Hypocretin/orexin overexpression induces an insomnia-like phenotype in zebrafish
Hypocretin/orexin overexpression induces an insomnia-like phenotype in zebrafish
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DOI：
10.1523/jneurosci.4332-06.2006
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发表时间：
2006-12-20
影响因子：
5.3
通讯作者：
Schier, Alexander F.
中科院分区：
文献类型：
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作者：
Prober, David A.;Rihel, Jason;Schier, Alexander F.
多达 10% 的人类患有慢性睡眠障碍，但调节睡眠的遗传机制基本上仍然未知。因此，开发简单且具有成本效益的脊椎动物模型来研究睡眠的基因调控至关重要。最具特征的哺乳动物睡眠/觉醒调节剂是下丘脑分泌素/食欲素 (Hcrt)，其缺失会导致睡眠障碍发作性睡病，并且还与进食行为、能量稳态、体温调节、奖励寻求、成瘾和母性行为有关。在这里，我们报告胚胎和幼虫斑马鱼 Hcrt 神经元的表达模式和轴突投射与哺乳动物中的表达模式和轴突投射惊人地相似。我们发现，斑马鱼幼虫早在发育第五天就表现出强大的运动睡眠/觉醒行为，并且 Hcrt 过度表达可促进和巩固觉醒并抑制休息。与患有失眠症的人类类似，Hcrt 过度表达的幼虫会过度兴奋，并且在夜间启动和维持休息的能力显着降低。值得注意的是，Hcrt 功能受运动活动中正常昼夜节律振荡的调节，但不需要正常昼夜节律振荡。我们的 Hcrt 过度表达斑马鱼模型表明，Hcrt 的祖先功能是促进运动和抑制休息，并将有助于发现调节 Hcrt 功能和睡眠的神经回路、基因和药物。
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.