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The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness

Key Points

  • The neurological condition of narcolepsy, characterized by an orexin (hypocretin) deficiency, has shown that orexins have an important role in regulating sleep and wakefulness and in the maintenance of arousal.

  • Orexin neurons are activated during wakefulness, whereas during sleep they are inhibited.

  • Both the orexin 1 and orexin 2 receptors are involved in the regulation of sleep and wakefulness.

  • Orexin neurons regulate monoaminergic and cholinergic nuclei in the brain stem to regulate sleep and wakefulness.

  • Orexin neurons also have links with the arcuate nucleus that regulates feeding, and with the dopaminergic reward system in the ventral tegmental nucleus.

  • Input from the limbic system to orexin neurons might be important for emotional arousal and for sympathetic responses during emotional events.

  • The responsiveness of orexin neurons to peripheral metabolic cues, such as leptin and glucose, indicate that they might act as sensors for the metabolic status of animals.

  • These findings indicate that orexin neurons provide a crucial link between energy balance, emotion, reward systems and arousal.

Abstract

Sleep and wakefulness are regulated to occur at appropriate times that are in accordance with our internal and external environments. Avoiding danger and finding food, which are life-essential activities that are regulated by emotion, reward and energy balance, require vigilance and therefore, by definition, wakefulness. The orexin (hypocretin) system regulates sleep and wakefulness through interactions with systems that regulate emotion, reward and energy homeostasis.

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Figure 1: Schematic drawing showing main projections of orexin neurons.
Figure 2: Sleep state abnormalities in orexin receptor-knockout mice.
Figure 3: Interactions of orexin neurons with other brain regions implicated in sleep and wakefulness.
Figure 4: Mechanisms by which the orexin system stabilizes sleep and wakefulness.

References

  1. Sakurai, T. 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). Describes the discovery of orexins and their two target receptors, the determination of their exact structures and the evidence that the peptides stimulate short-term food intake.

    CAS  Article  PubMed  Google Scholar 

  2. Haynes, A. C. et al. Anorectic, thermogenic and anti-obesity activity of a selective orexin-1 receptor antagonist in ob/ob mice. Regul. Pept. 104, 153–159 (2002).

    CAS  Article  PubMed  Google Scholar 

  3. Haynes, A. C. et al. A selective orexin-1 receptor antagonist reduces food consumption in male and female rats. Regul. Pept. 96, 45–51 (2000).

    CAS  Article  PubMed  Google Scholar 

  4. Edwards, C. M. et al. The effect of the orexins on food intake: comparison with neuropeptide Y, melanin-concentrating hormone and galanin. J. Endocrinol. 160, R7–R12 (1999).

    CAS  Article  PubMed  Google Scholar 

  5. Peyron, C. et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nature Med. 9, 991–997 (2000).

    Article  CAS  Google Scholar 

  6. Thannickal, T. C. et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 27, 469–474 (2000). References 5 6 provide evidence that, in most cases, human narcolepsy–cataplexy is probably a neurodegenerative disease of orexin neurons.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Chemelli, R. M. et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, 437–451 (1999).

    CAS  Article  PubMed  Google Scholar 

  8. Lin, L. et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98, 365–376 (1999). References 7 8 provide evidence that a deficiency of orexin or the orexin receptor 2 results in a narcoleptic phenotype in mice and dogs.

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  10. Boutrel, B. et al. Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior. Proc. Natl Acad. Sci. USA 102, 19168–19173 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Yamanaka, A. et al. Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 38, 701–713 (2003). Shows that orexin neurons are directly regulated by glucose, leptin and ghrelin, and are necessary for augmenting arousal during fasting.

    CAS  Article  PubMed  Google Scholar 

  12. Akiyama, M. et al. Reduced food anticipatory activity in genetically orexin (hypocretin) neuron-ablated mice. Eur. J. Neurosci. 20, 3054–3062 (2004).

    Article  PubMed  Google Scholar 

  13. Mieda, M. et al. Orexin neurons function in an efferent pathway of a food-entrainable circadian oscillator in eliciting food-anticipatory activity and wakefulness. J. Neurosci. 24, 10493–10501 (2004). References 12 13 show that orexin neurons convey an efferent signal from a putative food-entrainable oscillator to increase wakefulness and locomotor activity.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Sakurai, T. et al. Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice. Neuron 46, 297–308 (2005).

    CAS  Article  PubMed  Google Scholar 

  15. Yoshida, K., McCormack, S., Espana, R. A., Crocker, A. & Scammell, T. E. Afferents to the orexin neurons of the rat brain. J. Comp. Neurol. 494, 845–861 (2006). References 14 15 map the neuronal input to orexin neurons.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Harris, G. C., Wimmer, M. & Aston-Jones, G. A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437, 556–559 (2005).

    CAS  Article  PubMed  Google Scholar 

  17. Narita, M. et al. Direct involvement of orexinergic systems in the activation of the mesolimbic dopamine pathway and related behaviors induced by morphine. J. Neurosci. 26, 398–405 (2006). References 16 17 demonstrate roles for orexin neurons and ventral tegmental orexin receptors in reward-based learning and memory.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  19. Mignot, E. 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 

  20. American Academy of Sleep Medicine, Diagnostic Classification Steering Committee. The International Classification of Sleep Disorders: Diagnostic and Coding Manual. (American Academy of Sleep Medicine, 2005).

  21. Crocker, A. et al. Concomitant loss of dynorphin, NARP, and orexin in narcolepsy. Neurology 65, 1184–1188 (2005).

    CAS  Article  PubMed  Google Scholar 

  22. Kadotani, H., Faraco, J. & Mignot, E. Genetic studies in the sleep disorder narcolepsy. Genome Res. 8, 427–434 (1998).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Nambu, T. et al. Distribution of orexin neurons in the adult rat brain. Brain Res. 827, 243–260 (1999).

    CAS  Article  PubMed  Google Scholar 

  26. Peyron, C. et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J. Neurosci. 18, 9996–10015 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Marcus, J. N. et al. Differential expression of orexin receptors 1 and 2 in the rat brain. J. Comp. Neurol. 435, 6–25 (2001). Comprehensive report on the distribution of orexin receptor mRNAs in the rat brain.

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  29. Nakamura, T. et al. Orexin-induced hyperlocomotion and stereotypy are mediated by the dopaminergic system. Brain Res. 873, 181–187 (2000).

    CAS  Article  PubMed  Google Scholar 

  30. 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. 22, 9453–9464 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Brown, R. E., Sergeeva, O. A., Eriksson, K. S. & Haas, H. L. Convergent excitation of dorsal raphe serotonin neurons by multiple arousal systems (orexin/hypocretin, histamine and noradrenaline). J. Neurosci. 22, 8850–8859 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Yamanaka, A. et al. Orexins activate histaminergic neurons via the orexin 2 receptor. Biochem. Biophys. Res. Commun. 290, 1237–1245 (2002).

    CAS  Article  Google Scholar 

  33. Vanni-Mercier, G., Sakai, K. & Jouvet, M. Neurons specifiques de l'eveil dans l'hypothalamus posterieur du chat. C. R. Acad. Sci., III 298, 195–200 (1984).

    CAS  Google Scholar 

  34. Eggermann, E. et al. Orexins/hypocretins excite basal forebrain cholinergic neurones. Neuroscience 108, 177–181 (2001).

    CAS  Article  PubMed  Google Scholar 

  35. Alam, M. N., Szymusiak, R., Gong, H., King, J. & McGinty, D. Adenosinergic modulation of rat basal forebrain neurons during sleep and waking: neuronal recording with microdialysis. J. Physiol. 521, 679–690 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 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. 571, 50–63 (1992).

    CAS  Article  PubMed  Google Scholar 

  37. Xi, M., 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. 901, 259–264 (2001).

    CAS  Article  PubMed  Google Scholar 

  38. Takahashi, K., Koyama, Y., Kayama, Y. & Yamamoto, M. Effects of orexin on the laterodorsal tegmental neurones. Psychiatry Clin. Neurosci. 56, 335–336 (2002).

    CAS  Article  PubMed  Google Scholar 

  39. Takakusaki, K. et al. Orexinergic projections to the midbrain mediate alternation of emotional behavioral states from locomotion to cataplexy. J. Physiol. 568, 1003–1020 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Huang, Z. L. et al. Arousal effect of orexin A depends on activation of the histaminergic system. Proc. Natl. Acad. Sci. USA 98, 9965–9970 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  42. Willie, J. T. 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). Demonstrates distinct roles of each orexin receptor subtype in the regulation of sleep and wakefulness.

    CAS  Article  PubMed  Google Scholar 

  43. Mieda, M. et al. Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice. Proc. Natl Acad. Sci. USA 101, 4649–4654 (2004). Demonstrates rescue of the narcolepsy–cataplexy phenotype of orexin neuron-ablated mice by genetic and pharmacological means, providing evidence that receptor agonists might be of potential value for treating human narcolepsy.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. Estabrooke, I. V. et al. Fos expression in orexin neurons varies with behavioral state. J. Neurosci. 21, 1656–1662 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. Yoshida, Y. 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. 14, 1075–1081 (2001).

    CAS  Article  PubMed  Google Scholar 

  46. Mileykovskiy, B. Y., Kiyashchenko, L. I. & Siegel, J. M. Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron 46, 787–798 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Lee, M. G., Hassani, O. K. & Jones, B. E. Discharge of identified orexin/hypocretin neurons across the sleep–waking cycle. J. Neurosci. 25, 6716–6720 (2005). References 46 47 report in vivo activity of orexin neurons during states of sleep and wakefulness.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Schuld, A., Hebebrand, J., Geller, F. & Pollmacher, T. Increased body-mass index in patients with narcolepsy. Lancet 355, 1274–1275 (2000).

    CAS  Article  PubMed  Google Scholar 

  49. Lammers, G. J. et al. Spontaneous food choice in narcolepsy. Sleep 19, 75–76 (1996).

    CAS  Article  PubMed  Google Scholar 

  50. Hara, J., Yanagisawa, M. & Sakurai, T. Difference in obesity phenotype between orexin-knockout mice and orexin neuron-deficient mice with same genetic background and environmental conditions. Neurosci. Lett. 380, 239–242 (2005).

    CAS  Article  PubMed  Google Scholar 

  51. Yamada, H., Okumura, T., Motomura, W., Kobayashi, Y. & Kohgo, Y. Inhibition of food intake by central injection of anti-orexin antibody in fasted rats. Biochem. Biophys. Res. Commun. 267, 527–531 (2000).

    CAS  Article  PubMed  Google Scholar 

  52. Yamanaka, A. et al. Orexin-induced food intake involves neuropeptide Y pathway. Brain Res. 24, 404–409 (2000).

    Article  Google Scholar 

  53. Muroya, S. et al. Orexins (hypocretins) directly interact with neuropeptide Y, POMC and glucose-responsive neurons to regulate Ca2+ signaling in a reciprocal manner to leptin: orexigenic neuronal pathways in the mediobasal hypothalamus. Eur. J. Neurosci. 19, 1524–1534 (2004).

    Article  PubMed  Google Scholar 

  54. Thorpe, A. J. & Kotz, C. M. Orexin A in the nucleus accumbens stimulates feeding and locomotor activity. Brain Res. 1050, 156–162 (2005).

    CAS  Article  PubMed  Google Scholar 

  55. Baldo, B. A. et al. Activation of a subpopulation of orexin/hypocretin-containing hypothalamic neurons by GABAA receptor-mediated inhibition of the nucleus accumbens shell, but not by exposure to a novel environment. Eur. J. Neurosci. 19, 376–386 (2004).

    Article  PubMed  Google Scholar 

  56. Challet, E., Pevet, P. & Malan, A. Effect of prolonged fasting and subsequent refeeding on free-running rhythms of temperature and locomotor activity in rats. Behav. Brain. Res. 84, 275–284 (1997).

    CAS  Article  PubMed  Google Scholar 

  57. Itoh, T. et al. Effects of 24-hr fasting on methamphetamine- and apomorphine-induced locomotor activities, and on monoamine metabolism in mouse corpus striatum and nucleus accumbens. Pharmacol. Biochem. Behav. 35, 391–396 (1990).

    CAS  Article  PubMed  Google Scholar 

  58. Mieda, M., Williams, S. C., Richardson, J. A., Tanaka, K. & Yanagisawa, M. The dorsomedial hypothalamic nucleus as a putative food-entrainable circadian pacemaker. Proc. Natl Acad. Sci. USA 103, 12150–12155 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. Gooley, J. J., Schomer, A. & Saper, C. B. The dorsomedial hypothalamic nucleus is critical for the expression of food-entrainable circadian rhythms. Nature Neurosci. 9, 398–407 (2006).

    CAS  Article  PubMed  Google Scholar 

  60. Shirasaka, T., Nakazato, M., Matsukura, S., Takasaki, M. & Kannan, H. Sympathetic and cardiovascular actions of orexins in conscious rats. Am. J. Physiol. 277, R1780–R1785 (1999).

    CAS  PubMed  Google Scholar 

  61. Kayaba, Y. et al. Attenuated defense response and low basal blood pressure in orexin knockout mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 285, R581–R593 (2003).

    Article  PubMed  Google Scholar 

  62. Zhang, W., Sakurai, T., Fukuda, Y. & Kuwaki, T. Orexin neuron-mediated skeletal muscle vasodilation and shift of baroreflex during defense response in mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 290, R1654–R1663 (2006).

    CAS  Article  PubMed  Google Scholar 

  63. Lubkin, M. & Stricker-Krongrad, A. Independent feeding and metabolic actions of orexins in mice. Biochem. Biophys. Res. Commun. 253, 241–245 (1998).

    CAS  Article  PubMed  Google Scholar 

  64. Borgland, S. L., Taha, S. A., Sarti, F., Fields, H. L. & Bonci, A. Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine. Neuron 49, 589–601 (2006).

    CAS  Article  PubMed  Google Scholar 

  65. Georgescu, D. et al. Involvement of the lateral hypothalamic peptide orexin in morphine dependence and withdrawal. J. Neurosci. 23, 3106–3111 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. Guilleminault, C., Carskadon, M. & Dement, W. C. On the treatment of rapid eye movement narcolepsy. Arch. Neurol. 30, 90–93 (1974).

    CAS  Article  PubMed  Google Scholar 

  67. Kuru, M. et al. Centrally administered orexin/hypocretin activates HPA axis in rats. Neuroreport 11, 1977–1980 (2000).

    CAS  Article  PubMed  Google Scholar 

  68. Sakamoto, F., Yamada, S. & Ueta, Y. Centrally administered orexin-A activates corticotropin-releasing factor-containing neurons in the hypothalamic paraventricular nucleus and central amygdaloid nucleus of rats: possible involvement of central orexins on stress-activated central CRF neurons. Regul. Pept. 118, 183–191 (2004).

    CAS  Article  PubMed  Google Scholar 

  69. Winsky-Sommerer, R. et al. Interaction between the corticotropin-releasing factor system and hypocretins (orexins): a novel circuit mediating stress response. J. Neurosci. 24, 11439–11448 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. Li, Y., Gao, X. B., Sakurai, T. & van den Pol, A. N. Hypocretin/Orexin excites hypocretin neurons via a local glutamate neuron-A potential mechanism for orchestrating the hypothalamic arousal system. Neuron 36, 1169–1181 (2002).

    CAS  Article  PubMed  Google Scholar 

  71. Yamanaka, A., Muraki, Y., Tsujino, N., Goto, K. & Sakurai, T. Regulation of orexin neurons by the monoaminergic and cholinergic systems. Biochem. Biophys. Res. Commun. 303, 120–129 (2003).

    CAS  Article  PubMed  Google Scholar 

  72. Yamanaka, A. et al. Orexin neurons are directly and indirectly regulated by catecholamines in a complex manner. J. Neurophysiol. 96, 284–298 (2006).

    CAS  Article  PubMed  Google Scholar 

  73. Grivel, J. et al. The wake-promoting hypocretin/orexin neurons change their response to noradrenaline after sleep deprivation. J. Neurosci. 25, 4127–4130 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. Tsujino, N. et al. Cholecystokinin activates orexin/hypocretin neurons through the cholecystokinin A receptor. J. Neurosci. 25, 7459–7469 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. Liu, Z. W. & Gao, X. B. Adenosine inhibits activity of hypocretin/orexin neurons by the A1 receptor in the lateral hypothalamus: a possible sleep-promoting effect. J. Neurophysiol. 97, 837–848 (2007).

    CAS  Article  PubMed  Google Scholar 

  76. Burdakov, D., Gerasimenko, O. & Verkhratsky, A. Physiological changes in glucose differentially modulate the excitability of hypothalamic melanin-concentrating hormone and orexin neurons in situ. J. Neurosci. 25, 2429–2433 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. Burdakov, D. et al. Tandem-pore K+ channels mediate inhibition of orexin neurons by glucose. Neuron 50, 711–722 (2006). Shows a novel mechanism by which glucose regulates the activity of orexin neurons.

    CAS  Article  PubMed  Google Scholar 

  78. Cai, X. J. et al. Hypoglycemia activates orexin neurons and selectively increases hypothalamic orexin-B levels: responses inhibited by feeding and possibly mediated by the nucleus of the solitary tract. Diabetes 50, 105–112 (2001).

    CAS  Article  PubMed  Google Scholar 

  79. Williams, G. et al. The hypothalamus and the control of energy homeostasis: different circuits, different purposes. Physiol. Behav. 74, 683–701 (2001).

    CAS  Article  PubMed  Google Scholar 

  80. Agnati, L. F., Zoli, M., Stromberg, I. & Fuxe, K. Intercellular communication in the brain: wiring versus volume transmission. Neuroscience 69, 711–726 (1995).

    CAS  Article  PubMed  Google Scholar 

  81. Elias, C. F. et al. Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area. J. Comp. Neurol. 402, 442–459 (1998).

    CAS  Article  PubMed  Google Scholar 

  82. Takenoya, F. et al. Neuronal interactions between galanin-like-peptide- and orexin- or melanin-concentrating hormone-containing neurons. Regul. Pept. 126, 79–83 (2005).

    CAS  Article  PubMed  Google Scholar 

  83. Kayaba, Y. et al. Attenuated defense response and low basal blood pressure in orexin knockout mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 285, R581–R593 (2003).

    Article  PubMed  Google Scholar 

  84. Shiromani, P. J., Armstrong, D. M., Berkowitz, A., Jeste, D. V. & Gillin, J. C. Distribution of choline acetyltransferase immunoreactive somata in the feline brainstem: implications for REM sleep generation. Sleep 11, 1–16 (1988).

    CAS  Article  PubMed  Google Scholar 

  85. Berthoud, H. R. Mind versus metabolism in the control of food intake and energy balance. Physiol. Behav. 81, 781–793 (2004).

    CAS  Article  PubMed  Google Scholar 

  86. Reid, M. S. et al. Neuropharmacological characterization of basal forebrain cholinergic stimulated cataplexy in narcoleptic canines. Exp. Neurol. 151, 89–104 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. 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. 18, 4705–4721 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. Lu, J. et al. Selective activation of the extended ventrolateral preoptic nucleus during rapid eye movement sleep. J. Neurosci. 22, 4568–4576 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. Xie, X. et al. GABAB receptor-mediated modulation of hypocretin/orexin neurones in mouse hypothalamus. J. Physiol. 574, 399–414 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. Leak, R. K. & Moore, R. Y. Topographic organization of suprachiasmatic nucleus projection neurons. J. Comp. Neurol. 433, 312–334 (2001).

    CAS  Article  PubMed  Google Scholar 

  91. Muraki, Y. et al. Serotonergic regulation of the orexin/hypocretin neurons through the 5-HT1A receptor. J. Neurosci. 24, 7159–7166 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. Morairty, S., Rainnie, D., McCarley, R. & Greene, R. Disinhibition of ventrolateral preoptic area sleep-active neurons by adenosine:a new mechanism for sleep promotion. Neuroscience 123, 451–457 (2004).

    CAS  Article  PubMed  Google Scholar 

  93. Arrigoni, E., Chamberlin, N. L., Saper, C. B. & McCarley, R. W. Adenosine inhibits basal forebrain cholinergic and noncholinergic neurons in vitro. Neuroscience 140, 403–413 (2006).

    CAS  Article  PubMed  Google Scholar 

  94. Huang, Z. L. et al. Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. Nature Neurosci. 8, 858–859 (2005).

    CAS  Article  PubMed  Google Scholar 

  95. Sakurai, T. Roles of orexins and orexin receptors in central regulation of feeding behavior and energy homeostasis. CNS Neurol. Disord. Drug Targets 5, 313–325 (2006).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  97. Gallopin, T. et al. Identification of sleep-promoting neurons in vitro. Nature 404, 992–995 (2000).

    CAS  Article  PubMed  Google Scholar 

  98. de Lecea, L. et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl Acad. Sci. USA 95, 322–327 (1998). Describes the independent discovery of the transcript that encodes orexins, the prediction that two peptides are encoded by the transcript, and the detection of the peptides in dense-core vesicles at synapses.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. Zhu, Y. et al. 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. 92, 259–266 (2003).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  101. Zeitzer, J. M., Nishino, S. & Mignot, E. The neurobiology of hypocretins (orexins), narcolepsy and related therapeutic interventions. Trends Pharmacol. Sci. 27, 368–374 (2006).

    CAS  Article  PubMed  Google Scholar 

  102. Davis, M. & Whalen, P. The amygdala: vigilance and emotion. Mol. Psychiat. 6, 13–34 (2001).

    CAS  Article  Google Scholar 

  103. LeDoux, J. The emotional brain, fear, and the amygdala. Cell. Mol. Neurobiol. 23, 727–738 (2003).

    Article  PubMed  Google Scholar 

  104. Phelps, E. A. & LeDoux, J. E. Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron 48, 175–187 (2005).

    CAS  Article  PubMed  Google Scholar 

  105. Acuna-Goycolea, C. & van den Pol, A. N. Glucagon-like peptide 1 excites hypocretin/orexin neurons by direct and indirect mechanisms: implications for viscera-mediated arousal. J. Neurosci. 24, 8141–8152 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  106. Wollmann, G., Acuna-Goycolea, C. & van den Pol, A. N. Direct excitation of hypocretin/orexin cells by extracellular ATP at P2X receptors. J. Neurophysiol. 94, 2195–2206 (2005).

    CAS  Article  PubMed  Google Scholar 

  107. Fu, L. Y., Acuna-Goycolea, C. & van den Pol, A. N. Neuropeptide Y inhibits hypocretin/orexin neurons by multiple presynaptic and postsynaptic mechanisms: tonic depression of the hypothalamic arousal system. J. Neurosci. 24, 8741–8751 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  108. Martin, J. H. Neuroanatomy: Text and Atlas 2nd edn (Appleton & Lange, Stamford, Connecticut, 1996).

    Google Scholar 

  109. Brisbare-Roch, C. et al. Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nature Med. 13, 150–155 (2007).

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

This study was supported in part by a grant-in-aid for scientific research from The 21st Century COE Program from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan; the University of Tsukuba Project Research; the ERATO Yanagisawa Orphan Receptor Project from the Japan Science and Technology Corporation; and anorexia nervosa research from the Japanese Ministry of Health, Labour and Welfare.

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Supplementary information S1 (table)

Phenotypes of rodent narcolepsy models produced by genetic engineering (PDF 83 kb)

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DATABASES

OMIM

narcolepsy

FURTHER INFORMATION

Sakurai's laboratory

Glossary

Narcolepsy

A neurological condition mostly characterized by excessive daytime sleepiness, uncontrollable sleep attacks and disorder of REM sleep.

Limbic system

A collection of cortical and subcortical structures important for processing memory and emotional information. Prominent structures include the hippocampus and amygdala.

Ghrelin

Stomach-derived orexigenic peptide.

Leptin

An adipocyte-derived protein hormone that has a key role in regulating energy intake and energy expenditure.

Rapid eye movement sleep

(REM sleep) The stage of sleep characterized by rapid movements of the eyes.

Cataplexy

An episodic condition featuring loss of muscle function, ranging from slight weakness (such as limpness at the neck or knees, sagging facial muscles or inability to speak clearly) to complete body collapse.

Orthodromic and antidromic activation

Neural stimulation in the same and the opposite direction of the physiological nerve conductance, respectively.

Food anticipatory activity

(FAA). Behavioural activation induced by restricted access to food; a manifestation of the food-entrained oscillator.

mPer1

The PER1 gene is a core clock factor that has an essential role in generating circadian rhythms. mPer1 is the mouse counterpart of the human PER1 gene.

Bmal1

Bmal1 (brain and muscle arnt-like protein 1) is a putative clock gene which encodes a basic helix-loop-helix-PAS transcription factor.

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Sakurai, T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci 8, 171–181 (2007). https://doi.org/10.1038/nrn2092

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  • DOI: https://doi.org/10.1038/nrn2092

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