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: 6.75). 01/2007; 26(51):13400-10. DOI: 10.1523/JNEUROSCI.4332-06.2006
Source: PubMed

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.

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    ABSTRACT: Background Sleep is characterized by extended periods of quiescence and reduced responsiveness to sensory stimuli. Animals ranging from insects to mammals adapt to environments with limited food by suppressing sleep and enhancing their response to food cues, yet little is known about the genetic and evolutionary relationship between these processes. The blind Mexican cavefish, Astyanax mexicanus is a powerful model for elucidating the genetic mechanisms underlying behavioral evolution. A. mexicanus comprises an extant ancestral- type surface dwelling morph and at least five independently evolved cave populations. Evolutionary convergence on sleep loss and vibration attraction behavior, which is involved in prey seeking, have been documented in cavefish raising the possibility that enhanced sensory responsiveness underlie changes in sleep. Results We established a system to study sleep and vibration attraction behavior in adult A. mexicanus and used high coverage quantitative trait loci (QTL) mapping to investigate the functional and evolutionary relationship between these traits. Analysis of surface-cave F2 hybrid fish and an outbred cave population indicates that independent genetic factors underlie changes in sleep/locomotor activity and vibration attraction behavior. High-coverage QTL mapping with genotyping-by-sequencing technology identify two novel QTL intervals that associate with locomotor activity and include the narcolepsy-associated tp53 regulating kinase. These QTLs represent the first genomic localization of locomotor activity in cavefish and are distinct from two QTLs previously identified as associating with vibration attraction behavior. Conclusions Taken together, these results localize genomic regions underlying sleep/locomotor and sensory changes in cavefish populations and provide evidence that sleep loss evolved independently from enhanced sensory responsiveness.
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    ABSTRACT: Dopamine (DA) has long been known to have modulatory effects on vertebrate motor circuits. However, the types of information encoded by supraspinal DAergic neurons and their relationship to motor behavior remain unknown. By conducting electrophysiological recordings from awake, paralyzed zebrafish larvae that can produce behaviorally relevant activity patterns, we show that supraspinal DAergic neurons generate two forms of output: tonic spiking and phasic bursting. Using paired supraspinal DA neuron and motoneuron recordings, we further show that these firing modes are associated with specific behavioral states. Tonic spiking is prevalent during periods of inactivity while bursting strongly correlates with locomotor output. Targeted laser ablation of supraspinal DA neurons reduces motor episode frequency without affecting basic parameters of motor output, strongly suggesting that these cells regulate spinal network excitability. Our findings reveal how vertebrate motor circuit flexibility is temporally controlled by supraspinal DAergic pathways and provide important insights into the functional significance of this evolutionarily conserved cell population. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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    ABSTRACT: Several organisms irrespective of their complexity in structure and function have an inbuilt circadian rhythm. Zebrafish could be used as an alternate model animal in sleep research as it exhibits similar sleep-wake dynamics as mammals and Drosophila. In this study, we have analysed the adult zebrafish brain for its differential proteome and gene expression during perturbed light/dark cycle. A total of 53 and 25 proteins including sncb, peroxiredoxins and TCR alpha were identified based on two-dimensional gel electrophoresis Fourier transform mass spectrometer/ion trap tandem mass spectrometer and differential in-gel electrophoresis MALDI TOF MS/MS analysis, respectively, with at least 1.5-fold changes between the control and experimental brains. Real time-polymerase chain reaction revealed that many circadian pathway-associated genes, such as per1b, bmal1b, cry1b, bmal2 and nr1d2, were differentially regulated during continuous light/dark exposures. It is hypothesized that the differential regulation of these genes might lead to the discovery of potential diagnostic markers for gaining insight into the light/dark-associated stress in humans.
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Jun 4, 2014