Neural circuit control of fluid and solute clearance during sleep

程序摘要：该提案旨在确定控制动脉周围的神经回路机制。 脑脊液(CSF)抽吸和液体和溶质的淋巴清除。我们已经开发出一种 合作量化脑脊液在人类和小鼠中的传输动力学，跨越多个尺度 分子运输、神经元和神经胶质活性、血管和全脑流体动力学。我们建议 睡眠期间协调的神经活动会推动整体和局部血液容量的变化，而这反过来又是 脑脊液转运的主要驱动力。我们的模型建立了一个新的概念框架，即神经元 电路通过它们对星形胶质细胞和血管系统的影响来控制清除，打开了一系列可测试的 跨越空间尺度和物种的假设。 项目1将建立定量的流体动力学模型，以确定动脉扩张是如何通过 神经活动，驱动动脉周围脑脊液泵送和跨长度尺度的淋巴流出。两种小鼠的模型 人类从项目2-4中的实验中获得了信息，将推动假设在这些项目中进行测试。 项目2将剖析神经活动如何将钙离子/cAMP信号传递到神经血管单位，从而 改变血管周围空间的物理尺寸和功能特性。组合的病毒标签 单个细胞群体的光遗传刺激将揭示神经对脑脊液流量的影响，通过测量 粒子跟踪。该项目还将提供第一个系统分析，将动脉周围脑脊液流入与 淋巴溶质清除。项目3将剖析局部神经和全局神经调节驱动因素 使用光发生和化学发生操作的NREM睡眠期间的血管动力学。此外，本地和 睡眠期间的全球动脉动态将被成像，提供有关脑脊液血管泵的关键信息 有动静。项目4将使用基于核磁共振的新技术来确定神经活动和大规模液体是如何 人脑中的流动是联系在一起的。通过感官刺激和成像来驱动局部神经活动 自发性神经血管和脑脊液在唤醒状态下的动力学，它将测试 在清醒和非快速眼动睡眠中，神经活动模式会影响血流动力学和脑脊液流量。这些项目 将由专注于病毒工具、数据科学和管理的核心提供支持，所有这些核心都由 内部和外部咨询委员会。 总而言之，这些项目将提供对神经机制的定量、基于电路的理解 在睡眠期间控制脑液流动和溶质清除。

Program abstract: This proposal aims to identify the neural circuit mechanisms that control periarterial cerebrospinal fluid (CSF) pumping and glymphatic clearance of fluid and solutes. We have developed a collaboration to quantify CSF transport dynamics in both humans and mice across several scales, spanning molecular transport, neuronal and glial activity, vascular and brain-wide fluid dynamics. We propose that coordinated neural activity during sleep drives global and local changes in blood volume, which in turn are the primary drivers of CSF transport. Our model establishes a novel conceptual framework, namely that neuronal circuits control clearance via their effects on astrocytes and the vasculature, opening an array of testable hypotheses across spatial scales and species. Project 1 will build quantitative fluid-dynamical models to establish how arterial dilation, mediated by neural activity, drives periarterial CSF pumping and glymphatic efflux across length scales. Models for both mice and humans, informed by experiments in Projects 2-4, will drive hypotheses to be tested in those Projects. Project 2 will dissect how neural activity transmits Ca2+/cAMP signaling to the neurovascular unit, thereby altering the physical dimensions and functional properties of the perivascular spaces. Viral tagging combined with optogenetic stimulation of individual cell populations will reveal neural effects on CSF flow, measured by particle tracking. The Project will also provide the first systematic analysis linking periarterial CSF inflow with glymphatic solute clearance. Project 3 will dissect the local neural and global neuromodulatory drivers of vasodynamics during NREM sleep using optogenetic and chemogenetic manipulations. Additionally, local and global arterial dynamics during sleep will be imaged, providing key information on the vascular pumping of CSF movement. Project 4 will use novel MRI-based techniques to establish how neural activity and large-scale fluid flow are linked in the human brain. By driving local neural activity with sensory stimulation, and imaging spontaneous neurovascular and CSF dynamics across arousal states, it will test how specific spatiotemporal patterns of neural activity affect hemodynamics and CSF flow in wakefulness and NREM sleep. The Projects will be supported by Cores focused on Viral Tools, Data Science, and Administration, all overseen by Internal and External Advisory committees. Together, the Projects will provide a quantitative, circuit-based understanding of the neural mechanisms governing brain fluid flow and solute clearance during sleep.