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The Journal of Neuroscience, June 3, 2009, 29(22):7148-7157; doi:10.1523/JNEUROSCI.5629-08.2009

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Behavioral/Systems/Cognitive
Identifying Sleep Regulatory Genes Using a Drosophila Model of Insomnia

Laurent Seugnet,¹ Yasuko Suzuki,¹ Matthew Thimgan,¹ Jeff Donlea,¹ Sarah I. Gimbel,² Laura Gottschalk,¹ Steve P. Duntley,³ and Paul J. Shaw¹

¹Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110, ²Neuroscience Program, University of California, San Diego, San Diego, California 92093, and ³Department of Neurology, Washington University Sleep Medicine Center, St. Louis, Missouri 63108

Correspondence should be addressed to Dr. Paul J. Shaw, Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8108, St. Louis, MO 63110. Email: shawp{at}pcg.wustl.edu

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.

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Received Nov. 25, 2008; revised April 1, 2009; accepted April 13, 2009.

Correspondence should be addressed to Dr. Paul J. Shaw, Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8108, St. Louis, MO 63110. Email: shawp{at}pcg.wustl.edu

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