Current Neurology and Neuroscience Reports

, Volume 10, Issue 3, pp 174–179 | Cite as

Hypocretins in the Control of Sleep and Wakefulness

Article

Abstract

During the past 10 years since the discovery of hypocretins (Hcrt, also called orexins), the list of their physiologic implications has been growing, from their primary roles in the sleep–wake cycle and feeding to the control of the cardiovascular system, pain, locomotion, stress, and addiction as well as their involvement in psychiatric disorders such as panic, anxiety, and depression. This diverse set of functions is consistent with the localization of Hcrt neurons in the lateral hypothalamus, a major integrating center of sensory inputs and emotional processes, and their widespread excitatory projections throughout the brain. Newly developed optical tools allow us to manipulate the activity of genetically identified neurons with millisecond precision in vivo and to test specific hypotheses about the causal relationships between Hcrt cells and specific behaviors. Here, we review the basic roles of the Hcrt peptides and discuss how these new technologies increase our understanding of the underpinnings of alertness and arousal.

Keywords

Orexin Hypothalamus Arousal Optogenetics Feeding Narcolepsy 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of outstanding importance

  1. 1.
    de Lecea L, Kilduff TS, Peyron C, et al.: The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 1998, 95:322–327.CrossRefPubMedGoogle Scholar
  2. 2.
    Sakurai T, Amemiya A, Ishii M, et al.: Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998, 92:573–585.CrossRefPubMedGoogle Scholar
  3. 3.
    de Lecea L, Sutcliffe JG: The hypocretins and sleep. FEBS J 2005, 272:5675–5688.CrossRefPubMedGoogle Scholar
  4. 4.
    Peyron C, Tighe DK, van den Pol AN, et al.: Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 1998, 18:9996–10015.PubMedGoogle Scholar
  5. 5.
    Sutcliffe JG, de Lecea L: The hypocretins: excitatory neuromodulatory peptides for multiple homeostatic systems, including sleep and feeding. J Neurosci Res 2000, 62:161–168.CrossRefPubMedGoogle Scholar
  6. 6.
    van den Pol AN: Physiological characteristics of hypocretin/orexin neurons. In Hypocretins: Integrators of Physiological Functions. Edited by de Lecea L, Sutcliffe JG. New York: Springer; 2005:123–136.Google Scholar
  7. 7.
    Sutcliffe JG, de Lecea L: The hypocretins: setting the arousal threshold. Nat Rev Neurosci 2002, 3:339–349.CrossRefPubMedGoogle Scholar
  8. 8.
    •• Adamantidis AR, Zhang F, Aravanis AM, et al.: Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature 2007, 450:420–424. Adamantidis et al. applied optogenetic technology to the Hcrt system and showed that stimulation of Hcrt neurons is sufficient to increase the probability of an awakening event during slow-wave or REM sleep. This effect was blocked in Hcrt knockout mice and in the presence of an Hcrt-R1 antagonist, demonstrating that Hcrt peptides, and not other neurotransmitters, are necessary for the wake-promoting effects of Hcrt neurons.Google Scholar
  9. 9.
    Carter ME, Adamantidis A, Ohtsu H, et al.: Sleep homeostasis modulates hypocretin-mediated sleep-to-wake transitions. J Neurosci 2009, 29:10939–10949.CrossRefPubMedGoogle Scholar
  10. 10.
    Dube MG, Kalra SP, Kalra PS: Food intake elicited by central administration of orexins/hypocretins: identification of hypothalamic sites of action. Brain Res 1999, 842:473–477.CrossRefPubMedGoogle Scholar
  11. 11.
    Yamanaka A, Beuckmann CT, Willie JT, et al.: Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 2003, 38:701–713.CrossRefPubMedGoogle Scholar
  12. 12.
    Elias CF, Saper CB, Maratos-Flier E, et al.: Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area. J Comp Neurol 1998, 402:442–459.CrossRefPubMedGoogle Scholar
  13. 13.
    Horvath TL, Diano S, van den Pol AN: 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 1999, 19:1072–1087.PubMedGoogle Scholar
  14. 14.
    Adamantidis A, de Lecea L: Physiological arousal: a role for hypothalamic systems. Cell Mol Life Sci 2008, 65:1475–1488.CrossRefPubMedGoogle Scholar
  15. 15.
    Adamantidis A, de Lecea L: Sleep and metabolism: shared circuits, new connections. Trends Endocrinol Metab 2008, 19:362–370.CrossRefPubMedGoogle Scholar
  16. 16.
    Håkansson M, de Lecea L, Sutcliffe JG, et al.: Leptin receptor- and STAT3-immunoreactivities in hypocretin/orexin neurones of the lateral hypothalamus. J Neuroendocrinol 1999, 11:653–663.CrossRefPubMedGoogle Scholar
  17. 17.
    Yamamoto Y, Ueta Y, Date Y, et al.: Down regulation of the prepro-orexin gene expression in genetically obese mice. Brain Res Mol Brain Res 1999, 65:14–22.CrossRefPubMedGoogle Scholar
  18. 18.
    Yoshida Y, Fujiki N, Nakajima T, et al.: Fluctuation of extracellular hypocretin-1 (orexin A) levels in the rat in relation to the light-dark cycle and sleep–wake activities. Eur J Neurosci 2001, 14:1075–1081.CrossRefPubMedGoogle Scholar
  19. 19.
    Fujiki N, Yoshida Y, Ripley B, et al.: Changes in CSF hypocretin-1 (orexin A) levels in rats across 24 hours and in response to food deprivation. Neuroreport 2001, 12:993–997.CrossRefPubMedGoogle Scholar
  20. 20.
    Wu MF, John J, Maidment N, et al.: Hypocretin release in normal and narcoleptic dogs after food and sleep deprivation, eating, and movement. Am J Physiol Regul Integr Comp Physiol 2002, 283:1079–1086.Google Scholar
  21. 21.
    Yamanaka A, Sakurai T, Katsumoto T, et al.: Chronic intracerebroventricular administration of orexin-A to rats increases food intake in daytime, but has no effect on body weight. Brain Res 1999, 849:248–252.CrossRefPubMedGoogle Scholar
  22. 22.
    Boutrel B, Kenny PJ, Specio SE, et al.: Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior. Proc Natl Acad Sci U S A 2005, 102:19168–19173.CrossRefPubMedGoogle Scholar
  23. 23.
    Narita M, Nagumo Y, Hashimoto S, et al.: Direct involvement of orexinergic systems in the activation of the mesolimbic dopamine pathway and related behaviors induced by morphine. J Neurosci 2006, 26:398–405.CrossRefPubMedGoogle Scholar
  24. 24.
    • Zheng H, Patterson LM, Berthoud HR: Orexin signaling in the ventral tegmental area is required for high-fat appetite induced by opioid stimulation of the nucleus accumbens. J Neurosci 2007, 27:11075–11082. This study provides evidence that projections from the nucleus accumbens (a prominent player in the reward system) to hypothalamic Hcrt field, activation of Hcrt neurons, and downstream signaling through Hcrt-R1 in the ventral tegmental area are critically involved in the accumbens-driven stimulation of palatable food intake.Google Scholar
  25. 25.
    Lin L, Faraco J, Li R, et al.: The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999, 98:365–376.CrossRefPubMedGoogle Scholar
  26. 26.
    Chemelli RM, Willie JT, Sinton CM, et al.: Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999, 98:437–451.CrossRefPubMedGoogle Scholar
  27. 27.
    Peyron C, Faraco J, Rogers W, et al.: A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000, 6:991–997.CrossRefPubMedGoogle Scholar
  28. 28.
    Thannickal TC, Moore RY, Nienhuis R, et al.: Reduced number of hypocretin neurons in human narcolepsy. Neuron 2000, 27:469–474.CrossRefPubMedGoogle Scholar
  29. 29.
    Jacobs BL, Azmitia EC: Structure and function of the brain serotonin system. Physiol Rev 1992, 72:165–229.PubMedGoogle Scholar
  30. 30.
    Berridge CW, Waterhouse BD: The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Rev 2003, 42:33–84.CrossRefPubMedGoogle Scholar
  31. 31.
    Lin JS: Brain structures and mechanisms involved in the control of cortical activation and wakefulness, with emphasis on the posterior hypothalamus and histaminergic neurons. Sleep Med Rev 2000, 4:471–503.CrossRefPubMedGoogle Scholar
  32. 32.
    Dehaene S, Changeux JP: Reward-dependent learning in neuronal networks for planning and decision making. Prog Brain Res 2000, 126:217–229.CrossRefPubMedGoogle Scholar
  33. 33.
    Rye DB, Jankovic J: Emerging views of dopamine in modulating sleep/wake state from an unlikely source: PD. Neurology 2002, 58:341–346.PubMedGoogle Scholar
  34. 34.
    Jones BE: Basic mechanisms of sleep–wake states. In Principles and Practice of Sleep Medicine, edn 3. Edited by Kryger MH, Roth T, Dement WC. Philadelphia: Saunders; 2000:134–154.Google Scholar
  35. 35.
    Bourgin P, Huitrón-Résendiz S, Spier AD, et al.: Hypocretin-1 modulates rapid eye movement sleep through activation of locus coeruleus neurons. J Neurosci 2000, 20:7760–7765.PubMedGoogle Scholar
  36. 36.
    Saper CB, Scammell TE, Lu J: Hypothalamic regulation of sleep and circadian rhythms. Nature 2005, 437:1257–1263.CrossRefPubMedGoogle Scholar
  37. 37.
    Siegel JM: Brainstem mechanisms generating REM sleep. In Principles and Practice of Sleep Medicine, edn 3. Edited by Kryger MH, Roth T, Dement WC. Philadelphia: Saunders; 2000:112–133.Google Scholar
  38. 38.
    Wightman RM, Robinson DL: Transient changes in mesolimbic dopamine and their association with “reward.” J Neurochem 2002, 82:721–735.CrossRefPubMedGoogle Scholar
  39. 39.
    Borgland SL, Taha SA, Sarti F, et al.: Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine. Neuron 2006, 49:589–601.CrossRefPubMedGoogle Scholar
  40. 40.
    Mileykovskiy BY, Kiyaschenko LI, Siegel JM: Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron 2005, 46:787–798.CrossRefPubMedGoogle Scholar
  41. 41.
    Lee MG, Hassani OK, Jones BE: Discharge of identified orexin/hypocretin neurons across the sleep–waking cycle. J Neurosci 2005, 25:6716–6720.CrossRefPubMedGoogle Scholar
  42. 42.
    Zhang S, Zeitzer JM, Yoshida Y, et al.: Lesions of the suprachiasmatic nucleus eliminate the daily rhythm of hypocretin-1 release. Sleep 2004, 27:619–627.PubMedGoogle Scholar
  43. 43.
    Estabrooke IV, McCarthy MT, Ko E, et al.: Fos expression in orexin neurons varies with behavioral state. J Neurosci 2001, 21:1656–1662.PubMedGoogle Scholar
  44. 44.
    Vyazovskiy VV, Olcese U, Lazimy YM, et al.: Cortical firing and sleep homeostasis. Neuron 2009, 63:865–878.CrossRefPubMedGoogle Scholar
  45. 45.
    Nishino S, Ripley B, Overeem S, et al.: Low cerebrospinal fluid hypocretin (Orexin) and altered energy homeostasis in human narcolepsy. Ann Neurol 2001, 50:381–388.CrossRefPubMedGoogle Scholar
  46. 46.
    Blouin AM, Thannickal TC, Worley PF, et al.: Narp immunostaining of human hypocretin (orexin) neurons: loss in narcolepsy. Neurology 2005, 65:1189–1192.CrossRefPubMedGoogle Scholar
  47. 47.
    Crocker A, España RA, Papadopoulou M, et al.: Concomitant loss of dynorphin, NARP, and orexin in narcolepsy. Neurology 2005, 65:1184–1188.CrossRefPubMedGoogle Scholar
  48. 48.
    • Johnson PL, Truitt W, Fitz SD, et al.: A key role for orexin in panic anxiety. Nat Med 2010, 16:111–115. This recent study based on translational experiments in a rat panic model and humans strongly suggests that aberrant functioning of the Hcrt system may underlie panic attacks and that blocking Hcrt-R1 signaling may be a therapeutic strategy to treat panic disorders.Google Scholar
  49. 49.
    • Brisbare-Roch C, Dingemanse J, Koberstein R, et al.: Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med 2007, 13:150–155. This study describes an Hcrt receptor antagonist that targets both Hcrt receptors, can be administered orally, readily crosses the blood–brain barrier, and reversibly blocks Hcrt function in vivo.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Psychiatry and Behavioral SciencesStanford School of MedicinePalo AltoUSA

Personalised recommendations