Cross-Species Analyses of the Molecular and Circuit Basis ofSleep

睡眠分子和电路基础的跨物种分析

• 批准号: 10885432
• 负责人: Mark N Wu
• 金额: $ 2.12万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2029-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10885432
• 关键词: Address; Animals; Arousal; Astrocytes; Behavior; Behavioral; Cells; Code; Dedications; Disease; Drosophila genus; Electrophysiology (science); Future; Genetic study; Goals; Homeostasis; Human; Investigation; Mediating; Methods; Molecular; Molecular Analysis; Multimodal Imaging; Mus; Nature; Neurobiology; Neuronal Plasticity; Neurons; Neurosciences Research; Pathway interactions; Physiology; Process; Program Research Project Grants; Regulation; Research; Role; Sleep; Sleep Disorders; Sleep disturbances; Somnambulism; Study models; Time; Work; circadian; circadian pacemaker; circadian regulation; human morbidity; imaging modality; improved; insight; multidisciplinary; neural; neural circuit; neurophysiology; novel strategies; sleep behavior; sleep regulation; suprachiasmatic nucleus

Summary Sleep is an enigmatic behavior that is conserved across the animal kingdom. The mechanisms underlying the regulation of sleep remain poorly understood, and the function of sleep is even more elusive. Yet, dysregulation of sleep is a major cause of human morbidity, and understanding why we sleep is a fundamental question in neuroscience research. We propose that gaining a deep understanding of sleep requires studying this process across molecular, circuit, neurophysiological, and behavioral levels. To accomplish this, our group has been using a multidisciplinary, cross-species approach (Drosophila and mice) to study sleep. The recent work of our group has coalesced around two main themes: how circadian time organizes sleep and arousal and how dedicated neural circuits encode homeostatic drive. Our investigations into these processes have led to new insights into 1) the conserved molecular mechanisms mediating the circadian regulation of sleep and arousal; 2) how different types of neural codes impact plasticity and behavior; and 3) how sleep drive is generated, released, and persists in time. In this research program project, we will build upon our prior studies of the circadian and homeostatic regulation of sleep and develop new approaches to investigate the neurophysiology and function of sleep. First, we will address whether the temporal coding mechanisms found in Drosophila clock neurons are also conserved in the mammalian suprachiasmatic nucleus. Compared to our understanding of the circadian clock, much less is known about the homeostatic regulation of sleep. Nevertheless, we predict that the nature of neural circuits underlying sleep homeostasis will be conserved, and we will seek to identify a sleep homeostatic integrator circuit in mice. Our studies of the cellular mechanisms mediating sleep homeostasis have led us to examine the role of astrocytes in sleep behavior. We plan to determine whether sleep-regulating molecular pathways in these cells are conserved and will perform systematic investigations into the role of astrocytes in regulating neuronal physiology and behavior. To fully exploit the power of the Drosophila model for studying sleep, we will develop a new multimodal imaging method for characterizing and quantifying sleep. Our research has largely focused on how sleep is regulated, but in the future will also address the function of sleep in neural plasticity using a simple, defined circuit and new electrophysiological methods. Finally, we are extending our studies into human disorders, including studying the genetic basis of familial sleepwalking. Our goal is to not only delineate conserved mechanisms underlying sleep and its function, but also to uncover fundamental neurobiological principles governing these processes.

总结 睡眠是一种神秘的行为，在动物王国中是保守的。的作用机制 对睡眠的调节仍然知之甚少，睡眠的功能更是难以捉摸。然而， 睡眠失调是人类发病的主要原因，了解我们为什么睡觉是一个基本的 神经科学研究中的问题。我们认为，要想深入了解睡眠， 这个过程跨越分子、电路、神经生理学和行为水平。为了实现这一目标，我们的团队 一直在使用多学科，跨物种的方法（果蝇和小鼠）来研究睡眠。近期 我们小组的工作围绕着两个主题：昼夜节律时间如何组织睡眠和觉醒 以及专用神经回路如何编码自我平衡驱动。我们对这些过程的调查 对1）介导睡眠昼夜节律调节的保守分子机制的新见解 唤醒; 2）不同类型的神经代码如何影响可塑性和行为;以及3）睡眠驱动如何 生成，释放，并持续时间。在这个研究项目中，我们将建立在我们以前的研究基础上， 的昼夜节律和睡眠的自我平衡调节，并开发新的方法来研究 神经生理学和睡眠功能。首先，我们将讨论是否时间编码机制发现， 在果蝇中，哺乳动物的视交叉上核中的时钟神经元也是保守的。比起我们 由于对生物钟的了解，对睡眠的稳态调节知之甚少。 尽管如此，我们预测睡眠稳态背后的神经回路的性质将是保守的， 我们将寻求识别小鼠中的睡眠稳态积分电路。我们对细胞机制的研究 调节睡眠稳态的研究使我们研究了星形胶质细胞在睡眠行为中的作用。我们计划 确定这些细胞中的睡眠调节分子通路是否是保守的， 对星形胶质细胞在调节神经元生理和行为中的作用的系统研究。充分 利用果蝇模型研究睡眠的力量，我们将开发一种新的多模态成像技术， 用于表征和量化睡眠的方法。我们的研究主要集中在睡眠是如何调节的， 但在未来，他还将使用一种简单的、定义明确的电路来解决睡眠在神经可塑性中的作用， 新的电生理学方法。最后，我们正在将研究扩展到人类疾病，包括 研究家族性梦游症的遗传基础我们的目标不仅是描绘保守的机制， 潜在的睡眠及其功能，但也揭示了基本的神经生物学原则，管理这些 流程.