title: A Zebrafish Genetic Screen Identifies Neuromedin U as a Regulator of Sleep/Wake States.
abstract: Neuromodulation of arousal states ensures that an animal appropriately responds to its environment and engages in behaviors necessary for survival. However, the molecular and circuit properties underlying neuromodulation of arousal states such as sleep and wakefulness remain unclear. To tackle this challenge in a systematic and unbiased manner, we performed a genetic overexpression screen to identify genes that affect larval zebrafish arousal. We found that the neuropeptide neuromedin U (Nmu) promotes hyperactivity and inhibits sleep in zebrafish larvae, whereas nmu mutant animals are hypoactive. We show that Nmu-induced arousal requires Nmu receptor 2 and signaling via corticotropin releasing hormone (Crh) receptor 1. In contrast to previously proposed models, we find that Nmu does not promote arousal via the hypothalamic-pituitary-adrenal axis, but rather probably acts via brainstem crh-expressing neurons. These results reveal an unexpected functional and anatomical interface between the Nmu system and brainstem arousal systems that represents a novel wake-promoting pathway.
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Cindy N
authors.initials: CN
authors.lastname: Chiu
authors.affiliation: Department of Cell and Developmental Biology, University College London, London, WC1E 6BT, UK; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Rihel
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Lee
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Chanpreet
authors.initials: C
authors.lastname: Singh
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Mosser
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Shijia
authors.initials: S
authors.lastname: Chen
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Viveca
authors.initials: V
authors.lastname: Sapin
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Uyen
authors.initials: U
authors.lastname: Pham
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Jae
authors.initials: J
authors.lastname: Engle
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Brett J
authors.initials: BJ
authors.lastname: Niles
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Christin J
authors.initials: CJ
authors.lastname: Montz
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Sridhara
authors.initials: S
authors.lastname: Chakravarthy
authors.affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Zimmerman
authors.affiliation: Center for Cancer Systems Biology and Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kourosh
authors.initials: K
authors.lastname: Salehi-Ashtiani
authors.affiliation: Center for Cancer Systems Biology and Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Vidal
authors.affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA; Center for Brain Science, Harvard University, Cambridge, MA 02138, USA; Division of Sleep Medicine, Harvard University, Cambridge, MA 02138, USA. Electronic address: schier@fas.harvard.edu.
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Schier
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: dprober@caltech.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Prober
mesh_terms: D000367:Age Factors; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001933:Brain Stem / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D007814:Larva; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism*; D010913:Pituitary-Adrenal System / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D017463:Receptors, Complement 3b / Q000378:metabolism; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D012890:Sleep / Q000235:genetics*; D014851:Wakefulness / Q000235:genetics*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: C471210:2-methyl-4-(N-propyl-N-cycloproanemethylamino)-5-chloro-6-(2,4,6-trichloranilino)pyrimidine; D000814:Aniline Compounds; D009479:Neuropeptides; D011743:Pyrimidines; D017463:Receptors, Complement 3b; D017981:Receptors, Neurotransmitter; D029961:Zebrafish Proteins; C082444:neuromedin U receptor; C056900:neuromedin U