The long-range goal of the proposed project is to identify genes that regulate sleep and wakefulness in vertebrates. We will use zebrafish as a genetic system for such studies, because fish have the basic brain structures and peptides that regulate sleep in humans. We have developed high-throughput assays to measure sleep and wakefulness in zebrafish and found that the role of Hypocretin/Orexin signaling is conserved between zebrafish and mammals. We will screen 1,000 different zebrafish lines harboring disruptive insertions in genes that are expressed in the adult brain and have the potential to be drug targets. Mutants will be screened for defects in sleep and wakefulness using locomotor activity and arousal threshold. These studies will identify genes involved in sleep biology and provide functional data for a large number of biomedically relevant genes.

Public Health Relevance

As many as 10% of Americans suffer chronic sleep disturbances, but the genetic mechanisms that control sleep and wake states remain largely unknown. The discovery of genes that regulate sleep in zebrafish will help to uncover the molecular underpinnings of sleep and inform strategies for the treatment of sleep disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM085357-02
Application #
7628393
Study Section
Special Emphasis Panel (ZRG1-BDA-F (50))
Program Officer
Tompkins, Laurie
Project Start
2008-06-01
Project End
2011-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
2
Fiscal Year
2009
Total Cost
$335,833
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Merkle, Florian T; Maroof, Asif; Wataya, Takafumi et al. (2015) Generation of neuropeptidergic hypothalamic neurons from human pluripotent stem cells. Development 142:633-43
Lacoste, Alix M B; Schoppik, David; Robson, Drew N et al. (2015) A convergent and essential interneuron pathway for Mauthner-cell-mediated escapes. Curr Biol 25:1526-34
Rihel, Jason; Schier, Alexander F (2013) Sites of action of sleep and wake drugs: insights from model organisms. Curr Opin Neurobiol 23:831-40
Ahrens, Misha B; Orger, Michael B; Robson, Drew N et al. (2013) Whole-brain functional imaging at cellular resolution using light-sheet microscopy. Nat Methods 10:413-20
Varshney, Gaurav K; Lu, Jing; Gildea, Derek E et al. (2013) A large-scale zebrafish gene knockout resource for the genome-wide study of gene function. Genome Res 23:727-35
Levitz, Joshua; Pantoja, Carlos; Gaub, Benjamin et al. (2013) Optical control of metabotropic glutamate receptors. Nat Neurosci 16:507-16
Ahrens, Misha B; Li, Jennifer M; Orger, Michael B et al. (2012) Brain-wide neuronal dynamics during motor adaptation in zebrafish. Nature 485:471-7
Bianco, Isaac H; Ma, Leung-Hang; Schoppik, David et al. (2012) The tangential nucleus controls a gravito-inertial vestibulo-ocular reflex. Curr Biol 22:1285-95
Pauli, Andrea; Valen, Eivind; Lin, Michael F et al. (2012) Systematic identification of long noncoding RNAs expressed during zebrafish embryogenesis. Genome Res 22:577-91
Naumann, Eva A; Kampff, Adam R; Prober, David A et al. (2010) Monitoring neural activity with bioluminescence during natural behavior. Nat Neurosci 13:513-20

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