Development and Function of Sleep Circuits

睡眠电路的发展和功能

• 批准号: 9974143
• 负责人: Nicholas Stavropoulos
• 金额: $ 42.44万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9974143
• 关键词: Adult; Affect; Alzheimer' s Disease; Anatomy; Apical; Biological Models; Biology; Brain; Brain region; Chemicals; Clone Cells; Complex; Data; Dendrites; Development; Diagnosis; Drosophila genus; Dystonia; G-Protein-Coupled Receptors; GTP-Binding Protein beta Subunits; Genes; Genetic; Goals; Human; Lead; Life; Link; Mammals; Mitotic; Molecular; Molecular Target; Morphogenesis; Mus; Mushroom Bodies; Mutagenesis; Mutation; Neurodevelopmental Disorder; Neurons; Orthologous Gene; Output; Pathway interactions; Shapes; Sleep; Sleep Disorders; Sleep Wake Cycle; Sleep disturbances; Stroke; Structure; Synapses; Testing; To specify; Ubiquitination; autism spectrum disorder; clinically relevant; cullin-3; fly; in vivo; insight; locomotor control; mutant; nervous system disorder; neuroblast; neuron development; neuronal circuitry; sleep behavior; sleep regulation; sleep regulatory center; ubiquitin ligase

We have little current understanding of the genetic and molecular mechanisms that link brain development and the proper regulation of sleep throughout life. Understanding these mechanisms is a longstanding challenge in sleep biology with great clinical relevance. Neurodevelopmental disorders including autism are prevalent and closely associated with sleep disturbances, but the underlying genetic and neuroanatomical mechanisms remain obscure. Our studies use the powerful Drosophila model system to characterize a conserved genetic pathway whose activity is required during neuronal development for the sleep regulation in adulthood. This pathway is composed of Insomniac (Inc), the Cullin-3 (Cul3) ubiquitin ligase, and their targets. Reduced activity of this pathway in the developing brain severely curtails the duration and consolidation of sleep in adulthood. Our findings suggest that this pathway has two distinct developmental functions that influence the structure and function of the mushroom body, a sleep regulatory center in the fly brain. In Aim 1 we will determine whether inc acts in neuroblasts to control the proliferation and number of sleep-regulatory neurons. We will also validate Inc substrates, including a target that may link Inc to asymmetric neuroblast division. In Aim 2, we will determine whether inc acts post-mitotically to regulate the structure and anatomy of sleep-regulatory neurons. In Aim 3, we will determine how inc affects the function of sleep-regulatory circuits. Because all of the genes under study are conserved and expressed in the mammalian brain, our studies may provide insight into mechanisms underlying normal sleep, sleep dysfunction, and various neurological disorders.

我们目前对连接大脑的遗传和分子机制知之甚少 发展和适当的睡眠调节整个生命。了解这些机制是一个 睡眠生物学的长期挑战，具有很大的临床意义。神经发育障碍，包括 孤独症是普遍存在的，与睡眠障碍密切相关，但潜在的遗传和 神经解剖学机制仍不清楚。我们的研究使用强大的果蝇模型系统， 表征保守的遗传途径，其活性是神经元发育过程中所需的， 成年期的睡眠调节该途径由Insomniac（Inc）、Cullin-3（Cul 3）泛素 连接酶及其靶点。在发育中的大脑中，这种途径的活性降低， 和成年期睡眠的巩固。我们的研究结果表明，这一途径有两个不同的发展， 影响蘑菇体的结构和功能的功能，蘑菇体是苍蝇的睡眠调节中心。 个脑袋在目标1中，我们将确定inc是否作用于神经母细胞以控制细胞的增殖和数量 睡眠调节神经元我们还将验证Inc底物，包括可能将Inc与 成神经细胞分裂不对称。在目标2中，我们将确定inc是否在有丝分裂后调节细胞增殖， 睡眠调节神经元的结构和解剖。在目标3中，我们将确定inc如何影响 睡眠调节回路因为所有研究中的基因都是保守的，并在细胞中表达。 哺乳动物大脑，我们的研究可以提供深入了解正常睡眠，睡眠， 功能障碍和各种神经系统疾病。