Neural circuit control of fluid and solute clearance during sleep

项目摘要：本项目旨在确定控制动脉周围神经回路的机制 脑脊液（CSF）泵送和流体和溶质的胶质淋巴清除。我们已经开发出一种 合作，在几个尺度上量化人类和小鼠的CSF转运动力学， 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驱动着血容量的整体和局部变化，这反过来又是 CSF运输的主要驱动因素。我们的模型建立了一个新的概念框架，即神经元 神经回路通过对星形胶质细胞和血管系统的影响来控制清除， 跨空间尺度和物种的假设。 项目1将建立定量流体动力学模型，以确定动脉扩张，介导的 神经活动驱动动脉周围CSF泵送和跨长度尺度的胶质淋巴流出。两种小鼠的模型 而人类，通过项目2 - 4中的实验，将推动这些项目中的假设进行测试。 项目2将剖析神经活动如何将Ca 2 +/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。病毒标记组合 单个细胞群的光遗传学刺激将揭示对CSF流动的神经效应，通过 粒子追踪该项目还将提供第一个将动脉周围CSF流入与 胶质淋巴溶质清除率。项目3将剖析局部神经和全局神经调节驱动程序， 使用光遗传学和化学遗传学操作的NREM睡眠期间的血管动力学。此外，当地和 将对睡眠期间的整体动脉动力学进行成像，提供有关CSF血管泵送的关键信息 运动项目4将使用基于MRI的新技术来确定神经活动和大规模流体 在人脑中是相互联系的。通过感官刺激和成像来驱动局部神经活动 自发神经血管和CSF动力学跨越唤醒状态，它将测试如何特定的时空 神经活动模式影响清醒和NREM睡眠中的血液动力学和CSF流动。的项目 将由专注于病毒工具，数据科学和管理的核心提供支持，所有这些都由 内部和外部咨询委员会。 这些项目将共同提供对神经机制的定量，基于电路的理解 控制睡眠期间的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.