Cross-Species Analyses of the Molecular and Circuit Basis ofSleep

摘要 睡眠是一种神秘的行为，在整个动物界都是保守的。其背后的机制是 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一个主要原因，而了解我们睡眠的原因是一个基本的 神经科学研究中的问题。我们认为，要想深入了解睡眠需要研究 这个过程跨越分子、电路、神经生理和行为水平。为了做到这一点，我们的团队 一直在使用多学科、跨物种的方法(果蝇和老鼠)来研究睡眠。最近的 我们小组的工作围绕两个主题展开：昼夜节律如何组织睡眠和唤醒 以及专用神经回路如何编码体内平衡驱动力。我们对这些过程的调查导致了 对1)调节睡眠昼夜节律的保守分子机制和 唤醒；2)不同类型的神经编码如何影响可塑性和行为；以及3)睡眠驱动如何 及时生成、发布并持续存在。在这个研究项目中，我们将在以前研究的基础上再接再厉 睡眠的昼夜节律和动态平衡调节，并开发新的方法来研究 睡眠的神经生理学和功能。首先，我们将讨论是否发现了时态编码机制 在果蝇中，哺乳动物视交叉上核中的时钟神经元也是保守的。与我们的 对生物钟的了解，对睡眠的稳态调节知之甚少。 然而，我们预测睡眠稳态背后的神经回路的性质将是保守的，并且 我们将寻求在小鼠身上识别睡眠内稳态积分回路。我们对细胞机制的研究 调节睡眠动态平衡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保守并将执行 系统研究星形胶质细胞在调节神经元生理和行为中的作用。充分地 利用果蝇模型研究睡眠的力量，我们将开发一种新的多模式成像 描述和量化睡眠的方法。我们的研究主要集中在睡眠是如何调节的， 但在未来还将使用一个简单的、定义的电路和 新的电生理学方法。最后，我们正在将我们的研究扩展到人类疾病，包括 研究家族性梦游的遗传基础。我们的目标不仅是描述保守的机制 潜在的睡眠及其功能，但也揭示了支配这些的基本神经生物学原理 流程。

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.