 94 Steriade M, Datta S, Paré D, Oakson G, Curró Dossi R C. Neuronal activities in brain-stem cholinergic nuclei related to tonic activation processes in thalamocortical systems.  J Neurosci. 1990;  10(8) 2541-2559
• 95 Greene R W, Gerber U, McCarley R W. Cholinergic activation of medial pontine reticular formation neurons in vitro.  Brain Res. 1989;  476(1) 154-159
• 96 Sakai K, Crochet S, Onoe H. Pontine structures and mechanisms involved in the generation of paradoxical (REM) sleep.  Arch Ital Biol. 2001;  139(1–2) 93-107
• 97 Shiromani P J, Lai Y Y, Siegel J M. Descending projections from the dorsolateral pontine tegmentum to the paramedian reticular nucleus of the caudal medulla in the cat.  Brain Res. 1990;  517(1–2) 224-228
• 98 Hobson J A, McCarley R W, Wyzinski P W. Sleep cycle oscillation: reciprocal discharge by two brainstem neuronal groups.  Science. 1975;  189(4196) 55-58
• 99 Fenik V, Marchenko V, Janssen P, Davies R O, Kubin L. A5 cells are silenced when REM sleep-like signs are elicited by pontine carbachol.  J Appl Physiol. 2002;  93(4) 1448-1456
• 100 McGinty D J, Harper R M. Dorsal raphe neurons: depression of firing during sleep in cats.  Brain Res. 1976;  101(3) 569-575
• 101 Gervasoni D, Darracq L, Fort P, Soulière F, Chouvet G, Luppi P H. Electrophysiological evidence that noradrenergic neurons of the rat locus coeruleus are tonically inhibited by GABA during sleep.  Eur J Neurosci. 1998;  10(3) 964-970
• 102 Maloney K J, Mainville L, Jones B E. Differential c-Fos expression in cholinergic, monoaminergic, and GABAergic cell groups of the pontomesencephalic tegmentum after paradoxical sleep deprivation and recovery.  J Neurosci. 1999;  19(8) 3057-3072
• 103 Torterolo P, Yamuy J, Sampogna S, Morales F R, Chase M H. GABAergic neurons of the cat dorsal raphe nucleus express c-fos during carbachol-induced active sleep.  Brain Res. 2000;  884(1–2) 68-76
• 104 Datta S, Siwek D F. Single cell activity patterns of pedunculopontine tegmentum neurons across the sleep-wake cycle in the freely moving rats.  J Neurosci Res. 2002;  70(4) 611-621
• 105 Steriade M, Paré D, Datta S, Oakson G, Curró Dossi R. Different cellular types in mesopontine cholinergic nuclei related to ponto-geniculo-occipital waves.  J Neurosci. 1990;  10(8) 2560-2579
• 106 Ruch-Monachon M A, Jalfre M, Haefely W. Drugs and PGO waves in the lateral geniculate body of the curarized cat. IV. The effects of acetylcholine, GABA and benzodiazepines on PGO wave activity.  Arch Int Pharmacodyn Ther. 1976;  219(2) 308-325
• 107 Wu M F, Siegel J M. Facilitation of the acoustic startle reflex by ponto-geniculo-occipital waves: effects of PCPA.  Brain Res. 1990;  532(1–2) 237-241
• 108 Brooks D C, Gershon M D. An analysis of the effect of reserpine upon ponto- geniculo-occipital wave activity in the cat.  Neuropharmacology. 1972;  11 499-510
• 109 Quattrochi J J, Bazalakova M, Hobson J A. From synapse to gene product: prolonged expression of c-fos induced by a single microinjection of carbachol in the pontomesencephalic tegmentum.  Brain Res Mol Brain Res. 2005;  136(1–2) 164-176
• 110 Datta S, Li G, Auerbach S. Activation of phasic pontine-wave generator in the rat: a mechanism for expression of plasticity-related genes and proteins in the dorsal hippocampus and amygdala.  Eur J Neurosci. 2008;  27(7) 1876-1892
• 111 Verret L, Léger L, Fort P, Luppi P H. Cholinergic and noncholinergic brainstem neurons expressing Fos after paradoxical (REM) sleep deprivation and recovery.  Eur J Neurosci. 2005;  21(9) 2488-2504
• 112 Goutagny R, Luppi P H, Salvert D, Lapray D, Gervasoni D, Fort P. Role of the dorsal paragigantocellular reticular nucleus in paradoxical (rapid eye movement) sleep generation: a combined electrophysiological and anatomical study in the rat.  Neuroscience. 2008;  152(3) 849-857
• 113 Pompeiano O, Hoshino K. Tonic inhibition of dorsal pontine neurons during the postural atonia produced by an anticholinesterase in the decerebrate cat.  Arch Ital Biol. 1976;  114(3) 310-340
• 114 Hanriot L, Camargo N, Courau A C, Leger L, Luppi P H, Peyron C. Characterization of the melanin-concentrating hormone neurons activated during paradoxical sleep hypersomnia in rats.  J Comp Neurol. 2007;  505(2) 147-157
• 115 Verret L, Goutagny R, Fort P et al.. A role of melanin-concentrating hormone producing neurons in the central regulation of paradoxical sleep.  BMC Neurosci. 2003;  4 19
• 116 Chase M H, Morales F R. Control of motoneurons during sleep. In: Kryger MH, Roth T, Dement WC Principles of Sleep Medicine. 4th ed. Philadelphia; Elsevier Saunders 2005: 154-168
• 117 Morales F R, Sampogna S, Rampon C, Luppi P H, Chase M H. Brainstem glycinergic neurons and their activation during active (rapid eye movement) sleep in the cat.  Neuroscience. 2006;  142(1) 37-47
• 118 Kodama T, Lai Y Y, Siegel J M. Changes in inhibitory amino acid release linked to pontine-induced atonia: an in vivo microdialysis study.  J Neurosci. 2003;  23(4) 1548-1554
• 119 Lai Y Y, Kodama T, Siegel J M. Changes in monoamine release in the ventral horn and hypoglossal nucleus linked to pontine inhibition of muscle tone: an in vivo microdialysis study.  J Neurosci. 2001;  21(18) 7384-7391
• 120 Mileykovskiy B Y, Kiyashchenko L I, Siegel J M. Cessation of activity in red nucleus neurons during stimulation of the medial medulla in decerebrate rats.  J Physiol. 2002;  545(Pt 3) 997-1006
• 121 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(1–2) 348-350
• 122 Kohyama J, Lai Y Y, Siegel J M. Inactivation of the pons blocks medullary-induced muscle tone suppression in the decerebrate cat.  Sleep. 1998;  21(7) 695-699
• 123 Siegel J M, Nienhuis R, Tomaszewski K S. Rostral brainstem contributes to medullary inhibition of muscle tone.  Brain Res. 1983;  268(2) 344-348
• 124 Peever J H, Lai Y Y, Siegel J M. Excitatory effects of hypocretin-1 (orexin-A) in the trigeminal motor nucleus are reversed by NMDA antagonism.  J Neurophysiol. 2003;  89(5) 2591-2600
• 125 Brooks P L, Peever J H. Glycinergic and GABA(A)-mediated inhibition of somatic motoneurons does not mediate rapid eye movement sleep motor atonia.  J Neurosci. 2008;  28(14) 3535-3545
• 126 Morrison J L, Sood S, Liu H, Park E, Nolan P, Horner R L. GABAA receptor antagonism at the hypoglossal motor nucleus increases genioglossus muscle activity in NREM but not REM sleep.  J Physiol. 2003;  548(Pt 2) 569-583
• 127 Burgess C, Lai D, Siegel J, Peever J. An endogenous glutamatergic drive onto somatic motoneurons contributes to the stereotypical pattern of muscle tone across the sleep-wake cycle.  J Neurosci. 2008;  28(18) 4649-4660
• 128 Chan E, Steenland H W, Liu H, Horner R L. Endogenous excitatory drive modulating respiratory muscle activity across sleep-wake states.  Am J Respir Crit Care Med. 2006;  174(11) 1264-1273
• 129 Fenik V B, Davies R O, Kubin L. Noradrenergic, serotonergic and GABAergic antagonists injected together into the XII nucleus abolish the REM sleep-like depression of hypoglossal motoneuronal activity.  J Sleep Res. 2005;  14(4) 419-429
• 130 Jelev A, Sood S, Liu H, Nolan P, Horner R L. Microdialysis perfusion of 5-HT into hypoglossal motor nucleus differentially modulates genioglossus activity across natural sleep-wake states in rats.  J Physiol. 2001;  532(Pt 2) 467-481
• 131 Sood S, Raddatz E, Liu X, Liu H, Horner R L. Inhibition of serotonergic medullary raphe obscurus neurons suppresses genioglossus and diaphragm activities in anesthetized but not conscious rats.  J Appl Physiol. 2006;  100(6) 1807-1821
• 132 Taepavarapruk N, Taepavarapruk P, John J et al.. State-dependent release of glycine in Clarke's column of the upper lumbar spinal cord.  Sleep. 2003;  26 A11-A12
• 133 Miller J D, Farber J, Gatz P, Roffwarg H, German D C. Activity of mesencephalic dopamine and non-dopamine neurons across stages of sleep and walking in the rat.  Brain Res. 1983;  273(1) 133-141
• 134 Shouse M N, Staba R J, Saquib S F, Farber P R. Monoamines and sleep: microdialysis findings in pons and amygdala.  Brain Res. 2000;  860(1–2) 181-189
• 135 Shouse M N, Siegel J M, Wu M F, Szymusiak R, Morrison A R. Mechanisms of seizure suppression during rapid-eye-movement (REM) sleep in cats.  Brain Res. 1989;  505(2) 271-282
• 136 Maloney K J, Mainville L, Jones B E. c-Fos expression in dopaminergic and GABAergic neurons of the ventral mesencephalic tegmentum after paradoxical sleep deprivation and recovery.  Eur J Neurosci. 2002;  15(4) 774-778
• 137 Dahan L, Astier B, Vautrelle N, Urbain N, Kocsis B, Chouvet G. Prominent burst firing of dopaminergic neurons in the ventral tegmental area during paradoxical sleep.  Neuropsychopharmacology. 2007;  32(6) 1232-1241
• 138 Lu J, Jhou T C, Saper C B. Identification of wake-active dopaminergic neurons in the ventral periaqueductal gray matter.  J Neurosci. 2006;  26(1) 193-202
• 139 Mignot E, Nishino S, Sharp L H et al.. Heterozygosity at the canarc-1 locus can confer susceptibility for narcolepsy: induction of cataplexy in heterozygous asymptomatic dogs after administration of a combination of drugs acting on monoaminergic and cholinergic systems.  J Neurosci. 1993;  13(3) 1057-1064
• 140 Siegel J M, Nienhuis R, Fahringer H M et al.. Neuronal activity in narcolepsy: identification of cataplexy-related cells in the medial medulla.  Science. 1991;  252(5010) 1315-1318
• 141 Wu M F, Gulyani S A, Yau E, Mignot E, Phan B, Siegel J M. Locus coeruleus neurons: cessation of activity during cataplexy.  Neuroscience. 1999;  91(4) 1389-1399
• 142 John J, Wu M F, Boehmer L N, Siegel J M. Cataplexy-active neurons in the posterior hypothalamus: implications for the role of histamine in sleep and waking behavior.  Neuron. 2004;  42 619-634
• 143 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(9) 991-997
• 144 Thannickal T C, Moore R Y, Nienhuis R et al.. Reduced number of hypocretin neurons in human narcolepsy.  Neuron. 2000;  27(3) 469-474
• 145 Thannickal T C, Siegel J M, Nienhuis R, Moore R Y. Pattern of hypocretin (orexin) soma and axon loss, and gliosis, in human narcolepsy.  Brain Pathol. 2003;  13(3) 340-351
• 146 Fronczek R, Overeem S, Lee S Y et al.. Hypocretin (orexin) loss in Parkinson's disease.  Brain. 2007;  130(Pt 6) 1577-1585
• 147 Thannickal T C, Lai Y Y, Siegel J M. Hypocretin (orexin) cell loss in Parkinson's disease.  Brain. 2007;  130(Pt 6) 1586-1595
• 148 John J, Wu M F, Siegel J M. Systemic administration of hypocretin-1 reduces cataplexy and normalizes sleep and waking durations in narcoleptic dogs.  Sleep Res Online. 2000;  3(1) 23-28
• 149 Deadwyler S A, Porrino L, Siegel J M, Hampson R E. Systemic and nasal delivery of orexin-A (Hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates.  J Neurosci. 2007;  27(52) 14239-14247
• 150 Gulyani S, Wu M-F, Nienhuis R, John J, Siegel J M. Cataplexy-related neurons in the amygdala of the narcoleptic dog.  Neuroscience. 2002;  112(2) 355-365
• 151 Siegel J M. Hypocretin (orexin): role in normal behavior and neuropathology.  Annu Rev Psychol. 2004;  55 125-148
• 152 Siegel J M, Boehmer L N. Narcolepsy and the hypocretin system—where motion meets emotion.  Nat Clin Pract Neurol. 2006;  2(10) 548-556
• 153 Kiyashchenko L I, Mileykovskiy B Y, Maidment N et al.. Release of hypocretin (orexin) during waking and sleep states.  J Neurosci. 2002;  22(13) 5282-5286
• 154 Blouin A M, Fried I, Staba R J et al.. Hypocretin release during wake and sleep in the human brain. Abstract Viewer/Itinerary Planner. Washington, DC; Society for Neuroscience 2007
• 155 van den Pol A N, Gao X B, Obrietan K, Kilduff T S, Belousov A B. Presynaptic and postsynaptic actions and modulation of neuroendocrine neurons by a new hypothalamic peptide, hypocretin/orexin.  J Neurosci. 1998;  18(19) 7962-7971
• 156 John J, Wu M-F, Kodama T, Siegel J M. Intravenously administered hypocretin-1 alters brain amino acid release: an in vivo microdialysis study in rats.  J Physiol. 2003;  548(Pt 2) 557-562
• 157 Liu R J, van den Pol A N, Aghajanian G K. Hypocretins (orexins) regulate serotonin neurons in the dorsal raphe nucleus by excitatory direct and inhibitory indirect actions.  J Neurosci. 2002;  22(21) 9453-9464
• 158 Siegel J M. Narcolepsy: a key role for hypocretins (orexins).  Cell. 1999;  98(4) 409-412
• 159 Guilleminault C, Anognos A. Narcolepsy. In: Kryger MH, Roth T, Dement WC Principles and Practice of Sleep Medicine. 3rd ed. Philadelphia; WB Saunders 2000: 676-686
• 160 de Waal F B, Aureli F, Judge P G. Coping with crowding.  Sci Am. 2000;  282(5) 76-81
• 161 Siegel J M. The REM sleep-memory consolidation hypothesis.  Science. 2001;  294(5544) 1058-1063
• 162 Siegel J M. Clues to the functions of mammalian sleep.  Nature. 2005;  437(7063) 1264-1271
• 163 Siegel J M. Do all animals sleep?.  Trends Neurosci. 2008;  31(4) 208-213
• 164 Kripke D F. Sleep and mortality.  Psychosom Med. 2003;  65(1) 74