Functional and Developmental Analysis of Sleep Drive Circuitry

睡眠驱动电路的功能和发展分析

• 批准号: 10456631
• 负责人: Matthew Philip Brown
• 金额: $ 4.68万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456631
• 关键词: Address; Adult; Affect; Age; Animal Model; Automobile Driving; Behavior; Behavioral; Brain; Calcium; Characteristics; Chronic; Code; Data; Development; Drosophila genus; Drosophila melanogaster; Electrophysiology (science); Environment; Exhibits; Future; Generations; Genes; Health; Human; Image; Imaging Techniques; Impairment; Knowledge; Life; Mediating; Membrane Potentials; Mentorship; Molecular; Morphology; Neurodevelopmental Disorder; Neurons; Neurosciences Research; Phenotype; Phylogeny; Physiological; Play; Population; Positioning Attribute; Process; RNA Interference; RNA interference screen; Research; Research Activity; Role; Signal Transduction; Sleep; Sleep Deprivation; Synapses; Testing; Training; Training Activity; Work; analog; behavioral outcome; career; cholinergic; circadian pacemaker; critical period; experimental study; fly; grasp; insight; juvenile animal; mature animal; nervous system development; neural circuit; neurodevelopment; neuromechanism; neurotransmission; novel; patch clamp; postsynaptic; reconstitution; sleep behavior; sleep pattern; sleep regulation; tool; treatment strategy

1. Abstract Sleep is a behavior that is critical for maintaining human health, and its importance is underscored by its conservation across phylogeny. Much of the research on the neural mechanisms underlying sleep has been performed in adults. However, sleep is distinctly different in young animals and may play a key role in proper development of the nervous system. Not only do young animals of nearly all species sleep more than mature adults, this sleep is deeper and more consolidated. It is thought that this longer and deeper sleep may either be a consequence of and/or contribute to the greater developmental and plastic processes occurring in the brains of young animals. However, how this sleep of young animals is regulated is poorly understood, and how it contributes to the proper development of neural circuits remains understudied. Our lab recently discovered a group of neurons that control homeostatic sleep drive in mature animals. These neurons become highly active after sleep deprivation to trigger homeostatic rebound sleep in mature animals and are both necessary and sufficient for sleep drive. Intriguingly, we also found that these sleep drive neurons are highly active at baseline in young animals. These data, along with additional preliminary findings, have led me to hypothesize that this sleep drive circuit is responsible for inducing high baseline sleep in young animals and that this circuit undergoes a developmental switch to only control homeostatic sleep rebound in adults. My additional preliminary data also suggest that loss of sleep in young animals impairs normal sleep patterns in adults. Thus, I also hypothesize that ontogenetic sleep (sleep during development) plays an important role in proper development of sleep drive circuitry. In Aim 1, I propose to study this sleep drive circuit to address the molecular, cellular, and physiological mechanisms regulating sleep in young animals. In Aim 2, I will investigate the role of putative downstream sleep effector neurons in ontogenetic sleep and also ask whether ontogenetic sleep, in turn, affects the development of this sleep drive circuit. The experiments proposed in the above aims will help fill a significant gap in our knowledge about the neural circuitry controlling sleep throughout development. In addition, the resulting findings may deepen our understanding of the molecular and circuit principles governing generation of sleep drive more broadly. Importantly, performing this work will provide me with a strong conceptual and technical training in sleep and neural circuit analyses underlying behavior. With the support of my proposed mentorship team and the outstanding training environment, the research and training activities proposed here will ideally position me for a future career in academic neuroscience research.

1. 摘要 睡眠是一种对维持人类健康至关重要的行为，其重要性通过其 跨系统发育的保护。许多关于睡眠神经机制的研究 在成人中进行。然而，幼年动物的睡眠明显不同，并且可能在正常睡眠中发挥关键作用。 神经系统的发育。不仅几乎所有物种的幼年动物都比成年动物睡眠时间更长 成年人，这种睡眠更深、更巩固。人们认为这种更长更深的睡眠可能是 大脑中发生的更大的发育和可塑过程的结果和/或促成 的幼小动物。然而，人们对幼年动物的睡眠是如何调节的以及它是如何调节的却知之甚少。 对神经回路正常发育的贡献仍有待研究。我们的实验室最近发现了一个 控制成熟动物稳态睡眠驱动的神经元群。这些神经元变得高度活跃 睡眠剥夺后触发成熟动物体内平衡反弹睡眠，既是必要的，也是 足够睡眠驱动。有趣的是，我们还发现这些睡眠驱动神经元在基线时高度活跃 在幼小的动物中。这些数据以及其他初步发现使我推测这 睡眠驱动电路负责诱导幼年动物的高基线睡眠，并且该电路经历 仅控制成人稳态睡眠反弹的发育开关。我的额外初步数据也 研究表明，幼年动物的睡眠不足会损害成年动物的正常睡眠模式。因此，我也假设 个体发生睡眠（发育过程中的睡眠）在睡眠内驱力的正常发育中起着重要作用 电路。在目标 1 中，我建议研究这种睡眠驱动电路，以解决分子、细胞和生理学问题 调节幼年动物睡眠的机制。在目标 2 中，我将研究假定的下游睡眠的作用 个体发生睡眠中的效应神经元，并询问个体发生睡眠是否反过来影响发育 这个睡眠驱动电路。上述目标中提出的实验将有助于填补我们的重大空白 关于在整个发育过程中控制睡眠的神经回路的知识。此外，由此得出的结果 可能会加深我们对控制睡眠驱动力产生的分子和电路原理的理解 广泛地说。重要的是，执行这项工作将为我提供强有力的睡眠概念和技术培训 神经回路分析潜在的行为。在我提议的导师团队和 出色的培训环境，这里提出的研究和培训活动将为我提供理想的定位 未来从事学术神经科学研究的职业。