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Norepinephrine is required to promote wakefulness and for hypocretin-induced arousal in zebrafish

  1. Chanpreet Singh
  2. Grigorios Oikonomou
  3. David A Prober  Is a corresponding author
  1. California Institute of Technology, United States
Research Article
  • Cited 52
  • Views 3,297
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Cite this article as: eLife 2015;4:e07000 doi: 10.7554/eLife.07000

Abstract

Pharmacological studies in mammals suggest that norepinephrine (NE) plays an important role in promoting arousal. However, the role of endogenous NE is unclear, with contradicting reports concerning the sleep phenotypes of mice lacking NE due to mutation of dopamine β-hydroxylase (dbh). To investigate NE function in an alternative vertebrate model, we generated dbh mutant zebrafish. In contrast to mice, these animals exhibit dramatically increased sleep. Surprisingly, despite an increase in sleep,dbh mutant zebrafish have a reduced arousal threshold. These phenotypes are also observed in zebrafish treated with small molecules that inhibit NE signaling, suggesting that they are caused by the lack of NE. Using genetic overexpression of hypocretin (Hcrt) and optogenetic activation of hcrt-expressing neurons, we also find that NE is important for Hcrt-induced arousal. These results establish a role for endogenous NE in promoting arousal and indicate that NE is a critical downstream effector of Hcrt neurons.

Article and author information

Author details

  1. Chanpreet Singh

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Grigorios Oikonomou

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. David A Prober

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    For correspondence
    dprober@caltech.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All experiments followed standard protocols (Westerfield, 1993) in accordance with the California Institute of Technology Institutional Animal Care and Use Committee guidelines.

Reviewing Editor

  1. Louis Ptáček, University of California, San Francisco, United States

Publication history

  1. Received: February 13, 2015
  2. Accepted: September 14, 2015
  3. Accepted Manuscript published: September 16, 2015 (version 1)
  4. Version of Record published: October 16, 2015 (version 2)

Copyright

© 2015, Singh et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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    Funding: This work was supported in part by the Italian Ministry of Health (GR-2013-02355724 and Ricerca Corrente), MJFF, ALZ, Alzheimer's Research UK and the Weston Brain Institute (BAND2015), and Euronanomed III (Speedy) to FM; by the Spanish Ministerio de Economía y Competitividad [grant AGL2016-78054-R (AEI/FEDER, UE)] to J.M.T. and J.C.E.; A.M.-M. was supported by a fellowship from the INIA (FPI-SGIT-2015-02).