Genetic and neuronal regulation of sleep by adenosine in zebrafish

描述(申请人提供)：超过10%的美国人患有慢性睡眠障碍，估计每年花费1000亿美元。吸毒和酗酒严重扰乱睡眠，睡眠障碍增加了上瘾和复发的风险。因此，了解调节睡眠的机制对于预防和治疗成瘾至关重要。此外，大多数用于治疗最常见的睡眠障碍失眠的药物都是通过抑制GABA受体发挥作用的，而GABA受体是相对非特异性的睡眠靶点。这些药物只能缓解一些症状，而且往往会上瘾。因此，需要针对更具体的睡眠调节剂的新药。我们最近建立了斑马鱼作为脊椎动物系统，用于研究调节睡眠的遗传和神经机制。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，可以接受高通量的筛查和行为分析。这项提议有四个具体目标。首先，我们将使用遗传和药理学方法来确定哪些腺苷受体调节斑马鱼的睡眠/清醒状态。其次，我们将确定腺苷使用哪些神经底物来调节斑马鱼的睡眠。第三，我们将检验腺苷通过抑制下丘脑泌素系统促进睡眠的假说。第四，我们将验证腺苷通过调节其他睡眠调节系统的活动来调节睡眠的假设。这些实验将阐明腺苷如何调节睡眠，这可能为睡眠障碍的基础提供线索，并为睡眠障碍和成瘾提供新的治疗方法。

DESCRIPTION (provided by applicant): Over 10% of Americans suffer from chronic sleep disorders, with an estimated annual cost of $100 billion. Drug and alcohol addiction severely disrupt sleep, and sleep disorders increase the risk of addiction and relapse. Understanding the mechanisms that regulate sleep is thus critical for preventing and treating addiction. Furthermore, most drugs used to treat insomnia, the most common sleep disorder, act by inhibiting GABA receptors, which are relatively non-specific targets for sleep. These drugs only ameliorate some symptoms and are often addictive. Thus, new drugs that target more specific sleep regulators are needed. We recently established zebrafish as a vertebrate system for studying the genetic and neural mechanisms that regulate 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 screens and behavior assays. This proposal has four specific aims. First, we will use genetic and pharmacological approaches to determine which adenosine receptors regulate zebrafish sleep/wake states. Second, we will determine which neural substrates are used by adenosine to regulate zebrafish sleep. Third, we will test the hypothesis that adenosine promotes sleep by inhibiting the Hypocretin system. Fourth, we will test the hypothesis that adenosine regulates sleep by modulating the activities of other sleep regulatory systems. These experiments will clarify how adenosine regulates sleep, which may provide clues to the basis of sleep disorders and suggest novel therapies for sleep disorders and addiction.