Dataset Information

Hypocretin/orexin overexpression induces an insomnia-like phenotype in zebrafish.

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.

SUBMITTER: Prober DA

PROVIDER: S-EPMC6675014 | biostudies-literature | 2006 Dec

REPOSITORIES: biostudies-literature

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Hypocretin/orexin overexpression induces an insomnia-like phenotype in zebrafish.

Prober David A DA Rihel Jason J Onah Anthony A AA Sung Rou-Jia RJ Schier Alexander F AF

The Journal of neuroscience : the official journal of the Society for Neuroscience 20061201 51

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, ...[more]

PMID: 17182791

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Project description:The sleep disorder narcolepsy is caused by a vast reduction in neurons producing the hypocretin (orexin) neuropeptides. Based on the tight association with HLA, narcolepsy is believed to result from an autoimmune attack, but the cause of hypocretin cell loss is still unknown. We performed gene expression profiling in the hypothalamus to identify novel genes dysregulated in narcolepsy, as these may be the target of autoimmune attack or modulate hypocretin gene expression.We used microarrays to compare the transcriptome in the posterior hypothalamus of (1) narcoleptic versus control postmortem human brains and (2) transgenic mice lacking hypocretin neurons versus wild type mice. Hypocretin was the most downregulated gene in human narcolepsy brains. Among many additional candidates, only one, insulin-like growth factor binding protein 3 (IGFBP3), was downregulated in both human and mouse models and co-expressed in hypocretin neurons. Functional analysis indicated decreased hypocretin messenger RNA and peptide content, and increased sleep in transgenic mice overexpressing human IGFBP3, an effect possibly mediated through decreased hypocretin promotor activity in the presence of excessive IGFBP3. Although we found no IGFBP3 autoantibodies nor a genetic association with IGFBP3 polymorphisms in human narcolepsy, we found that an IGFBP3 polymorphism known to increase serum IGFBP3 levels was associated with lower CSF hypocretin-1 in normal individuals.Comparison of the transcriptome in narcolepsy and narcolepsy model mouse brains revealed a novel dysregulated gene which colocalized in hypocretin cells. Functional analysis indicated that the identified IGFBP3 is a new regulator of hypocretin cell physiology that may be involved not only in the pathophysiology of narcolepsy, but also in the regulation of sleep in normal individuals, most notably during adolescence. Further studies are required to address the hypothesis that excessive IGFBP3 expression may initiate hypocretin cell death and cause narcolepsy.

Project description:BackgroundSelective serotonin reuptake inhibitors (SSRIs) are considered as ﬁrst-line drugs for treating depressive disorders. Among the adverse effects reported with sertraline is sleep disturbances; however, the etiology lying beneath is obscure. Orexin, the most recently discovered neurotransmitter, is involved in the sleep cycle. It exerts its physiological actions through orexin or hypocretin type 1 and 2 receptors (HCRTR1 and HCRTR2). Dysfunction of the orexin system contributes to various psychiatric, neurologic and neuropsychiatric disorders. Thus, our study aimed to assess the possible association of genetic variation of HCRTR2 G1246A with hypersomnia reported with sertraline in a group of major depressive disorder (MDD) patients.Patients and methodsNinety-six newly diagnosed MDD patients were enrolled in our cohort study. MDD was assessed using DSM-V criteria. Insomnia Severity Index (ISI) was used to assess insomnia at baseline (week 0) and week 4. Blood samples were collected for further genotyping of HCRTR2 G1246A (rs2653349) using polymerase chain reaction-restriction fragment length polymorphism.ResultsA significant association between G1264A polymorphism of HCRTR2 and insomnia was observed. Insomnia with sertraline happens by 2.5-fold (P=0.022; odds ratio (OR)=2.5; 95% confidence interval (CI): 1.1-5.7) in patients having GG genotype. Patients with G allele experience insomnia by 2.1-fold more than A allele carriers (P=0.022; OR=2.1; 95% CI= 1.1-4.0). Subgroup analysis showed a significant association between GG genotype as well as the G allele and insomnia only in female MDD patients (P=0.011; OR=4.0; 95% CI=1.3-12.0 and P=0.033; OR=2.4; 95% CI=1.02-5.7, respectively).ConclusionIn conclusion, the G1246A variant might be a predictor for insomnia in MDD patients treated with sertraline. Our findings support the idea that some variants of the HCRTR might contribute to inter-individual variability in the sleep pattern of patients receiving antidepressants.

Dataset Information

Hypocretin/orexin overexpression induces an insomnia-like phenotype in zebrafish.

Publications

Hypocretin/orexin overexpression induces an insomnia-like phenotype in zebrafish.

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