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The Journal of Neuroscience, December 20, 2006, 26(51):13400-13410; doi:10.1523/JNEUROSCI.4332-06.2006

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

David A. Prober,¹ Jason Rihel,¹ Anthony A. Onah,¹ Rou-Jia Sung,¹ and Alexander F. Schier^1,2,3,4,5

¹Department of Molecular and Cellular Biology, ²Division of Sleep Medicine, ³Center for Brain Science, ⁴Harvard Stem Cell Institute, and ⁵Broad Institute, Harvard University, Cambridge, Massachusetts 02138

Correspondence should be addressed to David A. Prober or Alexander F. Schier, Department of Molecular and Cellular Biology, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138. Email: schier{at}mcb.harvard.edu, Email: prober{at}fas.harvard.edu

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.

Key words: hypocretin; orexin; sleep; insomnia; circadian rhythm; zebrafish

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Received Oct. 4, 2006; revised Nov. 9, 2006; accepted Nov. 13, 2006.

Correspondence should be addressed to David A. Prober or Alexander F. Schier, Department of Molecular and Cellular Biology, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138. Email: schier{at}mcb.harvard.edu, Email: prober{at}fas.harvard.edu

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