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A Zebrafish Genetic Screen Identifies Neuromedin U as a Regulator of Sleep/Wake States

Chiu, Cindy N. and Rihel, Jason and Lee, Daniel A. and Singh, Chanpreet and Mosser, Eric A. and Chen, Shijia and Sapin, Viveca and Pham, Uyen and Engle, Jae and Niles, Brett J. and Montz, Christin J. and Chakravarthy, Sridhara and Zimmerman, Steven and Salehi-Ashtiani, Kourosh and Vidal, Marc and Schier, Alexander F. and Prober, David A. (2016) A Zebrafish Genetic Screen Identifies Neuromedin U as a Regulator of Sleep/Wake States. Neuron, 89 (4). pp. 842-856. ISSN 0896-6273. PMCID PMC4851465. doi:10.1016/j.neuron.2016.01.007.

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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.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Rihel, Jason0000-0003-4067-2066
Lee, Daniel A.0000-0001-7411-2740
Singh, Chanpreet0000-0002-2697-3033
Salehi-Ashtiani, Kourosh0000-0002-6521-5243
Vidal, Marc0000-0003-3391-5410
Schier, Alexander F.0000-0002-5317-494X
Prober, David A.0000-0002-7371-4675
Additional Information:© 2016 Elsevier. Received 17 April 2015, Revised 16 November 2015, Accepted 24 December 2015, Available online 17 February 2016. We thank Melanie Pribisko, Alex Mack Cruz, Axel Dominguez, Sohini Khan, and Kenna Molinder for technical assistance. This work was supported by grants from the NIH (D.A.L.: NS084769; S. Chen: NS077842; A.F.S.: HL109625; D.A.P.: NS060996, NS070911, DA031367); the European Research Council Starting Grant and UCL Excellence Fellowship (J.R.); the High-Tech Fund of the Dana-Farber Cancer Institute and the Ellison Foundation (M.V.); and the Mallinckrodt, Rita Allen and the Brain and Behavior Research Foundations (D.A.P.). We declare no conflicts of interest. Author Contributions: A.F.S. and D.A.P. conceived the genetic screen. D.A.P. and J.R. designed and performed the experiments for the primary genetic screen. C.N.C., J.R., D.A.L., C.S., E.A.M., S. Chen, V.S., U.P., J.E., B.J.N., C.J.M., S. Chakravarthy, and D.A.P. performed secondary screening of human and zebrafish stable lines. All subsequent work was conceived by, and performed in the lab of, D.A.P., except that adult assays were performed by J.R. using a setup designed and built by S.Z. D.A.P. and C.N.C. generated mutants. C.N.C. designed, performed, and analyzed most Nmu experiments, except that C.S. performed some mutant experiments. K.S.-A. and M.V. provided reagents. C.N.C., J.R., A.F.S., and D.A.P. wrote the manuscript. D.A.P. and A.F.S. supervised the project.
Funding AgencyGrant Number
European Research Council (ERC)UNSPECIFIED
University College LondonUNSPECIFIED
Dana-Farber Cancer InstituteUNSPECIFIED
Ellison FoundationUNSPECIFIED
Mallinckrodt FoundationUNSPECIFIED
Rita Allen FoundationUNSPECIFIED
Brain and Behavior Research FoundationUNSPECIFIED
Issue or Number:4
PubMed Central ID:PMC4851465
Record Number:CaltechAUTHORS:20160218-075222867
Persistent URL:
Official Citation:Cindy N. Chiu, Jason Rihel, Daniel A. Lee, Chanpreet Singh, Eric A. Mosser, Shijia Chen, Viveca Sapin, Uyen Pham, Jae Engle, Brett J. Niles, Christin J. Montz, Sridhara Chakravarthy, Steven Zimmerman, Kourosh Salehi-Ashtiani, Marc Vidal, Alexander F. Schier, David A. Prober, A Zebrafish Genetic Screen Identifies Neuromedin U as a Regulator of Sleep/Wake States, Neuron, Volume 89, Issue 4, 17 February 2016, Pages 842-856, ISSN 0896-6273,
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:64542
Deposited By: George Porter
Deposited On:18 Feb 2016 16:15
Last Modified:06 May 2022 17:23

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