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

Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 01/2007; 26(51):13400-10. DOI: 10.1523/JNEUROSCI.4332-06.2006
Source: PubMed


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.

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    • "This species is a very prolific small vertebrate that, due to its size and the social nature, can be held in large numbers in small rack systems (up to 4000 fish in 250L water volume), demanding little cost and technical maintenance. In addition, the zebrafish shares many molecular pathways, genes and protein products with mammals (Faraco et al., 2006; Holzschuh et al., 2001; Kaslin, 2004; Kaslin and Panula, 2001; McLean and Fetcho, 2004; Mueller et al., 2004; Prober et al., 2006). Moreover, the majority of the genes already identified in this species is conserved and have homologs in mammals (Cerdà et al., 1998; Crollius and Weissenbach, 2005), which makes it an ideal model organism for embryology, development and disease studies (Sison and Gerlai, 2010). "
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    • "In another direction, overexpression of components of the orexinergic system also disrupts the SWC. For example in the zebrafish, overexpression of orexinergic neurons has been shown to induce an insomnia-like phenotype (Prober et al. 2006). Mice that overexpress prepro-orexin display sleep abnormalities, which include fragmentation of nREM sleep, reduced REM sleep, and increased motor activity during REM sleep, suggesting an inability to maintain sleep states. "
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    • "Similarly, prepro-orexin −/− and OX 2 R −/− mice have narcoleptic phenotypes (Chemelli et al., 1999; Willie et al., 2003). Furthermore, the overexpression of prepro-orexin induces an insomnia-like phenotype in zebrafish (Prober et al., 2006), whereas the ablation of zebrafish orexin neurons induces a narcolepsy-like phenotype (Elbaz et al., 2012). Second, an orexin CSF level lower (≤110 pg/mL) than normal (<200 pg/mL) is a cardinal symptom for human narcolepsy (Nishino et al., 2000), and orexin CSF concentrations correlate with the number of intact orexin neurons in rodents (Gerashchenko et al., 2003). "
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    ABSTRACT: Orexin and melanin-concentrating hormone (MCH) neurons reside in the lateral hypothalamic area (LHA) and regulate sleep and feeding behaviour in mammals. In rodents, orexin neurons are implicated in the regulation of wakefulness or palatable consumption, whereas MCH neurons are implicated in the regulation of rapid eye movement sleep episode duration or caloric consumption. This review explores the molecular, genetic and neuronal components of orexin and MCH signalling as mediators of arousal state transitions. These peptidergic signalling systems, which interconnect both with sleep centres in the LHA and feeding centres in the arcuate nucleus, may maintain the balance between sleep need and duration with hunger and food foraging.
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