Genetic and neuronal regulation of sleep by adenosine in zebrafish

腺苷对斑马鱼睡眠的遗传和神经元调节

• 批准号: 8085039
• 负责人: David Aaron Prober
• 金额: $ 35.06万
• 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: 2011-09-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8085039
• 关键词: Adenosine; Aequorin; Affect; Agonist; Alcohol dependence; American; Animals; Arousal; Behavior; Biological Assay; Brain; Chronic; Circadian Rhythms; Conflict (Psychology); Disease; Drosophila genus; Drug Addiction; Drug Delivery Systems; Drug usage; ERG gene; Ethers; FOS gene; GABA Receptor; Gene Structure; Genetic; Immunosuppressive Agents; In Situ Hybridization; L-Type Calcium Channels; Larva; Life; Link; Luminescent Proteins; Mammals; Mediating; Melatonin; Molecular; Monitor; Mutate; Nervous system structure; Neurologic; Neurons; Neurotransmitters; Orthologous Gene; Pathway interactions; Pharmaceutical Preparations; Polysomnography; Potassium Channel; Purinergic P1 Receptors; Recovery; Regulation; Relapse; Reporting; Risk; Role; Signal Transduction; Sleep; Sleep Deprivation; Sleep Disorders; Sleep Disorders Therapy; Sleep Wake Cycle; Sleeplessness; Study models; Symptoms; System; Testing; Therapeutic; Wakefulness; Zebrafish; addiction; base; calcium indicator; cost; high throughput screening; hypocretin; improved; mutant; neural circuit; neuromechanism; novel; prevent; receptor; relating to nervous system; research study; sleep regulation; small molecule

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. PUBLIC HEALTH RELEVANCE: 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. This proposal will use zebrafish to determine the genetic and neurological mechanisms through which adenosine regulates sleep. The proposed studies will improve understanding of the genetic and neuronal mechanisms that regulate sleep and may suggest new strategies to treat sleep and addiction disorders.

超过10%的美国人患有慢性睡眠障碍，估计每年的费用为1000亿美元。药物和酒精成瘾严重扰乱睡眠，睡眠障碍会增加成瘾和复发的风险。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，大多数用于治疗失眠（最常见的睡眠障碍）的药物通过抑制GABA受体起作用，而GABA受体是相对非特异性的睡眠靶点。这些药物只能改善某些症状，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。我们最近将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，因为它们具有被认为调节哺乳动物睡眠的基本大脑结构和基因，但也是光学透明的，适合高通量筛选和行为测定。这项建议有四个具体目标。首先，我们将使用遗传和药理学方法来确定腺苷受体调节斑马鱼的睡眠/觉醒状态。其次，我们将确定腺苷用于调节斑马鱼睡眠的神经底物。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设。第四，我们将检验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。 公共卫生相关性：药物和酒精成瘾严重扰乱睡眠，睡眠障碍增加成瘾和复发的风险。因此，了解调节睡眠的机制对于预防和治疗成瘾至关重要。这项提案将使用斑马鱼来确定腺苷调节睡眠的遗传和神经机制。这些研究将提高对调节睡眠的遗传和神经机制的理解，并可能提出治疗睡眠和成瘾障碍的新策略。