Skip to main content
SpringerLink
Log in

Orexin (Hypocretin) and Narcolepsy

  • Chapter
Narcolepsy

Abstract

Orexins (hypocretins) are neuropeptides expressed exclusively by neurons in the lateral and perifornical hypothalamus in the brain. Selective degeneration of orexin-producing neurons has been established as the cause of human narcolepsy, a debilitating neurological disease characterized by excessive daytime sleepiness and cataplexy. Orexin neurons are thought to maintain and stabilize wakefulness through their interaction with monoaminergic and cholinergic neurons implicated in the regulation of states of sleep and wakefulness, and they are mediated by two G-protein-coupled receptors that show differential expression patterns depending on brain region and neuron type. Furthermore, the replacement of orexins may prevent narcoleptic symptoms in animal models of narcolepsy. Thus, the discovery of a causal relationship between deficient orexin signaling and narcolepsy has allowed tremendous progress in our understanding of the pathophysiology of narcolepsy, as well as raised the possibility of novel diagnoses and treatments for narcolepsy. Here, we review the current understanding of how the orexinergic system regulates sleep and wakefulness and how its deficiency causes narcolepsy.

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 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 139.99
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

References

  1. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell. 1998;92(4):573–85.

    Article  PubMed  CAS  Google Scholar 

  2. de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett 2nd FS, Frankel WN, van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe JG. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA. 1998;95(1):322–7.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Mieda M, Tsujino N, Sakurai T. Differential roles of orexin receptors in the regulation of sleep/wakefulness. Front Endocrinol (Lausanne). 2013;4:57. doi:10.3389/fendo.2013.00057.

    CAS  Google Scholar 

  4. Belle MD, Hughes AT, Bechtold DA, Cunningham P, Pierucci M, Burdakov D, Piggins HD. Acute suppressive and long-term phase modulation actions of orexin on the mammalian circadian clock. J Neurosci. 2014;34(10):3607–21. doi:10.1523/JNEUROSCI.3388-13.2014.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Zhu Y, Miwa Y, Yamanaka A, Yada T, Shibahara M, Abe Y, Sakurai T, Goto K. Orexin receptor type-1 couples exclusively to pertussis toxin-insensitive G-proteins, while orexin receptor type-2 couples to both pertussis toxin-sensitive and -insensitive G-proteins. J Pharmacol Sci. 2003;92(3):259–66.

    Article  PubMed  CAS  Google Scholar 

  6. Date Y, Ueta Y, Yamashita H, Yamaguchi H, Matsukura S, Kangawa K, Sakurai T, Yanagisawa M, Nakazato M. Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proc Natl Acad Sci USA. 1999;96(2):748–53.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. 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(1–2):243–60.

    Article  PubMed  CAS  Google Scholar 

  8. Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, Kilduff TS. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci. 1998;18(23):9996–10015.

    PubMed  CAS  Google Scholar 

  9. Kilduff TS, Peyron C. The hypocretin/orexin ligand-receptor system: implications for sleep and sleep disorders. Trends Neurosci. 2000;23(8):359–65.

    Article  PubMed  CAS  Google Scholar 

  10. Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M, Cornford M, Siegel JM. Reduced number of hypocretin neurons in human narcolepsy. Neuron. 2000;27(3):469–74.

    Article  PubMed  CAS  Google Scholar 

  11. van den Pol AN. Hypothalamic hypocretin (orexin): robust innervation of the spinal cord. J Neurosci. 1999;19(8):3171–82.

    PubMed  Google Scholar 

  12. Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, Elmquist JK. Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol. 2001;435(1):6–25.

    Article  PubMed  CAS  Google Scholar 

  13. Mieda M, Hasegawa E, Kisanuki YY, Sinton CM, Yanagisawa M, Sakurai T. Differential roles of orexin receptor-1 and -2 in the regulation of non-REM and REM sleep. J Neurosci. 2011;31(17):6518–26. doi:10.1523/JNEUROSCI.6506-10.2011.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Mignot E. Genetic and familial aspects of narcolepsy. Neurology. 1998;50(2 Suppl 1):S16–22.

    Article  PubMed  CAS  Google Scholar 

  15. Sakurai T, Mieda M. Connectomics of orexin-producing neurons: interface of systems of emotion, energy homeostasis and arousal. Trends Pharmacol Sci. 2011;32(8):451–62. doi:10.1016/j.tips.2011.03.007.

    Article  PubMed  CAS  Google Scholar 

  16. Zeitzer JM, Nishino S, Mignot E. The neurobiology of hypocretins (orexins), narcolepsy and related therapeutic interventions. Trends Pharmacol Sci. 2006;27(7):368–74.

    Article  PubMed  CAS  Google Scholar 

  17. Dauvilliers Y, Arnulf I, Mignot E. Narcolepsy with cataplexy. Lancet. 2007;369(9560):499–511. doi:10.1016/S0140-6736(07)60237-2.

    Article  PubMed  Google Scholar 

  18. Sakurai T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci. 2007;8(3):171–81.

    Article  PubMed  CAS  Google Scholar 

  19. Nishino S, Mignot E. Pharmacological aspects of human and canine narcolepsy. Prog Neurobiol. 1997;52(1):27–78.

    Article  PubMed  CAS  Google Scholar 

  20. Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, Qiu X, de Jong PJ, Nishino S, Mignot E. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell. 1999;98(3):365–76.

    Article  PubMed  CAS  Google Scholar 

  21. Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y, Fitch TE, Nakazato M, Hammer RE, Saper CB, Yanagisawa M. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell. 1999;98(4):437–51.

    Article  PubMed  CAS  Google Scholar 

  22. Mignot E, Lammers GJ, Ripley B, Okun M, Nevsimalova S, Overeem S, Vankova J, Black J, Harsh J, Bassetti C, Schrader H, Nishino S. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol. 2002;59(10):1553–62.

    Article  PubMed  Google Scholar 

  23. Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet. 2000;355(9197):39–40. doi:10.1016/S0140-6736(99)05582-8.

    Article  PubMed  CAS  Google Scholar 

  24. Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, Nevsimalova S, Aldrich M, Reynolds D, Albin R, Li R, Hungs M, Pedrazzoli M, Padigaru M, Kucherlapati M, Fan J, Maki R, Lammers GJ, Bouras C, Kucherlapati R, Nishino S, Mignot E. 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):991–7.

    Article  PubMed  CAS  Google Scholar 

  25. Crocker A, Espana RA, Papadopoulou M, Saper CB, Faraco J, Sakurai T, Honda M, Mignot E, Scammell TE. Concomitant loss of dynorphin, NARP, and orexin in narcolepsy. Neurology. 2005;65(8):1184–8. Epub 2005 Sep 1114.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Dauvilliers Y, Arnulf I, Lecendreux M, Monaca Charley C, Franco P, Drouot X, d’Ortho MP, Launois S, Lignot S, Bourgin P, Nogues B, Rey M, Bayard S, Scholz S, Lavault S, Tubert-Bitter P, Saussier C, Pariente A, Narcoflu VF. Increased risk of narcolepsy in children and adults after pandemic H1N1 vaccination in France. Brain. 2013;136(Pt 8):2486–96. doi:10.1093/brain/awt187.

    Article  PubMed  Google Scholar 

  27. Hallmayer J, Faraco J, Lin L, Hesselson S, Winkelmann J, Kawashima M, Mayer G, Plazzi G, Nevsimalova S, Bourgin P, Hong SC, Honda Y, Honda M, Hogl B, Longstreth Jr WT, Montplaisir J, Kemlink D, Einen M, Chen J, Musone SL, Akana M, Miyagawa T, Duan J, Desautels A, Erhardt C, Hesla PE, Poli F, Frauscher B, Jeong JH, Lee SP, Ton TG, Kvale M, Kolesar L, Dobrovolna M, Nepom GT, Salomon D, Wichmann HE, Rouleau GA, Gieger C, Levinson DF, Gejman PV, Meitinger T, Young T, Peppard P, Tokunaga K, Kwok PY, Risch N, Mignot E. Narcolepsy is strongly associated with the T-cell receptor alpha locus. Nat Genet. 2009;41(6):708–11. doi:10.1038/ng.372.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Kornum BR, Kawashima M, Faraco J, Lin L, Rico TJ, Hesselson S, Axtell RC, Kuipers H, Weiner K, Hamacher A, Kassack MU, Han F, Knudsen S, Li J, Dong X, Winkelmann J, Plazzi G, Nevsimalova S, Hong SC, Honda Y, Honda M, Hogl B, Ton TG, Montplaisir J, Bourgin P, Kemlink D, Huang YS, Warby S, Einen M, Eshragh JL, Miyagawa T, Desautels A, Ruppert E, Hesla PE, Poli F, Pizza F, Frauscher B, Jeong JH, Lee SP, Strohl KP, Longstreth Jr WT, Kvale M, Dobrovolna M, Ohayon MM, Nepom GT, Wichmann HE, Rouleau GA, Gieger C, Levinson DF, Gejman PV, Meitinger T, Peppard P, Young T, Jennum P, Steinman L, Tokunaga K, Kwok PY, Risch N, Hallmayer J, Mignot E. Common variants in P2RY11 are associated with narcolepsy. Nat Genet. 2011;43(1):66–71. doi:10.1038/ng.734.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Partinen M, Saarenpaa-Heikkila O, Ilveskoski I, Hublin C, Linna M, Olsen P, Nokelainen P, Alen R, Wallden T, Espo M, Rusanen H, Olme J, Satila H, Arikka H, Kaipainen P, Julkunen I, Kirjavainen T. Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland. PLoS One. 2012;7(3), e33723. doi:10.1371/journal.pone.0033723.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Beuckmann CT, Sinton CM, Williams SC, Richardson JA, Hammer RE, Sakurai T, Yanagisawa M. Expression of a poly-glutamine-ataxin-3 transgene in orexin neurons induces narcolepsy-cataplexy in the rat. J Neurosci. 2004;24(18):4469–77. doi:10.1523/JNEUROSCI.5560-03.2004.

    Article  PubMed  CAS  Google Scholar 

  31. Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM, Sinton CM, Sugiyama F, Yagami K, Goto K, Yanagisawa M, Sakurai T. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron. 2001;30(2):345–54.

    Article  PubMed  CAS  Google Scholar 

  32. Tabuchi S, Tsunematsu T, Black SW, Tominaga M, Maruyama M, Takagi K, Minokoshi Y, Sakurai T, Kilduff TS, Yamanaka A. Conditional ablation of orexin/hypocretin neurons: a new mouse model for the study of narcolepsy and orexin system function. J Neurosci. 2014;34(19):6495–509. doi:10.1523/JNEUROSCI.0073-14.2014.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Ripley B, Fujiki N, Okura M, Mignot E, Nishino S. Hypocretin levels in sporadic and familial cases of canine narcolepsy. Neurobiol Dis. 2001;8(3):525–34. doi:10.1006/nbdi.2001.0389.

    Article  PubMed  CAS  Google Scholar 

  34. Mieda M, Willie JT, Hara J, Sinton CM, Sakurai T, Yanagisawa M. Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice. Proc Natl Acad Sci USA. 2004;101(13):4649–54. Epub 2004 Mar 4616.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. Fujiki N, Yoshida Y, Ripley B, Mignot E, Nishino S. Effects of IV and ICV hypocretin-1 (orexin A) in hypocretin receptor-2 gene mutated narcoleptic dogs and IV hypocretin-1 replacement therapy in a hypocretin-ligand-deficient narcoleptic dog. Sleep. 2003;26(8):953–9.

    PubMed  Google Scholar 

  36. Willie JT, Takahira H, Shibahara M, Hara J, Nomiyama M, Yanagisawa M, Sakurai T. Ectopic overexpression of orexin alters sleep/wakefulness states and muscle tone regulation during REM sleep in mice. J Mol Neurosci. 2011;43(2):155–61. doi:10.1007/s12031-010-9437-7.

    Article  PubMed  CAS  Google Scholar 

  37. Brisbare-Roch C, Dingemanse J, Koberstein R, Hoever P, Aissaoui H, Flores S, Mueller C, Nayler O, van Gerven J, de Haas SL, Hess P, Qiu C, Buchmann S, Scherz M, Weller T, Fischli W, Clozel M, Jenck F. Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med. 2007;13(2):150–5. Epub 2007 Jan 2028.

    Article  PubMed  CAS  Google Scholar 

  38. Espana RA, Scammell TE. Sleep neurobiology from a clinical perspective. Sleep. 2011;34(7):845–58. doi:10.5665/SLEEP.1112.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Pace-Schott EF, Hobson JA. The neurobiology of sleep: genetics, cellular physiology and subcortical networks. Nat Rev Neurosci. 2002;3(8):591–605. doi:10.1038/nrn895.

    Article  PubMed  CAS  Google Scholar 

  40. Hagan JJ, Leslie RA, Patel S, Evans ML, Wattam TA, Holmes S, Benham CD, Taylor SG, Routledge C, Hemmati P, Munton RP, Ashmeade TE, Shah AS, Hatcher JP, Hatcher PD, Jones DN, Smith MI, Piper DC, Hunter AJ, Porter RA, Upton N. Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proc Natl Acad Sci USA. 1999;96(19):10911–6.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  41. Adamantidis AR, Zhang F, Aravanis AM, Deisseroth K, de Lecea L. Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature. 2007;450(7168):420–4. Epub 2007 Oct 2017.

    Article  PubMed  CAS  Google Scholar 

  42. Tsunematsu T, Kilduff TS, Boyden ES, Takahashi S, Tominaga M, Yamanaka A. Acute optogenetic silencing of orexin/hypocretin neurons induces slow-wave sleep in mice. J Neurosci. 2011;31(29):10529–39. doi:10.1523/JNEUROSCI.0784-11.2011.

    Article  PubMed  CAS  Google Scholar 

  43. Sasaki K, Suzuki M, Mieda M, Tsujino N, Roth B, Sakurai T. Pharmacogenetic modulation of orexin neurons alters sleep/wakefulness states in mice. PLoS One. 2011;6(5), e20360. doi:10.1371/journal.pone.0020360.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  44. Bourgin P, Huitron-Resendiz S, Spier AD, Fabre V, Morte B, Criado JR, Sutcliffe JG, Henriksen SJ, de Lecea L. Hypocretin-1 modulates rapid eye movement sleep through activation of locus coeruleus neurons. J Neurosci. 2000;20(20):7760–5.

    PubMed  CAS  Google Scholar 

  45. Huang ZL, Qu WM, Li WD, Mochizuki T, Eguchi N, Watanabe T, Urade Y, Hayaishi O. Arousal effect of orexin A depends on activation of the histaminergic system. Proc Natl Acad Sci USA. 2001;98(17):9965–70. Epub 2001 Aug 9967.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  46. Espana RA, Baldo BA, Kelley AE, Berridge CW. Wake-promoting and sleep-suppressing actions of hypocretin (orexin): basal forebrain sites of action. Neuroscience. 2001;106(4):699–715.

    Article  PubMed  CAS  Google Scholar 

  47. Thakkar MM, Ramesh V, Strecker RE, McCarley RW. Microdialysis perfusion of orexin-A in the basal forebrain increases wakefulness in freely behaving rats. Arch Ital Biol. 2001;139(3):313–28.

    PubMed  CAS  Google Scholar 

  48. Xi MC, Morales FR, Chase MH. 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(1–2):259–64.

    Article  PubMed  CAS  Google Scholar 

  49. Horvath TL, Peyron C, Diano S, Ivanov A, Aston-Jones G, Kilduff TS, van Den Pol AN. Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system. J Comp Neurol. 1999;415(2):145–59.

    Article  PubMed  CAS  Google Scholar 

  50. van den Pol AN, Ghosh PK, Liu RJ, Li Y, Aghajanian GK, Gao XB. Hypocretin (orexin) enhances neuron activity and cell synchrony in developing mouse GFP-expressing locus coeruleus. J Physiol. 2002;541(Pt 1):169–85.

    PubMed  PubMed Central  Google Scholar 

  51. Brown RE, Sergeeva O, Eriksson KS, Haas HL. Orexin A excites serotonergic neurons in the dorsal raphe nucleus of the rat. Neuropharmacology. 2001;40(3):457–9.

    Article  PubMed  CAS  Google Scholar 

  52. Liu RJ, van den Pol AN, Aghajanian GK. Hypocretins (orexins) regulate serotonin neurons in the dorsal raphe nucleus by excitatory direct and inhibitory indirect actions. J Neurosci. 2002;22(21):9453–64.

    PubMed  CAS  Google Scholar 

  53. Bayer L, Eggermann E, Serafin M, Saint-Mleux B, Machard D, Jones B, Muhlethaler M. Orexins (hypocretins) directly excite tuberomammillary neurons. Eur J Neurosci. 2001;14(9):1571–5.

    Article  PubMed  CAS  Google Scholar 

  54. Eriksson KS, Sergeeva O, Brown RE, Haas HL. Orexin/hypocretin excites the histaminergic neurons of the tuberomammillary nucleus. J Neurosci. 2001;21(23):9273–9.

    PubMed  CAS  Google Scholar 

  55. Yamanaka A, Tsujino N, Funahashi H, Honda K, Guan JL, Wang QP, Tominaga M, Goto K, Shioda S, Sakurai T. Orexins activate histaminergic neurons via the orexin 2 receptor. Biochem Biophys Res Commun. 2002;290(4):1237–45.

    Article  PubMed  CAS  Google Scholar 

  56. Burlet S, Tyler CJ, Leonard CS. Direct and indirect excitation of laterodorsal tegmental neurons by Hypocretin/Orexin peptides: implications for wakefulness and narcolepsy. J Neurosci. 2002;22(7):2862–72.

    PubMed  CAS  Google Scholar 

  57. Eggermann E, Serafin M, Bayer L, Machard D, Saint-Mleux B, Jones BE, Muhlethaler M. Orexins/hypocretins excite basal forebrain cholinergic neurones. Neuroscience. 2001;108(2):177–81.

    Article  PubMed  CAS  Google Scholar 

  58. Li Y, Gao XB, Sakurai T, van den Pol AN. Hypocretin/Orexin excites hypocretin neurons via a local glutamate neuron-A potential mechanism for orchestrating the hypothalamic arousal system. Neuron. 2002;36(6):1169–81.

    Article  PubMed  CAS  Google Scholar 

  59. Yamanaka A, Tabuchi S, Tsunematsu T, Fukazawa Y, Tominaga M. Orexin directly excites orexin neurons through orexin 2 receptor. J Neurosci. 2010;30(38):12642–52. doi:10.1523/JNEUROSCI.2120-10.2010.

    Article  PubMed  CAS  Google Scholar 

  60. Lee MG, Hassani OK, Jones BE. Discharge of identified orexin/hypocretin neurons across the sleep-waking cycle. J Neurosci. 2005;25(28):6716–20.

    Article  PubMed  CAS  Google Scholar 

  61. Mileykovskiy BY, Kiyashchenko LI, Siegel JM. Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron. 2005;46(5):787–98.

    Article  PubMed  CAS  Google Scholar 

  62. Takahashi K, Lin JS, Sakai K. Neuronal activity of orexin and non-orexin waking-active neurons during wake-sleep states in the mouse. Neuroscience. 2008;153:860–70.

    Article  PubMed  CAS  Google Scholar 

  63. Blouin AM, Fried I, Wilson CL, Staba RJ, Behnke EJ, Lam HA, Maidment NT, Karlsson KAE, Lapierre JL, Siegel JM. Human hypocretin and melanin-concentrating hormone levels are linked to emotion and social interaction. Nat Commun. 2013;4:1547. doi:10.1038/ncomms2461.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Hondo M, Nagai K, Ohno K, Kisanuki Y, Willie JT, Watanabe T, Yanagisawa M, Sakurai T. Histamine-1 receptor is not required as a downstream effector of orexin-2 receptor in maintenance of basal sleep/wake states. Acta Physiol. 2010;198(3):287–94. doi:10.1111/j.1748-1716.2009.02032.x.

    Article  CAS  Google Scholar 

  65. Willie JT, Chemelli RM, Sinton CM, Tokita S, Williams SC, Kisanuki YY, Marcus JN, Lee C, Elmquist JK, Kohlmeier KA, Leonard CS, Richardson JA, Hammer RE, Yanagisawa M. Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep regulatory processes. Neuron. 2003;38(5):715–30.

    Article  PubMed  CAS  Google Scholar 

  66. Baker TL, Foutz AS, McNerney V, Mitler MM, Dement WC. Canine model of narcolepsy: genetic and developmental determinants. Exp Neurol. 1982;75(3):729–42.

    Article  PubMed  CAS  Google Scholar 

  67. Mochizuki T, Arrigoni E, Marcus JN, Clark EL, Yamamoto M, Honer M, Borroni E, Lowell BB, Elmquist JK, Scammell TE. Orexin receptor 2 expression in the posterior hypothalamus rescues sleepiness in narcoleptic mice. Proc Natl Acad Sci USA. 2011;108(11):4471–6. doi:10.1073/pnas.1012456108.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  68. Hasegawa E, Yanagisawa M, Sakurai T, Mieda M. Orexin neurons suppress narcolepsy via 2 distinct efferent pathways. J Clin Invest. 2014;124(2):604–16. doi:10.1172/JCI71017.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  69. Carter ME, Adamantidis A, Ohtsu H, Deisseroth K, de Lecea L. Sleep homeostasis modulates hypocretin-mediated sleep-to-wake transitions. J Neurosci. 2009;29(35):10939–49. doi:10.1523/JNEUROSCI.1205-09.2009.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  70. Hirai N, Nishino S. Recent advances in the treatment of narcolepsy. Curr Treat Options Neurol. 2011;13(5):437–57. doi:10.1007/s11940-011-0137-6.

    Article  PubMed  Google Scholar 

  71. Wu MF, Gulyani SA, Yau E, Mignot E, Phan B, Siegel JM. Locus coeruleus neurons: cessation of activity during cataplexy. Neuroscience. 1999;91(4):1389–99.

    Article  PubMed  CAS  Google Scholar 

  72. Wu MF, John J, Boehmer LN, Yau D, Nguyen GB, Siegel JM. Activity of dorsal raphe cells across the sleep-waking cycle and during cataplexy in narcoleptic dogs. J Physiol. 2004;554(Pt 1):202–15. doi:10.1113/jphysiol.2003.052134.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  73. Luppi PH, Clement O, Sapin E, Gervasoni D, Peyron C, Leger L, Salvert D, Fort P. The neuronal network responsible for paradoxical sleep and its dysfunctions causing narcolepsy and rapid eye movement (REM) behavior disorder. Sleep Med Rev. 2011;15(3):153–63. doi:10.1016/j.smrv.2010.08.002.

    Article  PubMed  Google Scholar 

  74. Carter ME, Yizhar O, Chikahisa S, Nguyen H, Adamantidis A, Nishino S, Deisseroth K, de Lecea L. Tuning arousal with optogenetic modulation of locus coeruleus neurons. Nat Neurosci. 2010;13(12):1526–33. doi:10.1038/nn.2682.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  75. Carter ME, Brill J, Bonnavion P, Huguenard JR, Huerta R, de Lecea L. Mechanism for Hypocretin-mediated sleep-to-wake transitions. Proc Natl Acad Sci USA. 2012;109(39):E2635–2644. doi:10.1073/pnas.1202526109.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  76. Dauvilliers Y, Siegel JM, Lopez R, Torontali ZA, Peever JH. Cataplexy—clinical aspects, pathophysiology and management strategy. Nat Rev Neurol. 2014;10(7):386–95. doi:10.1038/nrneurol.2014.97.

    Article  PubMed  CAS  Google Scholar 

  77. Sakurai T, Nagata R, Yamanaka A, Kawamura H, Tsujino N, Muraki Y, Kageyama H, Kunita S, Takahashi S, Goto K, Koyama Y, Shioda S, Yanagisawa M. Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice. Neuron. 2005;46(2):297–308. doi:10.1016/j.neuron.2005.03.010.

    Article  PubMed  CAS  Google Scholar 

  78. Yoshida K, McCormack S, Espana RA, Crocker A, Scammell TE. Afferents to the orexin neurons of the rat brain. J Comp Neurol. 2006;494(5):845–61. doi:10.1002/cne.20859.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Burgess CR, Oishi Y, Mochizuki T, Peever JH, Scammell TE. Amygdala lesions reduce cataplexy in orexin knock-out mice. J Neurosci. 2013;33(23):9734–42. doi:10.1523/JNEUROSCI.5632-12.2013.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  80. Boissard R, Fort P, Gervasoni D, Barbagli B, Luppi PH. Localization of the GABAergic and non-GABAergic neurons projecting to the sublaterodorsal nucleus and potentially gating paradoxical sleep onset. Eur J Neurosci. 2003;18(6):1627–39.

    Article  PubMed  Google Scholar 

  81. Gulyani S, Wu MF, Nienhuis R, John J, Siegel JM. Cataplexy-related neurons in the amygdala of the narcoleptic dog. Neuroscience. 2002;112(2):355–65.

    Article  PubMed  CAS  Google Scholar 

  82. Hong SB, Tae WS, Joo EY. Cerebral perfusion changes during cataplexy in narcolepsy patients. Neurology. 2006;66(11):1747–9. doi:10.1212/01.wnl.0000218205.72668.ab.

    Article  PubMed  Google Scholar 

  83. Schwartz S, Ponz A, Poryazova R, Werth E, Boesiger P, Khatami R, Bassetti CL. Abnormal activity in hypothalamus and amygdala during humour processing in human narcolepsy with cataplexy. Brain. 2008;131(Pt 2):514–22. doi:10.1093/brain/awm292.

    Article  PubMed  Google Scholar 

  84. Ponz A, Khatami R, Poryazova R, Werth E, Boesiger P, Bassetti CL, Schwartz S. Abnormal activity in reward brain circuits in human narcolepsy with cataplexy. Ann Neurol. 2010;67(2):190–200. doi:10.1002/ana.21825.

    Article  PubMed  Google Scholar 

  85. Ponz A, Khatami R, Poryazova R, Werth E, Boesiger P, Schwartz S, Bassetti CL. Reduced amygdala activity during aversive conditioning in human narcolepsy. Ann Neurol. 2010;67(3):394–8. doi:10.1002/ana.21881.

    PubMed  Google Scholar 

  86. Sears RM, Fink AE, Wigestrand MB, Farb CR, de Lecea L, Ledoux JE. Orexin/hypocretin system modulates amygdala-dependent threat learning through the locus coeruleus. Proc Natl Acad Sci USA. 2013;110(50):20260–5. doi:10.1073/pnas.1320325110.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  87. Soya S, Shoji H, Hasegawa E, Hondo M, Miyakawa T, Yanagisawa M, Mieda M, Sakurai T. Orexin receptor-1 in the locus coeruleus plays an important role in cue-dependent fear memory consolidation. J Neurosci. 2013;33(36):14549–57. doi:10.1523/JNEUROSCI.1130-13.2013.

    Article  PubMed  CAS  Google Scholar 

  88. Khatami R, Birkmann S, Bassetti CL. Amygdala dysfunction in narcolepsy-cataplexy. J Sleep Res. 2007;16(2):226–9. doi:10.1111/j.1365-2869.2007.00587.x.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Faculty of Medicine, Department of Molecular Neuroscience and Integrative Physiology, Kanazawa University, Kanazawa, Ishikawa, 920-8640, Japan

    Michihiro Mieda PhD & Takeshi Sakurai MD, PhD

Authors
  1. Michihiro Mieda PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takeshi Sakurai MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michihiro Mieda PhD .

Editor information

Editors and Affiliations

  1. Montefiore Medical Center Narcolepsy Institute, Bronx, New York, USA

    Meeta Goswami

  2. Montefiore Hospital Sleep-Wake Disorders Center, Bronx, New York, USA

    Michael J. Thorpy

  3. Somnogen Canada Inc, President and Chief Executive Officer, Toronto, Ontario, Canada

    S.R. Pandi-Perumal

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Mieda, M., Sakurai, T. (2016). Orexin (Hypocretin) and Narcolepsy. In: Goswami, M., Thorpy, M., Pandi-Perumal, S. (eds) Narcolepsy. Springer, Cham. https://doi.org/10.1007/978-3-319-23739-8_2

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-23739-8_2

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-23738-1

  • Online ISBN: 978-3-319-23739-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation