CaltechAUTHORS
Published February 17, 2016 | Version Accepted Version + Supplemental Material
Journal Article Open

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

Creators

  • 1. ROR icon California Institute of Technology
  • 2. ROR icon University College London
  • 3. ROR icon Harvard University
  • 4. ROR icon Dana-Farber Cancer Institute

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.

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.

Attached Files

Accepted Version - nihms750662.pdf

Supplemental Material - mmc1.pdf

Supplemental Material - mmc2.mp4

Supplemental Material - mmc3.mp4

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Additional details

Identifiers

PMCID
PMC4851465
Eprint ID
64542
Resolver ID
CaltechAUTHORS:20160218-075222867

Funding

NIH
NS084769
NIH
NS077842
NIH
HL109625
NIH
NS060996
NIH
NS070911
NIH
DA031367
European Research Council (ERC)
University College London
Dana-Farber Cancer Institute
Ellison Foundation
Mallinckrodt Foundation
Rita Allen Foundation
Brain and Behavior Research Foundation

Dates

Created
2016-02-18
Created from EPrint's datestamp field
Updated
2022-05-06
Created from EPrint's last_modified field