Skip to main content
SpringerLink
Log in

The Influence of Orexin on Sleep and Wakefulness

  • Chapter
Neuroendocrine Correlates of Sleep/Wakefulness

  • 3042 Accesses

Abstract

An exciting recent development in sleep research was the discovery of the importance for vigilance state control and narcolepsy-cataplexy of neurons containing orexin (also known as hypocretin) neuropeptides. Narcolepsycataplexy is a chronic, debilitating sleep disorder that is characterized by excessive daytime sleepiness, manifested as attacks of daytime somnolence at inappropriate times. 1–3 Narcoleptics also show symptoms that are considered indicative of abnormal REM (Rapid Eye Movement) sleep expression. These latter symptoms include cataplexy, hypnogogic hallucinations, sleep-onset REM periods, and sleep paralysis. In contrast to daytime sleepiness, the nighttime sleep of narcoleptics is fragmented and of poor quality, typically demonstrating lengthy periods of wakefulness after sleep onset

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. M.S. Aldrich, Diagnostic aspects of narcolepsy, Neurology 50, S2–S7 (1988).

    Google Scholar 

  2. C.M. Sinton, and R.W. McCarley, Neuroanatomical and neurophysiological aspects of sleep: Basic science and clinical relevance, Sem. Clin. Neuropsychiatry 5, 6–19 (2000).

    CAS  Google Scholar 

  3. C.M. Sinton, and R.W. McCarley, Sleep Disorders (Article 1483), in: Encyclopedia of Life Sciences (Macmillan, London, 2001); http://www.els.net.

    Google Scholar 

  4. L. Lin, J. Faraco, R. Li et al, The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene, Cell 98, 365–376 (1999).

    Article  PubMed  CAS  Google Scholar 

  5. M. Hungs, J. Fan, L. Lin, X. Lin, R.A. Maki, and E. Mignot, Identification and functional analysis of mutations in the hypocretin (orexin) genes of narcoleptic canines, Genome Res. 11 531–539 (2001).

    Article  PubMed  CAS  Google Scholar 

  6. R.M. Chemelli, J.T. Willie, C.M. Sinton, et al, Narcolepsy in orexin knockout mice: Molecular genetics of sleep regulation, Cell 98, 437–451 (1999).

    Article  PubMed  CAS  Google Scholar 

  7. J. Hara, C.T. Beuckmann, T. Nambu et al, Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity, Neuron 30, 345–354 (2001).

    Article  PubMed  CAS  Google Scholar 

  8. C.T. Beuckmann, C.M. Sinton, S.C. Williams et al, Expression of a poly-glutamine-ataxin-3 transgene in orexin neurons induces narcolepsy-cataplexy in the rat, J. Neurosci. 24, 4469–4477 (2004).

    Article  PubMed  CAS  Google Scholar 

  9. E. Mignot, Genetic and familial aspects of narcolepsy, Neurology 50, S16–S22 (1998).

    PubMed  CAS  Google Scholar 

  10. J.T. Willie, R.M. Chemelli, C.M. Sinton et al, Distinct narcolepsy syndromes in orexin receptor-2 and orexin null mice: molecular genetic dissection of non-REM and REM sleep regulatory processes, Neuron 38, 715–730 (2003).

    Article  PubMed  CAS  Google Scholar 

  11. C. Peyron, J. Faraco, W. Rogers et al, A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains, Nature Med. 6, 991–997 (2000).

    Article  PubMed  CAS  Google Scholar 

  12. M. Gencik, N. Dahmen, S. Wieczorek et al, A prepro-orexin gene polymorphism is associated with narcolepsy, Neurology 56, 115–117 (2001).

    PubMed  CAS  Google Scholar 

  13. S. Nishino, B. Ripley, S. Overeem, G.J. Lammers, and E. Mignot, Hypocretin (orexin) deficiency in human narcolepsy, Lancet 355, 39–40 (2000).

    Article  PubMed  CAS  Google Scholar 

  14. S. Nishino, B. Ripley, S. Overeem et al, Low cerebrospinal fluid hypocretin (orexin) and altered energy homeostasis in human narcolepsy, Ann. Neurol. 50, 381–388 (2001).

    Article  PubMed  CAS  Google Scholar 

  15. B. Ripley, S. Overeem, N. Fujiki et al, CSF hypocretin/orexin levels in narcolepsy and other neurological conditions, Neurology 57, 2253–2258 (2001).

    PubMed  CAS  Google Scholar 

  16. E. Mignot, G.J. Lammers, B. Ripley et al, The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias, Arch. Neurol. 59, 1553–1562 (2002).

    Article  PubMed  Google Scholar 

  17. T.C. Thannickal, R.Y. Moore, R. Nienhuis et al, Reduced number of hypocretin neurons in human narcolepsy, Neuron 27, 469–474 (2000).

    Article  PubMed  CAS  Google Scholar 

  18. S. Taheri, J.M. Zeitzer, and E. Mignot, The role of hypocretins (orexins) in sleep regulation and narcolepsy, Ann. Rev. Neurosci. 25, 283–313 (2002).

    Article  PubMed  CAS  Google Scholar 

  19. L. Lin, M. Hungs, and E. Mignot, Narcolepsy and the HLA region, J. Neuroimmunol. 117, 9–20 (2001).

    Article  PubMed  CAS  Google Scholar 

  20. M. Mieda, J.T. Willie, J. Hara, C.M. Sinton, T. Sakurai, and M. Yanagisawa, Orexin peptides prevent cataplexy and improve wakefulness in an orexin-ablated model of narcolepsy in mice, Proc. Natl. Acad. Sci. USA 101, 4649–4654 (2004).

    Article  PubMed  CAS  Google Scholar 

  21. L. de Lecea, T.S. Kilduff, C. Peyron et al, The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity, Proc. Natl. Acad. Sci. USA 95, 322–327 (1998).

    Article  PubMed  Google Scholar 

  22. C. Peyron, D. Tighe, A.N. van den Pol et al, Neurons containing hypocretin (orexin) project to multiple neuronal systems, J. Neurosci. 18, 9996–10015 (1998).

    PubMed  CAS  Google Scholar 

  23. A.N. van den Pol, Hypothalamic hypocretin (orexin): robust innervation of the spinal cord, J. Neurosci. 19, 3171–3182 (1999).

    PubMed  Google Scholar 

  24. J.T. Willie, R.M. Chemelli, C.M. Sinton, and M. Yanagisawa, To eat or to sleep? Orexin in the regulation of feeding and wakefulness, Ann. Rev. Neurosci. 24, 429–458 (2001).

    Article  PubMed  CAS  Google Scholar 

  25. A.V. Ferguson, and W.K. Samson, The orexin/hypocretin system: a critical regulator of neuroendocrine and autonomic function, Front. Neuroendocrinol. 24, 141–150 (2003).

    Article  PubMed  CAS  Google Scholar 

  26. T. Sakurai, A. Amemiya, M. Ishii et al, Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior, Cell 92, 573–585 (1998).

    Article  PubMed  CAS  Google Scholar 

  27. T. Nambu, T. Sakurai, K. Mizukami, Y. Hosoya, M. Yanagisawa, and K. Goto, Distribution of orexin neurons in the adult rat brain, Brain Res. 827, 243–260 (1999).

    Article  PubMed  CAS  Google Scholar 

  28. T.C. Chou, C.E. Lee, J. Lu et al, Orexin (hypocretin) neurons contain dynorphin, J. Neurosci. 21, RC168 (2001).

    PubMed  CAS  Google Scholar 

  29. C.F. Elias, C.B. Saper, E. Maratos-Flier et al, Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area, J. Comp. Neurol. 402, 442–459 (1998).

    Article  PubMed  CAS  Google Scholar 

  30. Y. Date, Y. Ueta, H. Yamashita et al, Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems, Proc. Natl. Acad. Sci. USA 96, 748–753 (1999).

    Article  PubMed  CAS  Google Scholar 

  31. T.L. Horvath, S. Diano, and A.N. van Den Pol, Synaptic interaction between hypocretin (orexin) and neuropeptide Y cells in the rodent and primate hypothalamus: a novel circuit implicated in metabolic and endocrine regulations, J. Neurosci. 19, 1072–1087 (1999).

    PubMed  CAS  Google Scholar 

  32. P. Trivedi, H. Yu, D.J. MacNeil, L.H.T. Van der Ploeg, and X.M. Guan, Distribution of orexin receptor mRNA in the rat brain, F.E.B.S. Lett. 438, 71–75 (1998).

    Article  CAS  Google Scholar 

  33. J.N. Marcus, C.J. Aschkenasi, C.E. Lee et al, Differential expression of orexin receptors 1 and 2 in the rat brain, J. Comp. Neurol. 435, 6–25 (2001).

    Article  PubMed  CAS  Google Scholar 

  34. C.J. Tyler, K.A. Kohlmeier, J.T. Willie et al, Orexin receptor-1 mediates multiple hypocretin/orexin (H/O) actions in laterodorsal tegmentum (LDT) and dorsal raphe (DR), in: Abstract Viewer/Itinerary Planner (Soc. Neurosci., Washington DC, 2002), program no. 776.12.

    Google Scholar 

  35. R.W. McCarley, Sleep neurophysiology: basic mechanisms underlying control of wakefulness and sleep, in: Sleep disorders medicine: basic science, technical considerations, and clinical aspects, 2nd ed., edited by S. Chokroverty (Butterworth-Heinemann, Woburn, MA, 1999), pp. 21–50.

    Google Scholar 

  36. R.W. McCarley, Human electrophysiology and basic sleep mechanisms, in: The American Psychiatric Publishing Textbook of Neuropsychiatry and Clinical Neuroscience, 4th ed., edited by S.C. Yudofsky and R.E. Hales (American Psychiatric Press, Washington DC, 2002), pp. 43–70.

    Google Scholar 

  37. J.M. Siegel, Brainstem mechanisms generating REM sleep, in: Principles and practice of sleep medicine, 3rd ed., edited by M.H. Kryger, T. Roth and W.C. Dement (Saunders, Philadelphia, PA, 2000), pp. 112–133.

    Google Scholar 

  38. A. Mitani, K. Ito, A.H. Hallanger, B.H. Wainer, K. Kataoka, and R.W. McCarley, Cholinergic projections from the laterodorsal and pedunculopontine tegmental nuclei to the pontine gigantocellular tegmental field in the cat, Brain Res. 451, 397–402 (1988).

    Article  PubMed  CAS  Google Scholar 

  39. D.J. McGinty, and R.M. Harper, Dorsal raphe neurons: Depression of firing during sleep in cats, Brain Res. 101, 569–575 (1976).

    Article  PubMed  CAS  Google Scholar 

  40. G. Aston-Jones, and F.E. Bloom, Activity of norepinephrine containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle, J. Neurosci. 1, 876–886 (1981).

    PubMed  CAS  Google Scholar 

  41. R.W. McCarley, R.W. Greene, D. Rainnie, and C.M. Portas, Brain stem neuromodulation and REM sleep, Sem. Neurosciences 7, 341–354 (1995)

    Article  CAS  Google Scholar 

  42. G. Vanni-Mercier, K. Sakai, and M. Jouvet, “Waking-state specific” neurons in the caudal hypothalamus of the cat, C. R. Acad. Sci. Biol. 298, 195–200 (1984).

    CAS  Google Scholar 

  43. J.M. Monti, Involvement of histamine in the control of the waking state, Life Sciences 53, 1331–1338 (1993).

    Article  PubMed  CAS  Google Scholar 

  44. M. Steriade, and R.W. McCarley, Brainstem Control of Wakefulness and Sleep (Plenum Press, New York, 1990).

    Google Scholar 

  45. T.L. Horvath, C. Peyron, S. Diano et al, Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system, J. Comp. Neurol. 415, 145–159 (1999).

    Article  PubMed  CAS  Google Scholar 

  46. J.J. Hagan, R.A. Leslie, S. Patel et al, Orexin A activates locus coeruleus cell firing and increases arousal in the rat, Proc. Natl. Acad. Sci. USA 96, 10911–10916 (1999).

    Article  PubMed  CAS  Google Scholar 

  47. R.E. Brown, O. Sergeeva, K.S. Eriksson, and H.L. Haas HL, Orexin A excites serotoninergic neurons in the dorsal raphe nucleus of the rat, Neuropharmacology 40, 457–459 (2001).

    Article  PubMed  CAS  Google Scholar 

  48. S. Burlet, C.J. Tyler, and C.S. Leonard, Direct and indirect excitation of laterodorsal tegmental neurons by hypocretin/orexin peptides: implications for wakefulness and narcolepsy, J. Neurosci. 22, 2862–2872 (2002).

    PubMed  CAS  Google Scholar 

  49. R.W. Greene, and R.W. McCarley, Cholinergic neurotransmission in the brainstem: implications for behavioral state control, in: Brain Cholinergic Systems, edited by M. Steriade and D. Biesold (Oxford University Press, New York, 1990) pp. 224–235.

    Google Scholar 

  50. M.M. Thakkar, V. Ramesh, E.G. Cape, S. Winston, R.E. Strecker, and R.W. McCarley, REM sleep enhancement and behavioral cataplexy following orexin (hypocretin) II receptor antisense perfusion in the pontine reticular formation, Sleep Res. Online 2, 112–120 (1999).

    PubMed  CAS  Google Scholar 

  51. M.C. Xi, F.R. Morales, and M.H. Chase, Effects on sleep and wakefulness of the injection of hypocretin-1 (orexin-A) into the laterodorsal tegmental nucleus of the cat, Brain Res. 901, 259–264 (2001).

    Article  PubMed  CAS  Google Scholar 

  52. L.I. Kiyashchenko, B.Y. Mileykovskiy, N. Maidment et al, Release of hypocretin (orexin) during waking and sleep states, J. Neurosci. 22, 5282–5286 (2002).

    PubMed  CAS  Google Scholar 

  53. C.B. Saper, T.C. Chou, and T.E. Scammell, The sleep switch: Hypothalamic control of sleep and wakefulness, Trends Neurosci. 24, 726–731 (2001).

    Article  PubMed  CAS  Google Scholar 

  54. J.G. Sutcliffe, and L. de Lecea, The hypocretins: setting the arousal threshold, Nature Rev. Neurosci. 3, 339–349 (2002).

    Article  CAS  Google Scholar 

  55. S. Taheri, D. Sunter, C. Dakin et al, Diurnal variation in orexin A immunoreactivity and prepro-orexin mRNA in the rat central nervous system, Neurosci. Lett. 279, 109–112 (2000).

    Article  PubMed  CAS  Google Scholar 

  56. N. Fujiki, Y. Yoshida, B. Ripley, K. Honda, E. Mignot, and S. Nishino, Changes in CSF hypocretin-1 (orexin A) levels in rats across 24 hours and in response to food deprivation, Neuroreport 12, 993–997 (2001).

    Article  PubMed  CAS  Google Scholar 

  57. Y. Yoshida, N. Fujiki, T. Nakajima et al, Fluctuation of extracellular hypocretin-1 (orexin A0 levels in the rat in relation to the light-dark cycle and sleep-wake activities, Eur. J. Neurosci. 14, 1075–1081 (2001).

    Article  PubMed  CAS  Google Scholar 

  58. Y. Hishikawa, and T. Shimizu, Physiology of REM sleep, cataplexy and sleep paralysis, Adv. Neurol. 67, 245–271 (1995).

    PubMed  CAS  Google Scholar 

  59. T. Mochizuki, A. Crocker, S. McCormick, M. Yanagisawa, T. Sakurai, and T.E. Scammell, Behavioral state instability in orexin knock-out mice, J. Neurosci. 24, 6291–6300 (2004).

    Article  PubMed  CAS  Google Scholar 

  60. C. Gottesmann, The transition from slow-wave sleep to paradoxical sleep: evolving facts and concepts of the neurophysiological processes underlying the intermediate stage of sleep, Neurosci. Biobehav. Rev. 20, 367–387 (1996).

    Article  PubMed  CAS  Google Scholar 

  61. F.J. Zorick, P.J. Salis, T. Roth, and M. Kramer, Narcolepsy and automatic behavior: a case report, J. Clin. Psychiatry 40, 194–197 (1979).

    PubMed  CAS  Google Scholar 

  62. S. Nishino, and E. Mignot, Pharmacological aspects of human and canine narcolepsy, Prog. Neurobiol. 52, 27–78 (1997).

    Article  PubMed  CAS  Google Scholar 

  63. J.M. Siegel, R. Moore, T. Thannickal, and R. Nienhuis, A brief history of hypocretin/orexin and narcolepsy, Neuropsychopharmacology 25, S14–S20 (2001).

    Article  PubMed  CAS  Google Scholar 

  64. C.T. Beuckmann, and M. Yanagisawa, Orexins: from neuropeptides to energy homeostasis and sleep/wake regulation, J. Mol. Med. 80, 329–342 (2002).

    Article  PubMed  CAS  Google Scholar 

  65. L. Bayer, E. Eggermann, M. Serafin et al, Orexins (hypocretins) directly excite tuberomammillary neurons, Eur. J. Neurosci. 14, 1571–1575 (2001).

    Article  PubMed  CAS  Google Scholar 

  66. T.L. Horvath, C. Peyron, S. Diano et al, Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system, J. Comp. Neurol. 415, 145–159 (1999).

    Article  PubMed  CAS  Google Scholar 

  67. E. Eggermann, M. Serafin, L. Bayer L et al, Orexins/hypocretins excite basal forebrain cholinergic neurones, Neuroscience 108, 177–181 (2001).

    Article  PubMed  CAS  Google Scholar 

  68. K.S. Eriksson, O. Sergeeva, R.E. Brown, and H.L. Haas, Orexin/hypocretin excites the histaminergic neurons of the tuberomammillary nucleus, J. Neurosci. 21, 9273–9279 (2001).

    PubMed  CAS  Google Scholar 

  69. M.M. Thakkar, V. Ramesh, R.E. Strecker, and R.W. McCarley, Microdialysis perfusion of orexin-A in the basal forebrain increases wakefulness in freely behaving rats, Arch. Ital. Biol. 139, 313–328 (2001).

    PubMed  CAS  Google Scholar 

  70. Z.L. Huang, W.M. Qu, W.D. Li et al, Arousal effect of orexin A depends on activation of the system, Proc. Natl. Acad. Sci. USA 98, 9965–9970 (2001).

    Article  PubMed  CAS  Google Scholar 

  71. L. Bayer, M. Serafin, E. Eggermann et al, Exclusive postsynaptic action of hypocretin-orexin on sublayer 6B cortical neurons, J. Neurosci. 24, 6760–6764 (2004).

    Article  PubMed  CAS  Google Scholar 

  72. B. Clancy, and L.J. Cauller, Widespread projections from subgriseal neurons (layer VII) to layer I in adult rat cortex, J. Comp. Neurol. 407, 275–286 (1999).

    Article  PubMed  CAS  Google Scholar 

  73. R.L. Reep, Cortical layer VII and persistent subplate cells in mammalian brains, Brain Behav. Evol. 56, 212–234 (2000).

    Article  PubMed  CAS  Google Scholar 

  74. D.J. Dijk, and C.A. Czeisler, 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. 15, 3526–353 (1995).

    PubMed  CAS  Google Scholar 

  75. D.J. Dijk, and C.A. Czeisler, Paradoxical timing of the circadian rhythm of sleep propensity serves to consolidate sleep and wakefulness in humans, Neurosci. Lett. 166, 63–68 (1994).

    Article  PubMed  CAS  Google Scholar 

  76. D.J. Dijk, and J.F. Duffy, A circadian perspective on human sleep-wake regulation and ageing, in: The Regulation of Sleep, edited by A.A. Borbély, O. Hayaishi, T.J. Sejnowski and J.S. Altman (Human Frontier Science Program, Strasbourg, 2000), pp. 212–222.

    Google Scholar 

  77. B. Dantz, D.M. Edgar, and W.C. Dement, Circadian rhythms in narcolepsy: studies on a 90 minute day, Electroenceph. Clin. Neurophysiol. 90, 24–35 (1994).

    Article  PubMed  CAS  Google Scholar 

  78. E. Mignot, A commentary on the neurobiology of the hypocretin/orexin system, Neuropsychopharmacology 25, S5–S13 (2001).

    Article  PubMed  CAS  Google Scholar 

  79. J.M. Zeitzer, C.L. Buckmaster, K.J. Parker, C.M. Hauck, D.M. Lyons, and E. Mignot, Circadian and homeostatic regulation of hypocretin in a primate model: implications for the consolidation of wakefulness, J. Neurosci. 23, 3555–3560 (2003).

    PubMed  CAS  Google Scholar 

  80. M. Mieda, S.C. Williams, C.M. Sinton, T. Sakurai, and M. Yanagisawa, Orexin Neurons Function in an Efferent Pathway of a Food-Entrainable Circadian Oscillator in Eliciting Food-Anticipatory Activity and Wakefulness, J. Neurosci. (in press) (2004).

    Google Scholar 

  81. A.B. Kirillov, C.D. Myre, and D.J. Woodward, Bistability, switches and working memory in a two-neuron inhibitory-feedback model, Biol. Cybern. 68, 441–449 (1993).

    Article  PubMed  CAS  Google Scholar 

  82. R.W. McCarley, and S.G. Massaquoi, Neurobiological structure of the revised limit cycle reciprocal interaction model of REM sleep cycle control, J. Sleep Res. 1, 132–137 (1992).

    Article  PubMed  Google Scholar 

  83. N. Kleitman, Sleep and Wakefulness, (University Chicago Press, Chicago, 1963), p.242.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX

    Christopher M. Sinton

  2. Department Molecular Genetics, UT Southwestern Medical Center, Dallas, TX

    Jon T. Willie

Authors
  1. Christopher M. Sinton
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jon T. Willie
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Physiology Faculty of Medicine, University of Buenos Aires, Argentina, Buenos Aires, 1121

    Daniel P. Cardinali

  2. SUNY Downstate Medical Center, Brooklyn, 11203, New York, USA

    S. R. Pandi-Perumal

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Springer Science+Business Media, Inc.

About this chapter

Cite this chapter

Sinton, C.M., Willie, J.T. (2006). The Influence of Orexin on Sleep and Wakefulness. In: Cardinali, D.P., Pandi-Perumal, S.R. (eds) Neuroendocrine Correlates of Sleep/Wakefulness. Springer, Boston, MA. https://doi.org/10.1007/0-387-23692-9_11

Download citation

Publish with us

Policies and ethics

Search

Navigation