title: Identifying sleep regulatory genes using a Drosophila model of insomnia.
abstract: Although it is widely accepted that sleep must serve an essential biological function, little is known about molecules that underlie sleep regulation. Given that insomnia is a common sleep disorder that disrupts the ability to initiate and maintain restorative sleep, a better understanding of its molecular underpinning may provide crucial insights into sleep regulatory processes. Thus, we created a line of flies using laboratory selection that share traits with human insomnia. After 60 generations, insomnia-like (ins-l) flies sleep 60 min a day, exhibit difficulty initiating sleep, difficulty maintaining sleep, and show evidence of daytime cognitive impairment. ins-l flies are also hyperactive and hyperresponsive to environmental perturbations. In addition, they have difficulty maintaining their balance, have elevated levels of dopamine, are short-lived, and show increased levels of triglycerides, cholesterol, and free fatty acids. Although their core molecular clock remains intact, ins-l flies lose their ability to sleep when placed into constant darkness. Whole-genome profiling identified genes that are modified in ins-l flies. Among those differentially expressed transcripts, genes involved in metabolism, neuronal activity, and sensory perception constituted over-represented categories. We demonstrate that two of these genes are upregulated in human subjects after acute sleep deprivation. Together, these data indicate that the ins-l flies are a useful tool that can be used to identify molecules important for sleep regulation and may provide insights into both the causes and long-term consequences of insomnia.
authors.affiliation: Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Seugnet
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Matthew
authors.initials: M
authors.lastname: Thimgan
authors.forename: Jeff
authors.initials: J
authors.lastname: Donlea
authors.forename: Sarah I
authors.initials: SI
authors.lastname: Gimbel
authors.forename: Laura
authors.initials: L
authors.lastname: Gottschalk
authors.forename: Steve P
authors.initials: SP
authors.lastname: Duntley
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Shaw
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D001362:Avoidance Learning / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001522:Behavior, Animal; D002784:Cholesterol / Q000378:metabolism; D002940:Circadian Rhythm / Q000235:genetics; D003285:Contractile Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D064448:Filamins; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008055:Lipids; D008124:Locomotion / Q000235:genetics; D008291:Malate Dehydrogenase / Q000378:metabolism; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D036361:Peptide Hormones / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D012890:Sleep / Q000235:genetics*; D012892:Sleep Deprivation / Q000503:physiopathology; D007319:Sleep Initiation and Maintenance Disorders / Q000235:genetics*; D018709:Statistics, Nonparametric; D013315:Stress, Psychological / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism; D014851:Wakefulness
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002784:Cholesterol; D003285:Contractile Proteins; D004298:Dopamine; D029721:Drosophila Proteins; D005230:Fatty Acids, Nonesterified; D064448:Filamins; D008055:Lipids; D008291:Malate Dehydrogenase; D008840:Microfilament Proteins; D018377:Neurotransmitter Agents; D036361:Peptide Hormones; D014280:Triglycerides; C495394:malic enzyme 2; human