A series of findings over the past decade has begun to identify the brain circuitry and neurotransmitters that regulate our daily cycles of sleep and wakefulness. The latter depends on a network of cell groups that activate the thalamus and the cerebral cortex. A key switch in the hypothalamus shuts off this arousal system during sleep. Other hypothalamic neurons stabilize the switch, and their absence results in inappropriate switching of behavioural states, such as occurs in narcolepsy. These findings explain how various drugs affect sleep and wakefulness, and provide the basis for a wide range of environmental influences to shape wake–sleep cycles into the optimal pattern for survival.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Scientific Reports Open Access 25 November 2022
Nature Communications Open Access 12 November 2022
Exploring the neurobiology of the premonitory phase of migraine preclinically – a role for hypothalamic kappa opioid receptors?
The Journal of Headache and Pain Open Access 30 September 2022
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Von Economo, C. Sleep as a problem of localization. J. Nerv. Ment. Dis. 71, 249–259 (1930).
Moruzzi, G. & Magoun, H. W. Brain stem reticular formation and activation of the EEG. Electroencephalogr. Clin. Neurol. 1, 455–473 (1949).
Starzl, T. E., Taylor, C. W. & Magoun, H. W. Ascending conduction in reticular activating system, with special reference to the diencephalon. J. Neurophysiol. 14, 461–477 (1951).
Saper, C. B., Chou, T. C. & Scammell, T. E. The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci. 24, 726–731 (2001).
Hallanger, A. H., Levey, A. I., Lee, H. J., Rye, D. B. & Wainer, B. H. The origins of cholinergic and other subcortical afferents to the thalamus in the rat. J. Comp. Neurol. 262, 104–124 (1987).
Strecker, R. E. et al. Adenosinergic modulation of basal forebrain and preoptic/anterior hypothalamic neuronal activity in the control of behavioral state. Behav. Brain Res. 115, 183–204 (2000).
McCormick, D. A. Cholinergic and noradrenergic modulation of thalamocortical processing. Trends Neurosci. 12, 215–220 (1989).
Krout, K. E., Belzer, R. E. & Loewy, A. D. Brainstem projections to midline and intralaminar thalamic nuclei of the rat. J. Comp. Neurol. 448, 53–101 (2002).
Saper, C. B. Organization of cerebral cortical afferent systems in the rat. II. Hypothalamocortical projections. J. Comp. Neurol. 237, 21 (1985).
Jones, B. E. Arousal systems. Front. Biosci. 8, S438–S451 (2003).
Ranson, S. W. Somnolence caused by hypothalamic lesions in monkeys. Arch Neurol. Psychiatr. 41, 1–23 (1939).
Gerashchenko, D., Blanco-Centurion, C., Greco, M. A. & Shiromani, P. J. Effects of lateral hypothalamic lesion with the neurotoxin hypocretin-2-saporin on sleep in Long-Evans rats. Neuroscience 116, 223–235 (2003).
Aston-Jones, G. & Bloom, F. E. Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle. J. Neurosci. 1, 876–886 (1981).
Fornal, C., Auerbach, S. & Jacobs, B. L. Activity of serotonin-containing neurons in nucleus raphe magnus in freely moving cats. Exp. Neurol. 88, 590–608 (1985).
Steininger, T. L., Alam, M. N., Gong, H., Szymusiak, R. & McGinty, D. Sleep-waking discharge of neurons in the posterior lateral hypothalamus of the albino rat. Brain Res. 840, 138–147 (1999).
Estabrooke, I. V. et al. Fos expression in orexin neurons varies with behavioral state. J. Neurosci. 21, 1656–1662 (2001).
Mileykovskiy, B. Y., Kiyashchenko, L. I. & Siegel, J. M. Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron 46, 787–798 (2005).
Lee, M. G, Hassani, O. K. & Jones, B. E. Discharge of identified orexin/hypocretin neurons across the wake-sleep cycle. J. Neurosci. 25, 6716–6720 (2005).
Verret, L. et al. A role of melanin-concentrating hormone producing neurons in the central regulation of paradoxical sleep. BMC Neurosci. 4, 19 (2003).
Lee, M. G., Hassani, O. K., Alonso, A. & Jones, B. E. Cholinergic basal forebrain neurons burst with theta during waking and paradoxical sleep. J. Neurosci. 25, 4365–4369 (2005).
Nauta, W. J. H. Hypothalamic regulation of sleep in rats. An experimental study. J. Neurophysiol. 9, 285–314 (1946).
McGinty, D. J. & Sterman, M. B. Sleep suppression after basal forebrain lesions in the cat. Science 160, 1253–1255 (1968).
Sherin, J. E., Shiromani, P. J., McCarley, R. W. & Saper, C. B. Activation of ventrolateral preoptic neurons during sleep. Science 271, 216–219 (1996).
Gaus, S. E., Strecker, R. E., Tate, B. A., Parker, R. A. & Saper, C. B. Ventrolateral preoptic nucleus contains sleep-active, galaninergic neurons in multiple mammalian species. Neuroscience 115, 285–294 (2002).
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).
Szymusiak, R., Alam, N., Steininger, T. L. & McGinty, D. Sleep-waking discharge patterns of ventrolateral preoptic/anterior hypothalamic neurons in rats. Brain Res. 803, 178–188 (1998).
Lu, J. et al. Selective activation of the extended ventrolateral preoptic nucleus during rapid eye movement sleep. J. Neurosci. 22, 4568–4576 (2002).
Lu, J., Greco, M. A., Shiromani, P. & Saper, C. B. Effect of lesions of the ventrolateral preoptic nucleus on NREM and REM sleep. J. Neurosci. 20, 3830–3842 (2000).
Verret, L. et al. Localization of the neurones potentially responsible for the inhibition of locus coeruleus noradrenergic neurones during paradoxical sleep in the rat. J. Comp. Neurol. (in the press).
Ko, E. M., Estabrooke, I. V., McCarthy, M. & Scammell, T. E. Wake-related activity of tuberomammillary neurons in rats. Brain Res. 992, 220–226 (2003).
John, J., Wu, M. F., Boehmer, L. N. & Siegel, J. M. Cataplexy-active neurons in the hypothalamus: implications for the role of histamine in sleep and waking behavior. Neuron 42, 619–634 (2004).
Chou, T. C. et al. Afferents to the ventrolateral preoptic nucleus. J. Neurosci. 22, 977–990 (2002).
Gallopin, T. et al. Identification of sleep-promoting neurons in vitro. Nature 404, 992–995 (2000).
Vincent, S. R., Hokfelt, T. & Wu, J. -Y. GABA neuron systems in hypothalamus and the pituitary gland. Neuroendocrinology 34, 117–125 (1982).
Chamberlin, N. L. et al. Effects of adenosine on GABAergic synaptic inputs to identified ventrolateral preoptic neurons. Neuroscience 119, 913–918 (2003).
Martin-Schild, S., Gerall, A. A., Kastin, A. J. & Zadina, J. E. Differential distribution of endomorphin 1- and endomorphin 2-like immunoreactivities in the CNS of the rodent. J. Comp Neurol. 405, 450–471 (1999).
Kohler, C. et al. Galanin immunoreactivity in hypothalamic neurons: further evidence for multiple chemical messengers in the tuberomammillary nucleus. J. Comp. Neurol. 250, 58–64 (1986).
Chou, T. C. Regulation of Wake-Sleep Timing: Circadian Rhythms and Bistability of Sleep-Wake States, 82–99. Thesis, Harvard Univ. (2003).
Ancoli-Israel, S. & Kripke, D. F. Prevalent sleep problems in the aged. Biofeedback Self Regul. 16, 349–359 (1991).
Hofman, M. A. & Swaab, D. F. The sexually dimorphic nucleus of the preoptic area in the human brain: a comparative morphometric study. J. Anat. 164, 55–72 (1989).
Allen, L. S., Hines, M., Shryne, J. E. & Gorski, R. A. Two sexually dimorphic cell groups in the human brain. J. Neurosci. 9, 497–506 (1989).
Byne, W. et al. The interstitial nuclei of the human anterior hypothalamus: an investigation of sexual variation in volume and cell size, number and density. Brain Res. 856, 254–258 (2000).
Wilson, S. A. K. Modern Problems in Neurology (Edward Arnold, London, 1928).
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).
de Lecea, L. et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl Acad. Sci. USA 95, 322–327 (1998).
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).
Chemelli, R. M. et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, 437–451 (1999).
Thannickal, T. C. et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 27, 469–474 (2000).
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. 6, 991–997 (2000).
Ripley, B. et al. CSF hypocretin/orexin levels in narcolepsy and other neurological conditions. Neurology 57, 2253–2258 (2001).
Scammell, T. E. The neurobiology, diagnosis, and treatment of narcolepsy. Ann. Neurol. 53, 154–166 (2003).
Peyron, C. . et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J. Neurosci. 18, 9996–10015 (1998).
Sakurai, T. . et al. Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice. Neuron 46, 297–308 (2005).
Yoshida, K., McCormack, S., Espana, R. A., Crocker, A. D. & Scammell, T. E. Afferents to the orexin neurons. J. Comp. Neurol. (in the press).
Marcus, J. N. . et al. Differential expression of orexin receptors 1 and 2 in the rat brain. J. Comp. Neurol. 435, 6–25 (2001).
Mochizuki, T. et al. Behavioral state instability in orexin knock-out mice. J. Neurosci. 24, 6291–6300 (2004).
Borbely, A. A. & Tobler, I. Brain Mechanisms of Sleep (eds McGinty, D. J. et al.) 35–44 (Raven, New York, 1985).
Achermann, P. & Borbely, A. A. Mathematical models of sleep regulation. Front. Biosci. 8, S683–S693 (2003).
Radulovacki, M., Virus, R. M., Djuricic-Nedelson, M. & Green, R. D. Adenosine analogs and sleep in rats. J. Pharmacol. Exp. Ther. 228, 268–274 (1984).
Benington, J. H. & Heller, H. C. Restoration of brain energy metabolism as the function of sleep. Prog. Neurobiol. 45, 347–360 (1995).
Kong, J. et al. Brain glycogen decreases with increased periods of wakefulness: implications for homeostatic drive to sleep. J. Neurosci. 22, 5581–5587 (2002).
Shepel, P. N., Ramonet, D., Stevens, P. & Geiger, J. D. Purine level regulation during energy depletion associated with graded excitatory stimulation in brain. Neurol. Res. 27, 139–148 (2005).
Porkka-Heiskanen, T., Strecker, R. E. & McCarley, R. W. Brain site-specificity of extracellular adenosine concentration changes during sleep deprivation and spontaneous sleep: an in vivo microdialysis study. Neuroscience 99, 507–517 (2000).
Scammell, T. E. et al. An adenosine A2a agonist increases sleep and induces Fos in ventrolateral preoptic neurons. Neuroscience 107, 653–663 (2001).
Dijk, D. J. & Czeisler, C. A. 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, 3526–3538 (1995).
Reppert, S. M. & Weaver, D. R. Coordination of circadian timing in mammals. Nature 418, 935–941 (2002).
Jin, X. et al. A molecular mechanism regulating rhythmic output from the suprachiasmatic circadian clock. Cell 96, 1–20 (1999).
Moore, R. Y. & Eichler, V. B. Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat. Brain Res. 42, 201–206 (1972).
Johnson, R. F., Moore, R. Y. & Morin, L. P. Loss of entrainment and anatomical plasticity after lesions of the hamster retinohypothalamic tract. Brain Res. 460, 297–313 (1988).
Cassone, V. M., Chesworth, M. J. & Armstrong, S. M. Entrainment of rat circadian rhythms by daily injection of melatonin depends upon the hypothalamic suprachiasmatic nuclei. Physiol. Behav. 36, 1111–1121 (1986).
Gooley, J. J., Lu, J., Fischer, D. & Saper, C. B. A broad role for melanopsin in nonvisual photoreception. J. Neurosci. 23, 7093–7106 (2003).
Watts, A. G., Swanson, L. W. & Sanchez-Watts, G. Efferent projections of the suprachiasmatic nucleus: I. Studies using anterograde transport of Phaseolus vulgaris leucoagglutinin in the rat. J. Comp. Neurol. 258, 204–229 (1987).
Lu, J. et al. Contrasting effects of ibotenate lesions of the paraventricular nucleus and subparaventricular zone on sleep-wake cycle and temperature regulation. J. Neurosci. 21, 4864–4874 (2001).
Deurveilher, S. & Semba, K. Indirect projections from the suprachiasmatic nucleus to major arousal-promoting cell groups in rat: implications for the circadian control of behavioural state. Neuroscience 130,165–183 (2005).
Chou, T. C. et al. Critical role of dorsomedial hypothalamic nucleus in a wide range of behavioral circadian rhythms. J. Neurosci. 23, 10691–10702 (2003).
Thompson, R., Swanson, L. W. & Canteras, N. Organization of projections from the dorsomedial nucleus of the hypothalamus: a PHA-L study in the rat. J. Comp. Neurol. 376, 143–173 (1997).
Aston-Jones, G., Chen, S., Zhu, Y. & Oshinsky, M. L. A neural circuit for circadian regulation of arousal. Nature Neurosci. 4, 732–738 (2001).
Saper, C. B., Lu, J., Chou, T. C. & Gooley, J. The hypothalamic integrator for circadian rhythms. Trends Neurosci. 28, 152–157 (2005).
Nyholm, H. Zur okologie von Myotis mystacinus (Leisl.) und M. daubentoni (Leisl.) (Chiroptera). Ann. Zool. Fenn. 2, 77–123 (1955).
Stephan, F. K. The “other” circadian system: food as a Zeitgeber. J. Biol. Rhythms 17, 284–292 (2002).
McEwen, B. S. & Stellar, E. Stress and the individual. Mechanisms leading to disease. Arch Intern. Med. 153, 2093–2101 (1993).
Krout, K. E., Kawano, J., Mettenleiter, T. C. & Loewy, A. D. CNS inputs to the suprachiasmatic nucleus of the rat. Neuroscience 110, 73–92 (2002).
Elmquist, J. K., Elias, C. F. & Saper, C. B. From lesions to leptin: hypothalamic control of food intake and body weight. Neuron 22, 221–232 (1999).
Elmquist, J. K., Ahima, R. S., Elias, C. F., Flier, J. S. & Saper, C. B. Leptin activates distinct projections from the dorsomedial and ventromedial hypothalamic nuclei. Proc. Natl Acad. Sci. USA 95, 741–746 (1998).
Saper, C. B. in The Rat Nervous System (ed. Paxinos, G.) 761–796 (Elsevier Academic, San Diego, 2004).
Schachter, S. C. & Saper, C. B. Vagus nerve stimulation. Epilepsia 39, 677–686 (1998).
Yamanaka, A. et al. Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 38, 701–713 (2003).
Nofzinger, E. A. et al. Functional neuroimaging evidence for hyperarousal in insomnia. Am. J. Psychiatry 161, 2126–2128 (2004).
Meier-Ewert, H. K. . et al. Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk. J. Am. Coll. Cardiol. 43, 678–683 (2004).
Van Dongen, H. P., Maislin, G., Mullington, J. M. & Dinges, D. F. The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep 26, 117–126 (2003).
Doran, S. M., Van Dongen, H. P. & Dinges, D. F. Sustained attention performance during sleep deprivation: evidence of state instability. Arch. Ital. Biol. 139, 253–267 (2001).
Prinz, P. N. Age impairments in sleep, metabolic, and immune functions. Exp. Gerontol. 39, 1739–1743 (2004).
Landrigan, C. P. et al. Effect of reducing interns' work hours on serious medical errors in intensive care units. N. Engl. J. Med. 351, 1838–1848 (2004).
Wisor, J. . et al. Dopaminergic role in stimulant-induced wakefulness. J. Neurosci. 21, 1787–1895 (2001).
Saper, C. B. & Scammell, T. E. Modafinil: a drug in search of a mechanism. Sleep 27, 11–12 (2004).
Roth, T. et al. Assessment of sleepiness and unintended sleep in Parkinson's disease patients taking dopamine agonists. Sleep Med. 4, 275–280 (2003).
Nelson, L. E. et al. The 4-2 adrenoreceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects. Anaesthesiology 98, 428–436 (2003).
Rudolf, U. & Mohler, H. Analysis of GABAA receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics. Annu. Rev. Pharmacol. Toxicol. 44, 475–498 (2004).
Wisden, W., Laurie, D. J., Monyer, H. & Seeburg, P. The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalons, mesencephalon. J. Neurosci. 12, 1040–1062 (1992).
Lancel, M., Wetter, T. C., Steiger, A. & Mathias, S. Effect of the GABAA agonist gaboxadol on nocturnal sleep and hormone secretion in healthy elderly subjects. Am. J. Physiol. Endocrinol. Metab. 281, E130–E137 (2001).
This work was supported by United States Public Health Service grants.
The authors declare competing financial interests: Dr Saper is a consultant for Sepracor, Inc and Merck, Inc. Dr Thomas Scammell is a consultant for Cephalon Inc and Orphan Medical Inc.
Author Information Reprints and permissions information is available at npg.nature.com/reprintsandpermissions.
About this article
Cite this article
Saper, C., Scammell, T. & Lu, J. Hypothalamic regulation of sleep and circadian rhythms. Nature 437, 1257–1263 (2005). https://doi.org/10.1038/nature04284
This article is cited by
Nonlinear Dynamics (2023)
Exploring the neurobiology of the premonitory phase of migraine preclinically – a role for hypothalamic kappa opioid receptors?
The Journal of Headache and Pain (2022)
Communications Biology (2022)
Nature Communications (2022)
Rest-activity rhythms and tract specific white matter lesions in older adults at risk for cognitive decline
Molecular Psychiatry (2022)