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• W2034261913 abstract "Sleep remains one of the least understood phenomena in biology—even its role in synaptic plasticity remains debatable. Since sleep was recognized to be regulated genetically, intense research has launched on two fronts: the development of model organisms for deciphering the molecular mechanisms of sleep and attempts to identify genetic underpinnings of human sleep disorders. In this Review, we describe how unbiased, high-throughput screens in model organisms are uncovering sleep regulatory mechanisms and how pathways, such as the circadian clock network and specific neurotransmitter signals, have conserved effects on sleep from Drosophila to humans. At the same time, genome-wide association studies (GWAS) have uncovered ∼14 loci increasing susceptibility to sleep disorders, such as narcolepsy and restless leg syndrome. To conclude, we discuss how these different strategies will be critical to unambiguously defining the function of sleep. Sleep remains one of the least understood phenomena in biology—even its role in synaptic plasticity remains debatable. Since sleep was recognized to be regulated genetically, intense research has launched on two fronts: the development of model organisms for deciphering the molecular mechanisms of sleep and attempts to identify genetic underpinnings of human sleep disorders. In this Review, we describe how unbiased, high-throughput screens in model organisms are uncovering sleep regulatory mechanisms and how pathways, such as the circadian clock network and specific neurotransmitter signals, have conserved effects on sleep from Drosophila to humans. At the same time, genome-wide association studies (GWAS) have uncovered ∼14 loci increasing susceptibility to sleep disorders, such as narcolepsy and restless leg syndrome. To conclude, we discuss how these different strategies will be critical to unambiguously defining the function of sleep. Sleep remains one of the big mysteries in biology. As a state that seemingly freezes all productive activity and puts animals in danger of being caught by predators, sleep must serve an important purpose because it has survived many years of evolution. Nevertheless, the function of sleep and the molecular processes that produce the need to sleep both remain elusive (Frank, 2006Frank M.G. The mystery of sleep function: current perspectives and future directions.Rev. Neurosci. 2006; 17: 375-392Crossref PubMed Google Scholar, Mignot, 2008Mignot E. Why we sleep: the temporal organization of recovery.PLoS Biol. 2008; 6: e106Crossref PubMed Scopus (60) Google Scholar). In the past decade, researchers have made progress in addressing fundamental questions regarding sleep, and several clinical centers have even established sleep as an independent medical discipline. Major advances include the identification of molecules regulating sleep (Allada and Siegel, 2008Allada R. Siegel J.M. Unearthing the phylogenetic roots of sleep.Curr. Biol. 2008; 18: R670-R679Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, Andretic et al., 2008aAndretic R. Franken P. Tafti M. Genetics of sleep.Annu. Rev. Genet. 2008; 42: 361-388Crossref PubMed Scopus (52) Google Scholar, Cirelli, 2009Cirelli C. The genetic and molecular regulation of sleep: from fruit flies to humans.Nat. Rev. Neurosci. 2009; 10: 549-560Crossref PubMed Scopus (102) Google Scholar, Crocker and Sehgal, 2010Crocker A. Sehgal A. Genetic analysis of sleep.Genes Dev. 2010; 24: 1220-1235Crossref PubMed Scopus (42) Google Scholar) and the realization that sleep disorders are extremely common and numerous. These disorders include insomnia, breathing disturbances during sleep (i.e., sleep apnea), movement disorders during sleep (i.e., restless leg syndrome, periodic leg movements), and sleep-wake state dissociation disorders (i.e., narcolepsy, rapid eye movement [REM] sleep behavior disorder, sleep walking). It is now clear that sleep is genetically controlled. Although environmental factors can impact the duration and intensity of sleep, genetic regulation is borne out by the heritability of sleep traits (Ambrosius et al., 2008Ambrosius U. Lietzenmaier S. Wehrle R. Wichniak A. Kalus S. Winkelmann J. Bettecken T. Holsboer F. Yassouridis A. Friess E. Heritability of sleep electroencephalogram.Biol. Psychiatry. 2008; 64: 344-348Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, De Gennaro et al., 2008De Gennaro L. Marzano C. Fratello F. Moroni F. Pellicciari M.C. Ferlazzo F. Costa S. Couyoumdjian A. Curcio G. Sforza E. et al.The electroencephalographic fingerprint of sleep is genetically determined: a twin study.Ann. Neurol. 2008; 64: 455-460Crossref PubMed Scopus (82) Google Scholar), the identification of specific genetic polymorphisms that affect these traits (Maret et al., 2005Maret S. Franken P. Dauvilliers Y. Ghyselinck N.B. Chambon P. Tafti M. Retinoic acid signaling affects cortical synchrony during sleep.Science. 2005; 310: 111-113Crossref PubMed Scopus (68) Google Scholar, Tafti et al., 2003Tafti M. Petit B. Chollet D. Neidhart E. de Bilbao F. Kiss J.Z. Wood P.A. Franken P. Deficiency in short-chain fatty acid beta-oxidation affects theta oscillations during sleep.Nat. Genet. 2003; 34: 320-325Crossref PubMed Scopus (90) Google Scholar), and the existence of familial sleep disorders. Genetic model systems—zebrafish, fruit flies, and worms—were recently developed for studying sleep, and they are starting to reveal the molecular underpinnings of sleep (Allada and Siegel, 2008Allada R. Siegel J.M. Unearthing the phylogenetic roots of sleep.Curr. Biol. 2008; 18: R670-R679Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, Andretic et al., 2008aAndretic R. Franken P. Tafti M. Genetics of sleep.Annu. Rev. Genet. 2008; 42: 361-388Crossref PubMed Scopus (52) Google Scholar, Cirelli, 2009Cirelli C. The genetic and molecular regulation of sleep: from fruit flies to humans.Nat. Rev. Neurosci. 2009; 10: 549-560Crossref PubMed Scopus (102) Google Scholar, Crocker and Sehgal, 2010Crocker A. Sehgal A. Genetic analysis of sleep.Genes Dev. 2010; 24: 1220-1235Crossref PubMed Scopus (42) Google Scholar). Some researchers may question the relevance of these model organisms for mammalian sleep. However, we contend that the function and regulation of sleep are likely conserved through evolution, and thus, it would be strange to restrict sleep research to only a few species. For example, some would argue that the worm sleep model, which consists of developmental periods of low activity (i.e., quiescence), is dramatically different from human sleep, but we note that characteristics of sleep vary greatly even among different mammalian species. Indeed, the genetic model systems for studying sleep may not recapitulate all aspects of human sleep, but the prediction is that some key features will be conserved. As we describe in this Review, molecular and genetic studies in these model systems are, in fact, beginning to uncover regulatory mechanisms underlying sleep, which are conserved from worms to mammals. The idea of using model systems to understand a biological process of interest is clearly not new. However, until about a decade ago, studies of sleep were primarily restricted to a few mammalian and avian species. This restriction was partially because sleep was defined on the basis of altered brain electrical activity, recorded through electroencephalograms (EEGs), and this definition was not easily applied to other animals. EEGs reveal three major states of behavior: wake, rapid eye movement (REM) sleep, and non-REM (NREM sleep). In humans, REM and NREM sleep occur in 90 min cycles through a night of sleep. NREM sleep is divided into stages 1–3, which together with REM constitute the normal “sleep architecture.” Furthermore, human sleep is mostly consolidated into a single period during the night. This phenomenon is observed in only a few other mammals that, compared with humans, have less consolidated sleep and wake periods, which alternate during the day and night. Slow wave sleep is the deepest stage of sleep, and this occurs during stage 3 of NREM. Many brain areas are active during REM sleep; thus, the quiescence in neural activity typically associated with sleep actually occurs during NREM sleep. Although the EEG definition of sleep, which is based upon electrical activity patterns at the cortical level, precluded its study in animals that do not have a well-defined cortex, pioneering efforts of a few researchers identified sleep-like states in several species of fish, reptiles, amphibians, and even some invertebrates, such as cockroach, bees, and octopus (Campbell and Tobler, 1984Campbell S.S. Tobler I. Animal sleep: a review of sleep duration across phylogeny.Neurosci. Biobehav. Rev. 1984; 8: 269-300Crossref PubMed Scopus (204) Google Scholar). These researchers proposed specific behavioral criteria to define sleep, but such practice was not widely accepted. What eventually changed the field was the realization that other fields had made rapid progress by using simple animal models (Hendricks et al., 2000bHendricks J.C. Sehgal A. Pack A.I. The need for a simple animal model to understand sleep.Prog. Neurobiol. 2000; 61: 339-351Crossref PubMed Scopus (54) Google Scholar). In particular, circadian biology was often cited as an example of a field in which molecular mechanisms identified in flies and fungi turned out to be conserved in humans (Hendricks et al., 2000bHendricks J.C. Sehgal A. Pack A.I. The need for a simple animal model to understand sleep.Prog. Neurobiol. 2000; 61: 339-351Crossref PubMed Scopus (54) Google Scholar). Thus, sleep researchers developed simple animal models by using primarily the criteria for a sleep-like state proposed originally by Campbell and Tobler, 1984Campbell S.S. Tobler I. Animal sleep: a review of sleep duration across phylogeny.Neurosci. Biobehav. Rev. 1984; 8: 269-300Crossref PubMed Scopus (204) Google Scholar. According to these criteria, a sleep-like state is (1) a reversible state during which voluntary movements do not occur; (2) controlled by a circadian clock; (3) accompanied by an increase in arousal threshold, such that stronger sensory stimuli are required to elicit a response from the animal; and (4) controlled by a homeostatic system that ensures adequate levels of the state. It is well known that sleep deprivation is followed by a compensatory increase in sleep, or sleep rebound, which reflects the essential nature of sleep. We now know that fish and fruit flies display periods of rest at night, which satisfy behavioral and physiological criteria for sleep (Hendricks et al., 2000aHendricks J.C. Finn S.M. Panckeri K.A. Chavkin J. Williams J.A. Sehgal A. Pack A.I. Rest in Drosophila is a sleep-like state.Neuron. 2000; 25: 129-138Abstract Full Text Full Text PDF PubMed Google Scholar, Prober et al., 2006Prober 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. 2006; 26: 13400-13410Crossref PubMed Scopus (152) Google Scholar, Shaw et al., 2000Shaw P.J. Cirelli C. Greenspan R.J. Tononi G. Correlates of sleep and waking in Drosophila melanogaster.Science. 2000; 287: 1834-1837Crossref PubMed Scopus (419) Google Scholar, Yokogawa et al., 2007Yokogawa T. Marin W. Faraco J. Pézeron G. Appelbaum L. Zhang J. Rosa F. Mourrain P. Mignot E. Characterization of sleep in zebrafish and insomnia in hypocretin receptor mutants.PLoS Biol. 2007; 5: e277Crossref PubMed Scopus (124) Google Scholar). Likewise, criteria for sleep are met by a quiescent state in worms—lethargus—although this occurs during development in conjunction with larval molts rather than as a 24 hr rhythm in adults (Raizen et al., 2008Raizen D.M. Zimmerman J.E. Maycock M.H. Ta U.D. You Y.J. Sundaram M.V. Pack A.I. Lethargus is a Caenorhabditis elegans sleep-like state.Nature. 2008; 451: 569-572Crossref PubMed Scopus (125) Google Scholar). Interestingly, the larval molts, and therefore lethargus, are regulated by the worm ortholog of the circadian clock gene, period (per), which regulates the timing of sleep in other organisms. This raises the intriguing possibility that lethargus is a primordial sleep state regulated by genes of the circadian clock but occurring in a developmental context. Synapses are formed during lethargus (Hallam and Jin, 1998Hallam S.J. Jin Y. lin-14 regulates the timing of synaptic remodelling in Caenorhabditis elegans.Nature. 1998; 395: 78-82Crossref PubMed Scopus (85) Google Scholar, White et al., 1978White J.G. Albertson D.G. Anness M.A. Connectivity changes in a class of motoneurone during the development of a nematode.Nature. 1978; 271: 764-766Crossref PubMed Google Scholar), which is also consistent with a proposed function of sleep. With genetic model systems now available, assays for sleep have shifted from measuring cortical electrical activity (EEGs) to directly monitoring rest and activity behavior. Video recordings can monitor many behavior states relatively easily, whereas “beam-break assays” can monitor locomotor activity (Hendricks et al., 2000aHendricks J.C. Finn S.M. Panckeri K.A. Chavkin J. Williams J.A. Sehgal A. Pack A.I. Rest in Drosophila is a sleep-like state.Neuron. 2000; 25: 129-138Abstract Full Text Full Text PDF PubMed Google Scholar, Prober et al., 2006Prober 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. 2006; 26: 13400-13410Crossref PubMed Scopus (152) Google Scholar, Shaw et al., 2000Shaw P.J. Cirelli C. Greenspan R.J. Tononi G. Correlates of sleep and waking in Drosophila melanogaster.Science. 2000; 287: 1834-1837Crossref PubMed Scopus (419) Google Scholar, Yokogawa et al., 2007Yokogawa T. Marin W. Faraco J. Pézeron G. Appelbaum L. Zhang J. Rosa F. Mourrain P. Mignot E. Characterization of sleep in zebrafish and insomnia in hypocretin receptor mutants.PLoS Biol. 2007; 5: e277Crossref PubMed Scopus (124) Google Scholar). Electrophysiological recordings of fly brains have revealed how the fly sleep state correlates with specific electrophysiological characteristics (Nitz et al., 2002Nitz D.A. van Swinderen B. Tononi G. Greenspan R.J. Electrophysiological correlates of rest and activity in Drosophila melanogaster.Curr. Biol. 2002; 12: 1934-1940Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, van Swinderen et al., 2004van Swinderen B. Nitz D.A. Greenspan R.J. Uncoupling of brain activity from movement defines arousal States in Drosophila.Curr. Biol. 2004; 14: 81-87Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar), but such recordings are clearly not practical for high-throughput or even day-to-day experiments. Even in the mouse (the preferred mammalian model for genetic approaches), researchers are starting to rely upon measurements of behavior to assay sleep instead of electrophysiological measurements (Pack et al., 2007Pack A.I. Galante R.J. Maislin G. Cater J. Metaxas D. Lu S. Zhang L. Von Smith R. Kay T. Lian J. et al.Novel method for high-throughput phenotyping of sleep in mice.Physiol. Genomics. 2007; 28: 232-238Crossref PubMed Scopus (53) Google Scholar). Importantly, these behavioral assays, used in different model systems, are corroborating a role for sleep-regulating molecules identified through more traditional approaches, and they are also identifying new components. Here we review the major classes of molecules identified thus far, focusing particularly on the findings derived from the newer models for sleep—fish, flies, and worms. For more details on the molecular analysis in mammals, we direct the reader to two excellent Reviews (Andretic et al., 2008aAndretic R. Franken P. Tafti M. Genetics of sleep.Annu. Rev. Genet. 2008; 42: 361-388Crossref PubMed Scopus (52) Google Scholar, Cirelli, 2009Cirelli C. The genetic and molecular regulation of sleep: from fruit flies to humans.Nat. Rev. Neurosci. 2009; 10: 549-560Crossref PubMed Scopus (102) Google Scholar). Regulation of sleep by various neurotransmitters was discovered, before the advent of modern genetic technologies, through pharmacological methods. Adenosine has long been touted as a major sleep-promoting molecule that acts primarily in the mammalian basal forebrain. Although there have been some challenges to this idea, the hypothesis nonetheless prevails (Bjorness and Greene, 2009Bjorness T.E. Greene R.W. Adenosine and sleep.Curr. Neuropharmacol. 2009; 7: 238-245Crossref PubMed Scopus (27) Google Scholar). Wake-promoting effects of caffeine are thought to be mediated by its antagonistic action on adenosine receptors (Basheer et al., 2004Basheer R. Strecker R.E. Thakkar M.M. McCarley R.W. Adenosine and sleep-wake regulation.Prog. Neurobiol. 2004; 73: 379-396Crossref PubMed Scopus (273) Google Scholar). Indeed, mice mutant for the A2A adenosine receptor show deficits in their response to caffeine (Huang et al., 2005Huang Z.L. Qu W.M. Eguchi N. Chen J.F. Schwarzschild M.A. Fredholm B.B. Urade Y. Hayaishi O. Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine.Nat. Neurosci. 2005; 8: 858-859Crossref PubMed Scopus (226) Google Scholar). However, mutants of other adenosine receptors show limited effects on sleep. Bjorness et al., 2009Bjorness T.E. Kelly C.L. Gao T. Poffenberger V. Greene R.W. Control and function of the homeostatic sleep response by adenosine A1 receptors.J. Neurosci. 2009; 29: 1267-1276Crossref PubMed Scopus (57) Google Scholar found that disrupting the A1 receptor only in the central nervous system reduces slow wave activity (an electrophysiological measure thought to reflect sleep drive) in response to sleep restriction, but it has no effect on baseline sleep. These findings suggest that adenosine is one of many neurotransmitters that regulate sleep, rather than being the dominant regulator (Bjorness and Greene, 2009Bjorness T.E. Greene R.W. Adenosine and sleep.Curr. Neuropharmacol. 2009; 7: 238-245Crossref PubMed Scopus (27) Google Scholar). Adenosine and caffeine have similar effects on Drosophila sleep as they do on mammalian sleep, and the Drosophila response to caffeine is attenuated by decreased signaling through the dopamine D1 receptor or reduced protein kinase A (PKA) activity (Andretic et al., 2008bAndretic R. Kim Y.C. Jones F.S. Han K.A. Greenspan R.J. Drosophila D1 dopamine receptor mediates caffeine-induced arousal.Proc. Natl. Acad. Sci. USA. 2008; 105: 20392-20397Crossref PubMed Scopus (29) Google Scholar, Wu et al., 2009Wu M.N. Ho K. Crocker A. Yue Z. Koh K. Sehgal A. The effects of caffeine on sleep in Drosophila require PKA activity, but not the adenosine receptor.J. Neurosci. 2009; 29: 11029-11037Crossref PubMed Scopus (33) Google Scholar). Surprisingly, the single known adenosine receptor in Drosophila is not required for wake-promoting effects of caffeine (Wu et al., 2009Wu M.N. Ho K. Crocker A. Yue Z. Koh K. Sehgal A. The effects of caffeine on sleep in Drosophila require PKA activity, but not the adenosine receptor.J. Neurosci. 2009; 29: 11029-11037Crossref PubMed Scopus (33) Google Scholar). Although this may be indicative of different mechanisms driving the response to caffeine (perhaps the inhibition of a phosphodiesterase, another known target of caffeine), one cannot exclude the possibility that other, unidentified adenosine receptors exist in Drosophila. Other neurotransmitters implicated in mammalian sleep are histamine, dopamine, acetylcholine, norepinephrine, all of which promote wakefulness, and GABA (gamma-aminobutyric acid), which promotes sleep (Andretic et al., 2008aAndretic R. Franken P. Tafti M. Genetics of sleep.Annu. Rev. Genet. 2008; 42: 361-388Crossref PubMed Scopus (52) Google Scholar, Cirelli, 2009Cirelli C. The genetic and molecular regulation of sleep: from fruit flies to humans.Nat. Rev. Neurosci. 2009; 10: 549-560Crossref PubMed Scopus (102) Google Scholar). Effects of serotonin are somewhat complicated; although it suppresses REM sleep, its effects on NREM are unclear and may even be stimulatory (Crocker and Sehgal, 2010Crocker A. Sehgal A. Genetic analysis of sleep.Genes Dev. 2010; 24: 1220-1235Crossref PubMed Scopus (42) Google Scholar). Genetic analysis in the mouse generally supports roles for these neurotransmitters in regulating sleep, although their effects are sometimes small and complicated, perhaps due to redundancy and compensation. In Drosophila, dopamine and octopamine, which acts similarly to norepinephrine, have robust wake-promoting effects, whereas GABA and serotonin promote sleep (Agosto et al., 2008Agosto J. Choi J.C. Parisky K.M. Stilwell G. Rosbash M. Griffith L.C. Modulation of GABAA receptor desensitization uncouples sleep onset and maintenance in Drosophila.Nat. Neurosci. 2008; 11: 354-359Crossref PubMed Scopus (64) Google Scholar, Andretic et al., 2005Andretic R. van Swinderen B. Greenspan R.J. Dopaminergic modulation of arousal in Drosophila.Curr. Biol. 2005; 15: 1165-1175Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, Crocker and Sehgal, 2008Crocker A. Sehgal A. Octopamine regulates sleep in drosophila through protein kinase A-dependent mechanisms.J. Neurosci. 2008; 28: 9377-9385Crossref PubMed Scopus (56) Google Scholar, Yuan et al., 2006Yuan Q. Joiner W.J. Sehgal A. A sleep-promoting role for the Drosophila serotonin receptor 1A.Curr. Biol. 2006; 16: 1051-1062Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). Analysis of the cellular circuitry underlying these effects is starting to reveal some interesting features. Dopamine invokes two different types of arousal, a startle response and normal wakefulness, and these are mediated by the same receptor but in different cellular loci (Lebestky et al., 2009Lebestky T. Chang J.S. Dankert H. Zelnik L. Kim Y.C. Han K.A. Wolf F.W. Perona P. Anderson D.J. Two different forms of arousal in Drosophila are oppositely regulated by the dopamine D1 receptor ortholog DopR via distinct neural circuits.Neuron. 2009; 64: 522-536Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar). Wake-promoting octopamine is released by neurons in the dorsal part of the fly brain, and it acts through the octopamine receptor OAMB located in neuroendocrine cells that produce Drosophila insulin-like-peptide (Dilp2) (Crocker et al., 2010Crocker A. Shahidullah M. Levitan I.B. Sehgal A. Identification of a neural circuit that underlies the effects of octopamine on sleep:wake behavior.Neuron. 2010; 65: 670-681Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). Many sleep-related effects of serotonin and dopamine are mediated by anatomical structures called the mushroom bodies, which are also independently implicated in sleep (Joiner et al., 2006Joiner W.J. Crocker A. White B.H. Sehgal A. Sleep in Drosophila is regulated by adult mushroom bodies.Nature. 2006; 441: 757-760Crossref PubMed Scopus (163) Google Scholar, Pitman et al., 2006Pitman J.L. McGill J.J. Keegan K.P. Allada R. A dynamic role for the mushroom bodies in promoting sleep in Drosophila.Nature. 2006; 441: 753-756Crossref PubMed Scopus (122) Google Scholar). Thus, the dopamine D1 receptor acts in mushroom bodies to modulate the response to caffeine and to prevent learning impairments induced by sleep deprivation, whereas serotonin acts through the d5-HT1A receptor in mushroom bodies to promote sleep (Andretic et al., 2008bAndretic R. Kim Y.C. Jones F.S. Han K.A. Greenspan R.J. Drosophila D1 dopamine receptor mediates caffeine-induced arousal.Proc. Natl. Acad. Sci. USA. 2008; 105: 20392-20397Crossref PubMed Scopus (29) Google Scholar, Seugnet et al., 2008Seugnet L. Suzuki Y. Vine L. Gottschalk L. Shaw P.J. D1 receptor activation in the mushroom bodies rescues sleep-loss-induced learning impairments in Drosophila.Curr. Biol. 2008; 18: 1110-1117Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, Yuan et al., 2006Yuan Q. Joiner W.J. Sehgal A. A sleep-promoting role for the Drosophila serotonin receptor 1A.Curr. Biol. 2006; 16: 1051-1062Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). Finally, a major target of sleep-promoting GABA is the large ventral lateral neurons (lLNvs) (Parisky et al., 2008Parisky K.M. Agosto J. Pulver S.R. Shang Y. Kuklin E. Hodge J.J. Kang K. Liu X. Garrity P.A. Rosbash M. Griffith L.C. PDF cells are a GABA-responsive wake-promoting component of the Drosophila sleep circuit.Neuron. 2008; 60: 672-682Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar). These are best known for their expression of circadian clock genes, although they do not appear to have a function in free-running circadian rhythms (Nitabach and Taghert, 2008Nitabach M.N. Taghert P.H. Organization of the Drosophila circadian control circuit.Curr. Biol. 2008; 18: R84-R93Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar). Instead, the lLNvs promote arousal in response to light (Shang et al., 2008Shang Y. Griffith L.C. Rosbash M. Light-arousal and circadian photoreception circuits intersect at the large PDF cells of the Drosophila brain.Proc. Natl. Acad. Sci. USA. 2008; 105: 19587-19594Crossref PubMed Scopus (94) Google Scholar, Sheeba et al., 2008Sheeba V. Fogle K.J. Kaneko M. Rashid S. Chou Y.T. Sharma V.K. Holmes T.C. Large ventral lateral neurons modulate arousal and sleep in Drosophila.Curr. Biol. 2008; 18: 1537-1545Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). GABA signaling, through the Resistance to dieldrin (Rdl) receptor, likely inhibits these neurons, allowing sleep to occur. Pharmacological studies in zebrafish have also implicated many of the neurotransmitters that regulate sleep in flies and mammals (Rihel et al., 2010Rihel J. Prober D.A. Arvanites A. Lam K. Zimmerman S. Jang S. Haggarty S.J. Kokel D. Rubin L.L. Peterson R.T. Schier A.F. Zebrafish behavioral profiling links drugs to biological targets and rest/wake regulation.Science. 2010; 327: 348-351Crossref PubMed Scopus (217) Google Scholar). These studies highlight the power of the fish system for identifying small molecules that affect sleep via high-throughput screens. Small molecules can be added to the water used to house the fish, allowing easy delivery and access. In addition, many different populations of fish, each treated with a different compound, can be assayed simultaneously through video recording. Through such a screen, Rihel et al. identified wake-promoting effects of β-adrenergic agonists, which is consistent with the Drosophila and mammalian data discussed above. Interestingly, as in Drosophila, selective serotonin reuptake inhibitors (SSRIs) decreased wake in zebrafish. These pharmacological approaches, together with the ease of high-throughput screening in flies and fish, may allow for more clear-cut answers regarding the role of individual sleep-regulating components. Neuropeptides also play a large role in regulating sleep, the best known being the hypocretins/orexins (Sakurai, 2007Sakurai T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness.Nat. Rev. Neurosci. 2007; 8: 171-181Crossref PubMed Scopus (442) Google Scholar). These neuropeptides underlie the sleep disorder narcolepsy, as described below in the section on human sleep genes. A sleep-regulating role for hypocretins is conserved in zebrafish (Faraco et al., 2006Faraco J.H. Appelbaum L. Marin W. Gaus S.E. Mourrain P. Mignot E. Regulation of hypocretin (orexin) expression in embryonic zebrafish.J. Biol. Chem. 2006; 281: 29753-29761Crossref PubMed Scopus (46) Google Scholar, Prober et al., 2006Prober 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. 2006; 26: 13400-13410Crossref PubMed Scopus (152) Google Scholar). Although orthologs of these molecules have not been found in flies, a different neuropeptide may function in an analogous fashion (Parisky et al., 2008Parisky K.M. Agosto J. Pulver S.R. Shang Y. Kuklin E. Hodge J.J. Kang K. Liu X. Garrity P.A. Rosbash M. Griffith L.C. PDF cells are a GABA-responsive wake-promoting component of the Drosophila sleep circuit.Neuron. 2008; 60: 672-682Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar). This peptide, pigment-dispersing factor (PDF), is secreted by central clock cells, ventral lateral neurons, in the fly brain. The small LNvs drive circadian rhythms in constant darkness, but the lLNvs are required for light-mediated arousal, which appears to depend upon PDF (Parisky et al., 2008Parisky K.M. Agosto J. Pulver S.R. Shang Y. Kuklin E. Hodge J.J. Kang K. Liu X. Garrity P.A. Rosbash M. Griffith L.C. PDF cells are a GABA-responsive wake-promoting component of the Drosophila sleep circuit.Neuron. 2008; 60: 672-682Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar). Thus, PDF may function in flies as hypocretin does in mammals, as a wake-promoting peptide secreted by neurons whose activity is suppressed during sleep by inhibitory neurotransmitters such as GABA (Figure 1). In both Drosophila and mammals, an arousal-promoting peptide (PDF and hypocretin, respectively) is secreted by cells within, or in the vicinity of, the central clock network. In mammals, hypocretin-producing neurons in the lateral hypothalamus receive circadian inputs from the central clock in the suprachaismatic nucleus (SCN) via the dorsomedial hypothalamus (DMH). (Circadian inputs are indicated in the lighter shaded box.) They are inhibited by GABAergic inputs from the ventrolateral preoptic (VLPO) area. In Drosophila, the large ventral lateral neurons (lLNvs) are part of the clock network although they are not required for free-running circadian rhythms. Instead they mediate light-driven arousal, at least in part through the release of PDF. As in mammals, GABAergic inputs to these neurons promote sleep. Some" @default.
• W2034261913 created "2016-06-24" @default.
• W2034261913 creator A5062817134 @default.
• W2034261913 creator A5073040042 @default.
• W2034261913 date "2011-07-01" @default.
• W2034261913 modified "2023-10-13" @default.
• W2034261913 title "Genetics of Sleep and Sleep Disorders" @default.
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