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Hypocretin/Orexin Overexpression Induces An Insomnia-Like Phenotype in Zebrafish

Prober, David A. and Rihel, Jason and Onah, Anthony A. and Sung, Rou-Jia and Schier, Alexander F. (2006) Hypocretin/Orexin Overexpression Induces An Insomnia-Like Phenotype in Zebrafish. Journal of Neuroscience, 26 (51). pp. 13400-13410. ISSN 0270-6474. PMCID PMC6675014. https://resolver.caltech.edu/CaltechAUTHORS:20150918-153127266

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Abstract

As many as 10% of humans suffer chronic sleep disturbances, yet the genetic mechanisms that regulate sleep remain essentially unknown. It is therefore crucial to develop simple and cost-effective vertebrate models to study the genetic regulation of sleep. The best characterized mammalian sleep/wake regulator is hypocretin/orexin (Hcrt), whose loss results in the sleep disorder narcolepsy and that has also been implicated in feeding behavior, energy homeostasis, thermoregulation, reward seeking, addiction, and maternal behavior. Here we report that the expression pattern and axonal projections of embryonic and larval zebrafish Hcrt neurons are strikingly similar to those in mammals. We show that zebrafish larvae exhibit robust locomotive sleep/wake behaviors as early as the fifth day of development and that Hcrt overexpression promotes and consolidates wakefulness and inhibits rest. Similar to humans with insomnia, Hcrt-overexpressing larvae are hyperaroused and have dramatically reduced abilities to initiate and maintain rest at night. Remarkably, Hcrt function is modulated by but does not require normal circadian oscillations in locomotor activity. Our zebrafish model of Hcrt overexpression indicates that the ancestral function of Hcrt is to promote locomotion and inhibit rest and will facilitate the discovery of neural circuits, genes, and drugs that regulate Hcrt function and sleep.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1523/JNEUROSCI.4332-06.2006DOIArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6675014/PubMed CentralArticle
http://www.jneurosci.org/content/26/51/13400/suppl/DC1PublisherSupplemental Material
ORCID:
AuthorORCID
Prober, David A.0000-0002-7371-4675
Additional Information:© 2006 Society for Neuroscience. Beginning six months after publication the Work will be made freely available to the public on SfN’s website to copy, distribute, or display under a Creative Commons Attribution 4.0 International (CC BY 4.0) license (https://creativecommons.org/licenses/by/4.0/). Received October 4, 2006. Revision received November 9, 2006. Accepted November 13, 2006. This work was supported by grants from the National Institutes of Health and the McKnight Endowment Fund for Neuroscience (A.F.S.). D.A.P. was supported by a fellowship from the Helen Hay Whitney Foundation. J.R. is a Bristol-Myers Squibb Fellow of the Life Sciences Research Foundation. We thank Wolfgang Driever, Su Guo, Shin-Ichi Higashijima, and Steve Wilson for providing in situ probes, Steven Zimmerman for technical assistance, Amir Karger for assistance with data analysis, Patrick Mabray and Irina Zhdanova for advice on behavioral assays, and Sebastian Kraves for comments on this manuscript.
Funders:
Funding AgencyGrant Number
NIHUNSPECIFIED
McKnight Endowment Fund for NeuroscienceUNSPECIFIED
Helen Hay Whitney FoundationUNSPECIFIED
Life Sciences Research FoundationUNSPECIFIED
Subject Keywords:hypocretin; orexin; sleep; insomnia; circadian rhythm; zebrafish
Issue or Number:51
PubMed Central ID:PMC6675014
Record Number:CaltechAUTHORS:20150918-153127266
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20150918-153127266
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:60352
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:18 Sep 2015 22:56
Last Modified:13 Apr 2020 23:09

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