Genetic Analysis of Histamine Signaling in Larval Zebrafish Sleep.
Genetic Analysis of Histamine Signaling in Larval Zebrafish Sleep.
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DOI：
10.1523/eneuro.0286-16.2017
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发表时间：
2017-01
期刊：
影响因子：
3.4
通讯作者：
Prober DA
中科院分区：
文献类型：
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作者：
Chen A;Singh C;Oikonomou G;Prober DA
对哺乳动物和斑马鱼的药理学研究表明，组胺在促进唤醒方面起着重要作用。然而，使用组胺合成或信号中断的啮齿动物进行的遗传研究仅揭示了轻微或无睡眠/觉醒表型。组胺在哺乳动物觉醒中的功能研究因其在免疫系统细胞中的产生及其在体液和细胞免疫中的作用而变得复杂，这可能对睡眠/觉醒状态产生深远影响。为了避免这种潜在的混淆，我们使用遗传学来探索组胺在调节斑马鱼睡眠中的作用，斑马鱼是一种昼夜活动的脊椎动物，其中组胺的产生仅限于大脑中的神经元。与啮齿动物遗传学研究相似，我们发现由于组氨酸脱羧酶（hdc）突变而缺乏组胺的斑马鱼表现出很大程度上正常的睡眠/觉醒行为。在几种组胺受体中含有预测无效突变的斑马鱼也缺乏强大的睡眠/觉醒表型，尽管我们无法证实这些突变体完全无功能。与一些啮齿类动物的研究一致，我们发现，过度表达神经肽下丘脑泌素（Hcrt）或刺激表达Hcrt的神经元引起的觉醒在hdc或hrh 1突变体中不被阻断。我们还发现，在缺乏组胺或Hcrt信号传导的动物中，表达Hcrt或组胺能神经元的数量分别不受影响。因此，虽然组胺信号的急性药理学操作已被证明对斑马鱼和哺乳动物的睡眠有深远的影响，但我们的研究结果表明，由于基因突变引起的组胺信号的慢性丢失对斑马鱼的睡眠只有微妙的影响，类似于啮齿动物。
Pharmacological studies in mammals and zebrafish suggest that histamine plays an important role in promoting arousal. However, genetic studies using rodents with disrupted histamine synthesis or signaling have revealed only subtle or no sleep/wake phenotypes. Studies of histamine function in mammalian arousal are complicated by its production in cells of the immune system and its roles in humoral and cellular immunity, which can have profound effects on sleep/wake states. To avoid this potential confound, we used genetics to explore the role of histamine in regulating sleep in zebrafish, a diurnal vertebrate in which histamine production is restricted to neurons in the brain. Similar to rodent genetic studies, we found that zebrafish that lack histamine due to mutation of histidine decarboxylase (hdc) exhibit largely normal sleep/wake behaviors. Zebrafish containing predicted null mutations in several histamine receptors also lack robust sleep/wake phenotypes, although we are unable to verify that these mutants are completely nonfunctional. Consistent with some rodent studies, we found that arousal induced by overexpression of the neuropeptide hypocretin (Hcrt) or by stimulation of hcrt-expressing neurons is not blocked in hdc or hrh1 mutants. We also found that the number of hcrt-expressing or histaminergic neurons is unaffected in animals that lack histamine or Hcrt signaling, respectively. Thus, while acute pharmacological manipulation of histamine signaling has been shown to have profound effects on zebrafish and mammalian sleep, our results suggest that chronic loss of histamine signaling due to genetic mutations has only subtle effects on sleep in zebrafish, similar to rodents.