Functional and Developmental Analysis of Sleep Drive Circuitry

1.摘要 睡眠是一种对维持人类健康至关重要的行为，其重要性因其 整个系统发展过程中的保守性。关于睡眠背后的神经机制的大部分研究一直是 在成年人身上表演。然而，在幼年动物中，睡眠是明显不同的，可能在适当的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睡得比成熟的多 成年人，这种睡眠更深，更巩固。据认为，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性过程的结果和/或贡献 幼小动物的生命。然而，幼年动物的这种睡眠是如何调节的，以及它是如何调节的，人们对此知之甚少 对神经回路的正确发展的贡献仍未被研究。我们实验室最近发现了一个 在成年动物中，一组控制稳态睡眠的神经元。这些神经元变得高度活跃 在睡眠剥夺后，触发动态平衡恢复睡眠在成熟动物中是必要的和 足以满足睡眠驱动力。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 在幼年动物身上。这些数据，加上其他的初步发现，让我假设这是 睡眠驱动回路负责诱导幼年动物的高基线睡眠，该回路经历 一种只控制成年人体内平衡睡眠反弹的发育转变。我的其他初步数据也 表明幼年动物睡眠不足会损害成年动物的正常睡眠模式。因此，我还假设 个体发生睡眠(发育中的睡眠)对睡眠驱动力的正确发展起着重要作用 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 调节幼年动物睡眠的机制。在目标2中，我将研究假定的下行睡眠的作用 个体发育睡眠中的效应神经元，并询问个体发育睡眠是否反过来影响发育 这一睡眠驱动电路的。上述目标中提出的实验将有助于填补我们在 在整个发育过程中控制睡眠的神经回路的知识。此外，由此得出的发现 可能会加深我们对控制睡眠驱动产生的分子和电路原理的理解 大体上说。重要的是，完成这项工作将为我提供强大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 卓越的培训环境，这里提出的研究和培训活动将使我成为 未来从事学术神经科学研究的职业。

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.