Mechanisms that regulate zebrafish Hypocretin neuron development and function

调节斑马鱼下丘脑分泌素神经元发育和功能的机制

• 批准号: 8788069
• 负责人: David Aaron Prober
• 金额: $ 34.34万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8788069
• 关键词: Adenosine; Affect; American; Anatomy; Arousal; Behavior; Biological Assay; Biological Models; Brain; Chronic; Chronic Insomnia; Data; Development; Disease; Exhibits; Foundations; Future; Gene Structure; Genes; Genetic; Goals; Health; Human; Hypothalamic structure; Image; Larva; Lead; Life; Mammals; Maps; Mediating; Melatonin; Modeling; Motor Activity; Narcolepsy; Neurons; Neuropharmacology; Neurotransmitters; Pharmaceutical Preparations; Potassium Channel; Relative (related person); Research; Signal Transduction; Sleep; Sleep Disorders; Study models; System; Techniques; Testing; Therapeutic; Wakefulness; Zebrafish; base; cost; cost effective; dopaminergic neuron; effective therapy; hypocretin; improved; meetings; neural circuit; neuromechanism; neuron development; neuroregulation; noradrenergic; novel; novel therapeutic intervention; overexpression; relating to nervous system; research study; sleep regulation; small molecule

DESCRIPTION (provided by applicant): Over 10% of humans suffer chronic sleep disorders, but the genetic and neural mechanisms that regulate sleep are poorly understood. The identification of defective Hypocretin/Orexin (Hcrt) signaling as a cause of narcolepsy provided a genetic entry point into sleep research, but an effective treatment for this disorder has not yet been found. Moreover, only a small fraction of sleep disorders are associated with narcolepsy, indicating that additional genes and neurons that control sleep and wakefulness remain to be identified. The objective of this proposal is to use zebrafish as a simple and cost-effective vertebrate model system to study Hcrt signaling and sleep. Zebrafish are a useful model for these studies because they have the basic brain structures and genes that are thought to regulate mammalian sleep, but are also optically transparent and amenable to high-throughput behavior assays. The proposed research has three aims. First, we will characterize the development of larval zebrafish Hcrt neurons at the single neuron level and test hypotheses about their development. Second, we will use genetic and pharmacological approaches to determine which neurons are activated by Hcrt signaling and which neurotransmitter systems are required for Hcrt-induced wakefulness. Third, we will determine whether other sleep regulators, including adenosine, melatonin, and Kv3-type potassium channels, affect sleep via the Hcrt system. These experiments will improve our understanding of Hcrt neuron development and function, may provide clues to the basis of sleep disorders such as chronic insomnia, and may lead to novel therapies for these disorders.

描述(申请人提供)：超过10%的人患有慢性睡眠障碍，但调节睡眠的遗传和神经机制尚不清楚。发现有缺陷的下丘脑素/食欲素(Hcrt)信号是发作性睡病的原因，这为睡眠研究提供了一个遗传学切入点，但尚未找到治疗这种疾病的有效方法。此外，只有一小部分睡眠障碍与嗜睡症有关，这表明控制睡眠和清醒的其他基因和神经元仍有待识别。这项建议的目的是利用斑马鱼作为一种简单且经济有效的脊椎动物模型系统来研究Hcrt信号和睡眠。斑马鱼是这些研究的有用模型，因为它们拥有被认为调节哺乳动物睡眠的基本大脑结构和基因，但它们也是光学透明的，可以接受高通量的行为分析。这项拟议的研究有三个目标。首先，我们将在单个神经元水平上表征斑马鱼幼体Hcrt神经元的发育，并检验有关其发育的假说。其次，我们将使用遗传学和药理学方法来确定哪些神经元被Hcrt信号激活，以及哪些神经递质系统是Hcrt诱导唤醒所必需的。第三，我们将确定其他睡眠调节剂，包括腺苷、褪黑素和Kv3型钾通道，是否通过HCRT系统影响睡眠。这些实验将提高我们对Hcrt神经元发育和功能的理解，可能为慢性失眠等睡眠障碍的基础提供线索，并可能导致这些疾病的新疗法。