There are many sleep phenotypes, which reflect the duration and intensity of sleep, as well as its circadian and homeostatic regulation.
In flies, mice and humans, at least ten genes have either been linked to a human sleep disorder or have been shown to strongly affect sleep.
Genes affecting sleep belong to four major functional categories: circadian regulation, neurotransmission, other signalling pathways and ion channels.
Mutations in voltage-dependent potassium channels produce some of the most striking sleep phenotypes described so far in both flies and mammals.
Sleep and waking affect the expression of hundreds of brain transcripts.
mRNAs with higher expression during waking are related to energy metabolism, cellular stress and synaptic potentiation, suggesting that sleep might serve to maintain synaptic homeostasis by downscaling synapses strengthened during waking.
It has been known for a long time that genetic factors affect sleep quantity and quality. Genetic screens have identified several mutations that affect sleep across species, pointing to an evolutionary conserved regulation of sleep. Moreover, it has also been recognized that sleep affects gene expression. These findings have given valuable insights into the molecular underpinnings of sleep regulation and function that might lead the way to more efficient treatments for sleep disorders.
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Medori, R. et al. Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene. N. Engl. J. Med. 326, 444–449 (1992). First study to show that a sleep disorder is caused by a gene mutation.
Tobler, I. et al. Altered circadian activity rhythms and sleep in mice devoid of prion protein. Nature 380, 639–642 (1996). First study in mice to show that a null mutation affects sleep regulation.
Tobler, I., Deboer, T. & Fischer, M. Sleep and sleep regulation in normal and prion protein-deficient mice. J. Neurosci. 17, 1869–1879 (1997).
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). Seminal study that identified the autosomal recessive mutation responsible for canine narcolepsy.
Chemelli, R. M. et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, 437–451 (1999). This study showed that mice lacking hypocretin/orexin have a narcolepsy-like phenotype.
Dauvilliers, Y., Maret, S. & Tafti, M. Genetics of normal and pathological sleep in humans. Sleep Med. Rev. 9, 91–100 (2005).
Huber, R., Ghilardi, M. F., Massimini, M. & Tononi, G. Local sleep and learning. Nature 430, 78–81 (2004). This study showed for the first time in humans that local changes in sleep intensity, as measured by SWA, are driven by learning.
Ambrosius, U. et al. Heritability of sleep electroencephalogram. Biol. Psychiatry 64, 344–348 (2008).
De Gennaro, L. et al. The electroencephalographic fingerprint of sleep is genetically determined: a twin study. Ann. Neurol. 64, 455–460 (2008).
Blake, H. & Gerard, R. Brain potentials during sleep. Am. J. Physiol. 119, 692–703 (1937).
Achermann, P. & Borbely, A. A. Mathematical models of sleep regulation. Front. Biosci. 8, s683–s693 (2003).
Cirelli, C. & Tononi, G. Is sleep essential? PLoS Biol. 6, e216 (2008).
Harbison, S. T. et al. Co-regulated transcriptional networks contribute to natural genetic variation in Drosophila sleep. Nature Genet. 41, 371–375 (2009).
Zhdanova, I. V., Wang, S. Y., Leclair, O. U. & Danilova, N. P. Melatonin promotes sleep-like state in zebrafish. Brain Res. 903, 263–268 (2001).
Prober, D. A., Rihel, J., Onah, A. A., Sung, R. J. & Schier, A. F. Hypocretin/orexin overexpression induces an insomnia-like phenotype in zebrafish. J. Neurosci. 26, 13400–13410 (2006).
Yokogawa, T. et al. Characterization of sleep in zebrafish and insomnia in hypocretin receptor mutants. PLoS Biol. 5, e277 (2007).
Raizen, D. M. et al. Lethargus is a Caenorhabditis elegans sleep-like state. Nature 451, 569–572 (2008).
Zhang, J., Obal, F., Jr, Fang, J., Collins, B. J. & Krueger, J. M. Non-rapid eye movement sleep is suppressed in transgenic mice with a deficiency in the somatotropic system. Neurosci. Lett. 220, 97–100 (1996).
Tafti, M. et al. Deficiency in short-chain fatty acid beta-oxidation affects theta oscillations during sleep. Nature Genet. 34, 320–325 (2003). First study in mice to use QTL analysis to identify a gene that affects a specific feature of the sleep EEG (theta rhythm during REM sleep).
Maret, S. et al. Retinoic acid signaling affects cortical synchrony during sleep. Science 310, 111–113 (2005).
Hu, W. P. et al. Altered circadian and homeostatic sleep regulation in prokineticin 2-deficient mice. Sleep 30, 247–256 (2007).
Kimura, M. et al. Conditional corticotropin-releasing hormone overexpression in the mouse forebrain enhances rapid eye movement sleep. Mol. Psychiatry 19 May 2009 (doi: 10.1038/mp.2009.46).
Schwarz, T. L., Tempel, B. L., Papazian, D. M., Jan, Y. N. & Jan, L. Y. Multiple potassium-channel components are produced by alternative splicing at the Shaker locus in Drosophila. Nature 331, 137–142 (1988).
Cirelli, C. et al. Reduced sleep in Drosophila Shaker mutants. Nature 434, 1087–1092 (2005). First gene with strong effects on sleep duration identified in flies using mutagenesis screening.
Bushey, D., Huber, R., Tononi, G. & Cirelli, C. Drosophila Hyperkinetic mutants have reduced sleep and impaired memory. J. Neurosci. 27, 5384–5393 (2007).
Koh, K. et al. Identification of SLEEPLESS, a sleep-promoting factor. Science 321, 372–376 (2008). Second gene with strong effects on sleep duration to be identified in flies using mutagenesis screening.
Steriade, M. The corticothalamic system in sleep. Front. Biosci. 8, D878–D899 (2003).
Guan, D. et al. Expression and biophysical properties of Kv1 channels in supragranular neocortical pyramidal neurones. J. Physiol. 571, 371–389 (2006).
Douglas, C. L. et al. Sleep in Kcna2 knockout mice. BMC Biol. 5, 42 (2007).
Misonou, H. & Trimmer, J. S. Determinants of voltage-gated potassium channel surface expression and localization in Mammalian neurons. Crit. Rev. Biochem. Mol. Biol. 39, 125–145 (2004).
Yuan, L. L. & Chen, X. Diversity of potassium channels in neuronal dendrites. Prog. Neurobiol. 78, 374–389 (2006).
Espinosa, F., Marks, G., Heintz, N. & Joho, R. H. Increased motor drive and sleep loss in mice lacking Kv3-type potassium channels. Genes Brain Behav. 3, 90–100 (2004).
Espinosa, F., Torres-Vega, M. A., Marks, G. A. & Joho, R. H. Ablation of Kv3.1 and Kv3.3 potassium channels disrupts thalamocortical oscillations in vitro and in vivo. J. Neurosci. 28, 5570–5581 (2008).
Rudy, B. & McBain, C. J. Kv3 channels: voltage-gated K+ channels designed for high-frequency repetitive firing. Trends Neurosci. 24, 517–526 (2001).
Liguori, R. et al. Morvan's syndrome: peripheral and central nervous system and cardiac involvement with antibodies to voltage-gated potassium channels. Brain 124, 2417–2426 (2001).
Crunelli, V., Cope, D. W. & Hughes, S. W. Thalamic T-type Ca2+ channels and NREM sleep. Cell Calcium 40, 175–190 (2006).
Lee, J., Kim, D. & Shin, H. S. Lack of delta waves and sleep disturbances during non-rapid eye movement sleep in mice lacking α1G-subunit of T-type calcium channels. Proc. Natl Acad. Sci. USA 101, 18195–18199 (2004).
Anderson, M. P. et al. Thalamic Cav3.1 T-type Ca2+ channel plays a crucial role in stabilizing sleep. Proc. Natl Acad. Sci. USA 102, 1743–1748 (2005).
Wisor, J. P. et al. A role for cryptochromes in sleep regulation. BMC Neurosci. 3, 20 (2002).
Hendricks, J. C. et al. Gender dimorphism in the role of cycle (BMAL1) in rest, rest regulation, and longevity in Drosophila melanogaster. J. Biol. Rhythms 18, 12–25 (2003).
Cirelli, C., Gutierrez, C. M. & Tononi, G. Extensive and divergent effects of sleep and wakefulness on brain gene expression. Neuron 41, 35–43 (2004). First genome-wide microarray study to show that hundreds of transcripts in the rat cerebral cortex change their expression because of sleep and waking, independent of circadian time.
Franken, P., Thomason, R., Heller, H. C. & O'Hara, B. F. A non-circadian role for clock-genes in sleep homeostasis: a strain comparison. BMC Neurosci. 8, 87 (2007).
Wisor, J. P. et al. Sleep deprivation effects on circadian clock gene expression in the cerebral cortex parallel electroencephalographic differences among mouse strains. J. Neurosci. 28, 7193–7201 (2008).
Rutter, J., Reick, M., Wu, L. C. & McKnight, S. L. Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors. Science 293, 510–514 (2001).
Reick, M., Garcia, J. A., Dudley, C. & McKnight, S. L. NPAS2: an analog of clock operative in the mammalian forebrain. Science 293, 506–509 (2001).
Kasischke, K. A., Vishwasrao, H. D., Fisher, P. J., Zipfel, W. R. & Webb, W. W. Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis. Science 305, 99–103 (2004).
Viola, A. U. et al. PER3 polymorphism predicts sleep structure and waking performance. Curr. Biol. 17, 613–618 (2007). First study in humans to identify a gene polymorphism that affects the response to sleep deprivation.
Goel, N., Banks, S., Mignot, E. & Dinges, D. F. PER3 polymorphism predicts cumulative sleep homeostatic but not neurobehavioral changes to chronic partial sleep deprivation. PLoS One 4, e5874 (2009).
Groeger, J. A. et al. Early morning executive functioning during sleep deprivation is compromised by a PERIOD3 polymorphism. Sleep 31, 1159–1167 (2008).
Van Dongen, H. P., Vitellaro, K. M. & Dinges, D. F. Individual differences in adult human sleep and wakefulness: leitmotif for a research agenda. Sleep 28, 479–496 (2005). Review of the data suggesting a genetic basis for the inter-individual variability in the response to sleep loss.
Lim, J., Choo, W. C. & Chee, M. W. Reproducibility of changes in behaviour and fMRI activation associated with sleep deprivation in a working memory task. Sleep 30, 61–70 (2007).
Toh, K. L. et al. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 291, 1040–1043 (2001). First study to identify a mutation responsible for FASPS.
Xu, Y. et al. Modeling of a human circadian mutation yields insights into clock regulation by PER2. Cell 128, 59–70 (2007).
Xu, Y. et al. Functional consequences of a CKIδ mutation causing familial advanced sleep phase syndrome. Nature 434, 640–644 (2005).
Okawa, M. & Uchiyama, M. Circadian rhythm sleep disorders: characteristics and entrainment pathology in delayed sleep phase and non-24-h sleep-wake syndrome. Sleep Med. Rev. 11, 485–496 (2007).
Sakurai, T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nature Rev. Neurosci. 8, 171–181 (2007).
Landolt, H. P. Sleep homeostasis: a role for adenosine in humans? Biochem. Pharmacol. 75, 2070–2079 (2008).
Retey, J. V. et al. A functional genetic variation of adenosine deaminase affects the duration and intensity of deep sleep in humans. Proc. Natl Acad. Sci. USA 102, 15676–15681 (2005). First study in humans to identify a gene polymorphism that affects the duration of NREM sleep and SLA.
Lonart, G., Tang, X., Simsek-Duran, F., Machida, M. & Sanford, L. D. The role of active zone protein Rab3 interacting molecule 1 α in the regulation of norepinephrine release, response to novelty, and sleep. Neuroscience 154, 821–831 (2008).
Colas, D., Wagstaff, J., Fort, P., Salvert, D. & Sarda, N. Sleep disturbances in Ube3a maternal-deficient mice modeling Angelman syndrome. Neurobiol. Dis. 20, 471–478 (2005).
Franken, P., Chollet, D. & Tafti, M. The homeostatic regulation of sleep need is under genetic control. J. Neurosci. 21, 2610–2621 (2001). This study used QTL analysis to show that sleep need, as measured by the increase in SLA after prolonged waking, is strongly influenced by genetic factors.
Andretic, R., Franken, P. & Tafti, M. Genetics of sleep. Annu. Rev. Genet. 42, 361–388 (2008).
Kato, A., Ozawa, F., Saitoh, Y., Hirai, K. & Inokuchi, K. vesl, a gene encoding VASP/Ena family related protein, is upregulated during seizure, long-term potentiation and synaptogenesis. FEBS Lett. 412, 183–189 (1997).
Brakeman, P. R. et al. Homer: a protein that selectively binds metabotropic glutamate receptors. Nature 386, 284–288 (1997).
Maret, S. et al. Homer1a is a core brain molecular correlate of sleep loss. Proc. Natl Acad. Sci. USA 104, 20090–20095 (2007).
Mackiewicz, M., Paigen, B., Naidoo, N. & Pack, A. I. Analysis of the QTL for sleep homeostasis in mice: Homer1a is a likely candidate. Physiol. Genomics 33, 91–99 (2008).
Diagana, T. T. et al. Mutation of Drosophila homer disrupts control of locomotor activity and behavioral plasticity. J. Neurosci. 22, 428–436 (2002).
Schenkein, J. & Montagna, P. Self management of fatal familial insomnia. Part 1: what is FFI? MedGenMed 8, 65 (2006).
Lugaresi, E. & Provini, F. Fatal familial insomnia and agrypnia excitata. Rev. Neurol. Dis. 4, 145–152 (2007).
Dossena, S. et al. Mutant prion protein expression causes motor and memory deficits and abnormal sleep patterns in a transgenic mouse model. Neuron 60, 598–609 (2008).
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).
Nishino, S. Clinical and neurobiological aspects of narcolepsy. Sleep Med. 8, 373–399 (2007).
Hallmayer, J. et al. Narcolepsy is strongly associated with the T-cell receptor alpha locus. Nature Genet. 41, 708–711 (2009).
Winkelmann, J. et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nature Genet. 39, 1000–1006 (2007).
Schormair, B. et al. PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome. Nature Genet. 40, 946–948 (2008).
Stefansson, H. et al. A genetic risk factor for periodic limb movements in sleep. N. Engl. J. Med. 357, 639–647 (2007).
Kimura, M. & Winkelmann, J. Genetics of sleep and sleep disorders. Cell. Mol. Life Sci. 64, 1216–1226 (2007).
Cirelli, C. & Tononi, G. Gene expression in the brain across the sleep-waking cycle. Brain Res. 885, 303–321 (2000).
Cirelli, C., LaVaute, T. M. & Tononi, G. Sleep and wakefulness modulate gene expression in Drosophila. J. Neurochem. 94, 1411–1419 (2005).
Cirelli, C., Faraguna, U. & Tononi, G. Changes in brain gene expression after long-term sleep deprivation. J. Neurochem. 98, 1632–1645 (2006).
Terao, A., Greco, M. A., Davis, R. W., Heller, H. C. & Kilduff, T. S. Region-specific changes in immediate early gene expression in response to sleep deprivation and recovery sleep in the mouse brain. Neuroscience 120, 1115–1124 (2003).
Terao, A. et al. Differential increase in the expression of heat shock protein family members during sleep deprivation and during sleep. Neuroscience 116, 187–200 (2003).
Terao, A. et al. Gene expression in the rat brain during sleep deprivation and recovery sleep: an Affymetrix GeneChip study. Neuroscience 137, 593–605 (2006).
Zimmerman, J. E. et al. Multiple mechanisms limit the duration of wakefulness in Drosophila brain. Physiol. Genomics 27, 337–350 (2006).
Mackiewicz, M. et al. Macromolecule biosynthesis - a key function of sleep. Physiol. Genomics 31, 441–457 (2007).
Jones, S., Pfister-Genskow, M., Benca, R. M. & Cirelli, C. Molecular correlates of sleep and wakefulness in the brain of the white-crowned sparrow. J. Neurochem. 105, 46–62 (2008).
Cirelli, C. & Tononi, G. Differences in gene expression between sleep and waking as revealed by mRNA differential display. Brain Res. Mol. Brain Res. 56, 293–305 (1998).
Shaw, P. J., Cirelli, C., Greenspan, R. J. & Tononi, G. Correlates of sleep and waking in Drosophila melanogaster. Science 287, 1834–1837 (2000).
Petit, J. M., Tobler, I., Allaman, I., Borbely, A. A. & Magistretti, P. J. Sleep deprivation modulates brain mRNAs encoding genes of glycogen metabolism. Eur. J. Neurosci. 16, 1163–1167 (2002).
Rhyner, T. A., Borbely, A. A. & Mallet, J. Molecular cloning of forebrain mRNAs which are modulated by sleep deprivation. Eur. J. Neurosci. 2, 1063–1073 (1990). Pioneer study that used subtractive cDNA cloning to identify rat forebrain transcripts affected by sleep deprivation.
Everson, C. A., Smith, C. B. & Sokoloff, L. Effects of prolonged sleep deprivation on local rates of cerebral energy metabolism in freely moving rats. J. Neurosci. 14, 6769–6778 (1994).
Wu, J. C. et al. The effect of sleep deprivation on cerebral glucose metabolic rate in normal humans assessed with positron emission tomography. Sleep 14, 155–162 (1991).
Cortelli, P. et al. Cerebral metabolism in fatal familial insomnia: relation to duration, neuropathology, and distribution of protease-resistant prion protein. Neurology 49, 126–133 (1997).
Naidoo, N., Giang, W., Galante, R. J. & Pack, A. I. Sleep deprivation induces the unfolded protein response in mouse cerebral cortex. J. Neurochem. 92, 1150–1157 (2005).
Cirelli, C., Shaw, P. J., Rechtschaffen, A. & Tononi, G. No evidence of brain cell degeneration after long-term sleep deprivation in rats. Brain Res. 840, 184–193 (1999).
Gopalakrishnan, A., Ji, L. L. & Cirelli, C. Sleep deprivation and cellular responses to oxidative stress. Sleep 27, 27–35 (2004).
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).
Hendricks, J. C. et al. A non-circadian role for cAMP signaling and CREB activity in Drosophila rest homeostasis. Nature Neurosci. 4, 1108–1115 (2001).
Vyazovskiy, V. V., Cirelli, C., Pfister-Genskow, M., Faraguna, U. & Tononi, G. Molecular and electrophysiological evidence for net synaptic potentiation in wake and depression in sleep. Nature Neurosci. 11, 200–208 (2008). This study showed that the overall synaptic strength in the rat cerebral cortex increases during waking and decreases during sleep.
Gilestro, G., Tononi, G. & Cirelli, C. Widespread changes in synaptic markers as a function of sleep and waking in Drosophila. Science 324, 109–112 (2009).
Donlea, J. M., Ramanan, N. & Shaw, P. J. Use-dependent plasticity in clock neurons regulates sleep need in Drosophila. Science 324, 105–108 (2009).
Reich, P., Driver, J. K. & Karnovsky, M. L. Sleep: effects on incorporation of inorganic phosphate into brain fractions. Science 157, 336–338 (1967).
Reich, P., Geyer, S. J., Steinbaum, L., Anchors, M. & Karnovsky, M. L. Incorporation of phosphate into rat brain during sleep and wakefulness. J. Neurochem. 20, 1195–1205 (1973).
Voronka, G., Demin, N. N. & Pevzner, L. Z. [Total protein content and quantity of basic proteins in neurons and neuroglia of rat brain supraoptic and red nuclei during natural sleep and deprivation of paradoxical sleep]. Dokl. Akad. Nauk SSSR 198, 974–977 (1971).
Drucker-Colin, R. R., Spanis, C. W., Cotman, C. W. & McGaugh, J. L. Changes in protein levels in perfusates of freely moving cats: relation to behavioral state. Science 187, 963–965 (1975).
Ramm, P. & Smith, C. T. Rates of cerebral protein synthesis are linked to slow wave sleep in the rat. Physiol. Behav. 48, 749–753 (1990).
Nakanishi, H. et al. Positive correlations between cerebral protein synthesis rates and deep sleep in Macaca mulatta. Eur. J. Neurosci. 9, 271–279 (1997).
Ibata, K., Sun, Q. & Turrigiano, G. G. Rapid synaptic scaling induced by changes in postsynaptic firing. Neuron 57, 819–826 (2008).
Born, J., Rasch, B. & Gais, S. Sleep to remember. Neuroscientist 12, 410–424 (2006).
Walker, M. P. & Stickgold, R. Sleep, memory, and plasticity. Annu. Rev. Psychol. 57, 139–166 (2006).
Steriade, M. Coherent oscillations and short-term plasticity in corticothalamic networks. Trends Neurosci. 22, 337–345 (1999).
Sejnowski, T. J. & Destexhe, A. Why do we sleep? Brain Res. 886, 208–223 (2000).
Tononi, G. & Cirelli, C. Sleep function and synaptic homeostasis. Sleep Med. Rev. 10, 49–62 (2006). This review suggested that a major function of sleep is to reduce synaptic strength in large brain areas and discusses how sleep could allow synaptic downscaling.
Mauch, D. H. et al. CNS synaptogenesis promoted by glia-derived cholesterol. Science 294, 1354–1357 (2001).
Christopherson, K. S. et al. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120, 421–433 (2005).
Hering, H., Lin, C. C. & Sheng, M. Lipid rafts in the maintenance of synapses, dendritic spines, and surface AMPA receptor stability. J. Neurosci. 23, 3262–3271 (2003).
Ganguly-Fitzgerald, I., Donlea, J. & Shaw, P. J. Waking experience affects sleep need in Drosophila. Science 313, 1775–1781 (2006).
Huber, R., Tononi, G. & Cirelli, C. Exploratory behavior, cortical BDNF expression, and sleep homeostasis. Sleep 30, 129–139 (2007).
Silber, M. H. et al. The visual scoring of sleep in adults. J. Clin. Sleep Med. 3, 121–131 (2007).
Pack, A. I. et al. Novel method for high-throughput phenotyping of sleep in mice. Physiol. Genomics 28, 232–238 (2007).
Werth, E., Achermann, P., Dijk, D. J. & Borbely, A. A. Spindle frequency activity in the sleep EEG: individual differences and topographic distribution. Electroencephalogr. Clin. Neurophysiol. 103, 535–542 (1997).
Tan, X., Campbell, I. G., Palagini, L. & Feinberg, I. High internight reliability of computer-measured NREM delta, sigma, and beta: biological implications. Biol. Psychiatry 48, 1010–1019 (2000).
Finelli, L. A., Achermann, P. & Borbély, A. A. Individual 'fingerprints' in human sleep EEG topography. Neuropsychopharmacology 25, S57–S62 (2001).
De Gennaro, L., Ferrara, M., Vecchio, F., Curcio, G. & Bertini, M. An electroencephalographic fingerprint of human sleep. Neuroimage 26, 114–122 (2005).
Buckelmuller, J., Landolt, H. P., Stassen, H. H. & Achermann, P. Trait-like individual differences in the human sleep electroencephalogram. Neuroscience 138, 351–356 (2006).
Tucker, A. M., Dinges, D. F. & Van Dongen, H. P. Trait interindividual differences in the sleep physiology of healthy young adults. J. Sleep Res. 16, 170–180 (2007).
van Beijsterveldt, C. E., Molenaar, P. C., de Geus, E. J. & Boomsma, D. I. Heritability of human brain functioning as assessed by electroencephalography. Am. J. Hum. Genet. 58, 562–573 (1996).
van Beijsterveldt, C. E. & van Baal, G. C. Twin and family studies of the human electroencephalogram: a review and a meta-analysis. Biol. Psychol. 61, 111–138 (2002).
van Beijsterveldt, C. E., Molenaar, P. C., de Geus, E. J. & Boomsma, D. I. Genetic and environmental influences on EEG coherence. Behav. Genet. 28, 443–453 (1998).
Chorlian, D. B. et al. Heritability of EEG coherence in a large sib-pair population. Biol. Psychol. 75, 260–266 (2007).
Porjesz, B. et al. Linkage disequilibrium between the beta frequency of the human EEG and a GABAA receptor gene locus. Proc. Natl Acad. Sci. USA 99, 3729–3733 (2002).
Hendricks, J. C. et al. Rest in Drosophila is a sleep-like state. Neuron 25, 129–138 (2000).
Tobler, I., Wigger, E., Durr, R. & Hajnal, A. C. elegans: a model organism to investigate the genetics of sleep and sleep homeostasis. J. Sleep Res. 13, 1 (2004).
Nitz, D. A., van Swinderen, B., Tononi, G. & Greenspan, R. J. Electrophysiological correlates of rest and activity in Drosophila melanogaster. Curr. Biol. 12, 1934–1940 (2002).
Huber, R. et al. Sleep homeostasis in Drosophila melanogaster. Sleep 27, 628–639 (2004).
Jeon, M., Gardner, H. F., Miller, E. A., Deshler, J. & Rougvie, A. E. Similarity of the C. elegans developmental timing protein LIN-42 to circadian rhythm proteins. Science 286, 1141–1146 (1999).
Koh, K., Evans, J. M., Hendricks, J. C. & Sehgal, A. A Drosophila model for age-associated changes in sleep:wake cycles. Proc. Natl Acad. Sci. USA 103, 13843–13847 (2006).
Hendricks, J. C., Kirk, D., Panckeri, K., Miller, M. S. & Pack, A. I. Modafinil maintains waking in the fruit fly Drosophila melanogaster. Sleep 26, 139–146 (2003).
Andretic, R., van Swinderen, B. & Greenspan, R. J. Dopaminergic modulation of arousal in Drosophila. Curr. Biol. 15, 1165–1175 (2005).
Crocker, A. & Sehgal, A. Octopamine regulates sleep in Drosophila through protein kinase A-dependent mechanisms. J. Neurosci. 28, 9377–9385 (2008).
Kume, K., Kume, S., Park, S. K., Hirsh, J. & Jackson, F. R. Dopamine is a regulator of arousal in the fruit fly. J. Neurosci. 25, 7377–7384 (2005).
Wisor, J. P. et al. Dopaminergic role in stimulant-induced wakefulness. J. Neurosci. 21, 1787–1794 (2001).
Agosto, J. et al. Modulation of GABAA receptor desensitization uncouples sleep onset and maintenance in Drosophila. Nature Neurosci. 11, 354–359 (2008).
Graves, L. A. et al. Genetic evidence for a role of CREB in sustained cortical arousal. J. Neurophysiol. 23, 23 (2003).
Renier, C. et al. Genomic and functional conservation of sedative-hypnotic targets in the zebrafish. Pharmacogenet. Genomics 17, 237–253 (2007).
Ruuskanen, J. O., Peitsaro, N., Kaslin, J. V., Panula, P. & Scheinin, M. Expression and function of α2 adrenoceptors in zebrafish: drug effects, mRNA and receptor distributions. J. Neurochem. 94, 1559–1569 (2005).
Van Buskirk, C. & Sternberg, P. W. Epidermal growth factor signaling induces behavioral quiescence in Caenorhabditis elegans. Nature Neurosci. 10, 1300–1307 (2007).
Kramer, A. et al. Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling. Science 294, 2511–2515 (2001).
Snodgrass-Belt, P., Gilbert, J. L. & Davis, F. C. Central administration of transforming growth factor-alpha and neuregulin-1 suppress active behaviors and cause weight loss in hamsters. Brain Res. 1038, 171–182 (2005).
Kushikata, T., Fang, J., Chen, Z., Wang, Y. & Krueger, J. M. Epidermal growth factor enhances spontaneous sleep in rabbits. Am. J. Physiol. 275, R509–R514 (1998).
Foltenyi, K., Greenspan, R. J. & Newport, J. W. Activation of EGFR and ERK by rhomboid signaling regulates the consolidation and maintenance of sleep in Drosophila. Nature Neurosci. 10, 1160–1167 (2007).
Morrow, J. D., Vikraman, S., Imeri, L. & Opp, M. R. Effects of serotonergic activation by 5-hydroxytryptophan on sleep and body temperature of C57BL/56J and interleukin-6-deficient mice are dose and time related. Sleep 31, 21–33 (2008).
Yuan, Q., Joiner, W. J. & Sehgal, A. A sleep-promoting role for the Drosophila serotonin receptor 1A. Curr. Biol. 16, 1051–1062 (2006).
You, Y. J., Kim, J., Raizen, D. M. & Avery, L. Insulin, cGMP, and TGF-β signals regulate food intake and quiescence in C. elegans: a model for satiety. Cell Metab. 7, 249–257 (2008).
This work was funded by US National Institutes of Health grants P20 MH077967 and R01 GM075315. I thank D. Bushey, S. Maret and G. Tononi for critical comments on the manuscript.
Supplementary information S1 (table)
Twin studies with heritability estimates for sleep phenotypes (% of variance explained by genetic effects) (PDF 206 kb)
Supplementary information S2 (table)
Studies in flies and mice using reverse and forward genetics to show effects of single candidate genes on sleep. (PDF 501 kb)
- Hypocretin/orexin system
A group of neurons in the posterior hypothalamus that have diffuse projections to the CNS and release hypocretins or orexins. These neuropeptides have been involved in the regulation of sleep and arousal, feeding and energy metabolism.
- Slow waves
Oscillations of cortical origin that have frequencies in the delta band.
- Rapid-eye-movement (REM) sleep
The second phase of sleep observed in mammals and birds. In REM sleep the muscle tone is reduced or absent, but the EEG is similar to waking. REM theta activity (4–7 Hz) is also present.
Waxing and waning oscillations of thalamic origin, the frequency of which is in the sigma band.
- Non-rapid eye movement (NREM) sleep
One of the two types of sleep observed in mammals and birds. NREM sleep includes slow-wave sleep, characterized mainly by large slow waves.
- Sleep consolidation
Consolidated sleep is characterized by long sleep episodes, little waking after sleep onset (WASO) and only few brief awakenings.
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Cirelli, C. The genetic and molecular regulation of sleep: from fruit flies to humans. Nat Rev Neurosci 10, 549–560 (2009). https://doi.org/10.1038/nrn2683
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