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.

Download full-text


Available from: Jason Rihel,
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Insomnia is a common clinical condition portrayed by difficulty in initiating or maintaining sleep, or non-restorative sleep with impairment of daytime functioning, such as irritability or fatigue during wakefulness. This ailment is one of the most rampant health concerns; however, it represents an everyday struggle to clinicians because of its many potential causes, unfamiliarity with behavioral treatments, and concerns about pharmacologic treatments. The etiology and pathophysiology of insomnia involve genetic, environmental, behavioral, and physiological factors culminating in hyperarousal.
    Milestones in Drug Therapy 01/2015; 49:191-207. DOI:10.1007/978-3-319-11514-6_9
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Bioscience Horizons 10/2014; 7:hzu008-hzu008. DOI:10.1093/biohorizons/hzu008
  • Source
    • "The conservation of the distribution pattern of H/O fibers also suggests a conservation of H/O function among vertebrates [8]–[10]. H/Os induce arousal in neonatal chickens [23] and larval zebrafish [24], and stimulate feeding and locomotion in fish [4]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hypocretin/Orexin (H/O) neuropeptides are released by a discrete group of neurons in the vertebrate hypothalamus which play a pivotal role in the maintenance of waking behavior and brain state control. Previous studies have indicated that the H/O neuronal development differs between mammals and fish; H/O peptide-expressing cells are detectable during the earliest stages of brain morphogenesis in fish, but only towards the end of brain morphogenesis (by ∼85% of embryonic development) in rats. The developmental emergence of H/O neurons has never been previously described in birds. With the goal of determining whether the chick developmental pattern was more similar to that of mammals or of fish, we investigated the emergence of H/O-expressing cells in the brain of chick embryos of different ages using immunohistochemistry. Post-natal chick brains were included in order to compare the spatial distribution of H/O cells with that of other vertebrates. We found that H/O-expressing cells appear to originate from two separate places in the region of the diencephalic proliferative zone. These developing cells express the H/O neuropeptide at a comparatively early age relative to rodents (already visible at 14% of the way through fetal development), thus bearing a closer resemblance to fish. The H/O-expressing cell population proliferates to a large number of cells by a relatively early embryonic age. As previously suggested, the distribution of H/O neurons is intermediate between that of mammalian and non-mammalian vertebrates. This work suggests that, in addition to its roles in developed brains, the H/O peptide may play an important role in the early embryonic development of non-mammalian vertebrates.
    PLoS ONE 09/2014; 9(9):e106977. DOI:10.1371/journal.pone.0106977 · 3.23 Impact Factor
Show more