Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Sleeping with the hypothalamus: emerging therapeutic targets for sleep disorders

Nature Neuroscience volume 5, pages 1071–1075 (2002)Cite this article

Abstract

Delineating the basic mechanisms that regulate sleep will likely result in the development of better treatments for sleep disorders. The hypothalamus is now recognized as a key center for sleep regulation, with hypothalamic neurotransmitter systems providing the framework for therapeutic advances. An increased awareness of the close interaction between sleep and homeostatic systems is also emerging. Progress has occurred in the understanding of narcolepsy—molecular techniques have identified the lateral hypothalamic hypocretin (orexin) neuropeptide system as key to the disorder. Other sleep disorders are now being tackled in the same way and are likely to yield to efforts combining basic and clinical research. Here we highlight the role of the hypothalamus in sleep physiology and discuss neurotransmitter systems, such as adenosine, dopamine, GABA, histamine and hypocretin, that may have therapeutic applications for sleep disorders.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Hypothalamic and brainstem sleep/wake regulation systems, in relation to common sleep disorders and their pharmacological treatment.

Rebecca Henretta

Similar content being viewed by others

References

  1. Kryger, M., Roth, T. & Dement, W.C. Principles and Practice of Sleep Medicine 3rd edn. (WB Saunders Company, New York, 2000).

    Google Scholar 

  2. Van Economo, C. Sleep as a problem of localization. J. Nerv. Mental Disease 71, 249–269 (1931).

    Article  Google Scholar 

  3. Bernardis, L.L. & Bellinger, L.L. The lateral hypothalamic area revisited: ingestive behavior. Neurosc. Behav. Rev. 20, 189–287 (1996).

    Article  CAS  Google Scholar 

  4. Moruzzi, G. & Magoun, H.W. Brain stem reticular formation and activation of the EEG. Electroencephalogr. Clin. Neurophysiol. 1, 455–473 (1949).

    Article  CAS  Google Scholar 

  5. Rechtschaffen, A., Bergmann, B.M., Everson, C.A., Kushida, C.A. & Gilliland, M.A. Sleep deprivation in the rat: X. Integration and discussion of the findings. Sleep 25, 68–87 (2002).

    Article  Google Scholar 

  6. Spiegel, K., Leproult, R. & Van Cauter, E. Impact of sleep debt on metabolic and endocrine function. Lancet 354, 1435–1439 (1999).

    Article  CAS  Google Scholar 

  7. Pace-Schott, E.F. & Hobson, J.A. The neurobiology of sleep: genetics, cellular physiology and subcortical networks. Nat. Rev. Neurosci. 3, 591–605 (2002).

    Article  CAS  Google Scholar 

  8. Steriade, M. Arousal: revisiting the reticular activating system. Science 272, 225–226 (1996).

    Article  CAS  Google Scholar 

  9. Wisor, J.P., Nishino, S., Sora, I., Uhl, G.H., Mignot, E. & Edgar, D.M. Dopaminergic role in stimulant-induced wakefulness. J. Neurosci. 21, 1787–1794 (2001).

    Article  CAS  Google Scholar 

  10. Miller, J.D., Farber, J., Gatz, P., Roffwarg, H. & German, D.C. Activity of mesencephalic dopamine and non-dopamine neurons across stages of sleep and walking in the rat. Brain Res. 273, 133–141 (1983).

    Article  CAS  Google Scholar 

  11. Rye, D.B. & Jankovic, J. Emerging views of dopamine in modulating sleep/wake state from an unlikely source: PD. Neurology 58, 341–346 (2002).

    Article  Google Scholar 

  12. Lu, J., Xu, M. & Saper, C.B. Identification of wake-active dopaminergic neurons in the ventral periaqueducal gray. Sleep 25, supplement, A290 (2002).

    Google Scholar 

  13. Smith, T.A. Type A gamma-aminobutyric acid (GABAA) receptor subunits and benzodiazepine binding: significance to clinical syndromes and their treatment. Br. J. Biomed. Sci. 58, 111–121 (2001).

    CAS  PubMed  Google Scholar 

  14. Crestani, F., Martin, J.R., Mohler, H. & Rudolph, U. Mechanism of action of the hypnotic zolpidem in vivo. Br. J. Pharmacol. 131, 1251–1254 (2000).

    Article  CAS  Google Scholar 

  15. Tobler, I., Kopp, C., Deboer, T. & Rudolph, U. Diazepam-induced changes in sleep: role of the alpha 1 GABA(A) receptor subtype. Proc. Natl. Acad. Sci. USA 98, 6464–6469 (2001).

    Article  CAS  Google Scholar 

  16. Bernasconi, R., Mathivet, P., Bischoff, S. & Marescaux, C. Gamma-hydroxybutyric acid: an endogenous neuromodulator with abuse potential? Trends Pharmacol. Sci. 20, 135–141 (1999).

    Article  CAS  Google Scholar 

  17. Strecker, R.E. et al. Extracellular histamine levels in the feline preoptic/anterior hypothalamic area during natural sleep-wakefulness and prolonged wakefulness: an in vivo microdialysis study. Neuroscience 113, 663–670 (2002).

    Article  CAS  Google Scholar 

  18. Parmentier, R., Ohtsu, H., Djebbara-Hannas, Z., Valatx, J.L., Watanabe, T. & Lin, J.S. Anatomical, physiological, and pharmacological characteristics of histidine decarboxylase knock-out mice: evidence for the role of brain histamine in behavioral and sleep-wake control. J. Neurosci. 22, 7695–7711 (2002).

    Article  CAS  Google Scholar 

  19. Dugovic, C. et al. Sleep in mice lacking the histamine H3 receptor, a putative genetic animal model for REM behavior disorder. Sleep 25, supplement, A114 (2002).

    Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  23. 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).

    Article  CAS  Google Scholar 

  24. Kiyashchenko, L.I. et al. Release of hypocretin (orexin) during waking and sleep states. J. Neurosci. 22, 5282–5286 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  27. Suntsova, N., Szymusiak, R., Alam, M.N., Guzman-Marin, R. & McGinty, D. Sleep-waking discharge patterns of median preoptic nucleus neurons in rats. J. Physiol. 543, 665–677 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  29. Edgar, D.M., Dement, W.C. & Fuller, C.A. Effect of SCN lesions on sleep in squirrel monkeys: evidence for opponent processes in sleep-wake regulation. J. Neurosci. 13, 1065–1079 (1993).

    Article  CAS  Google Scholar 

  30. Wager-Smith, K. & Kay, S.A. Circadian rhythm genetics: from flies to mice to humans. Nat. Genet. 26, 23–27 (2000).

    Article  CAS  Google Scholar 

  31. Kramer, A. et al. Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling. Science 294, 2511–2515 (2001).

    Article  CAS  Google Scholar 

  32. Cheng, M.Y. et al. Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Nature 417, 405–410 (2002).

    Article  CAS  Google Scholar 

  33. Shaw, P.J., Tononi, G., Greenspan, R.J. & Robinson, D.F. Stress response genes protect against lethal effects of sleep deprivation in Drosophila. Nature 417, 287–291 (2002).

    Article  CAS  Google Scholar 

  34. Naylor, E. et al. The circadian clock mutation alters sleep homeostasis in the mouse. J. Neurosci. 20, 8138–8143 (2000).

    Article  CAS  Google Scholar 

  35. Porkka-Heiskanen, T., Strecker, R.E., Thakkar, M., Bjorkum, A.A., Greene, R.W. & McCarley, R.W. Adenosine: a mediator of the sleep-inducing effects of prolonged wakefulness. Science 276, 1265–1268 (1997).

    Article  CAS  Google Scholar 

  36. Kubin, L., Tojima, H., Reignier, C., Pack, A.I. & Davies, R.O. Interaction of serotonergic excitatory drive to hypoglossal motoneurons with carbachol-induced, REM sleep-like atonia. Sleep 19, 187–195 (1996).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Stanford University Center for Narcolepsy, 701 Welch Road B, Room 145, Palo Alto, 94304-5742, California, USA

    Emmanuel Mignot, Shahrad Taheri & Seiji Nishino

Authors
  1. Emmanuel Mignot
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shahrad Taheri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Seiji Nishino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Emmanuel Mignot.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mignot, E., Taheri, S. & Nishino, S. Sleeping with the hypothalamus: emerging therapeutic targets for sleep disorders. Nat Neurosci 5 (Suppl 11), 1071–1075 (2002). https://doi.org/10.1038/nn944

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn944

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing