Neural circuit control of fluid and solute clearance during sleep

睡眠期间液体和溶质清除的神经回路控制

基本信息

批准号：
10673147
负责人：
Patrick James Drew
金额：
$ 241.76万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10673147
关键词：
Advisory Committees Affect Arousal Arteries Astrocytes Automobile Driving Biological Blood Blood Vessels Blood Volume Brain Cell Nucleus Cells Cephalic Cerebrospinal Fluid Collaborations Compensation Coupled Cyclic AMP Data Science Dimensions Elements Event Excision Fiber G-Protein-Coupled Receptors Human Hyperemia Image Individual Kinetics Length Link Liquid substance Magnetic Resonance Imaging Maps Measurement Measures Mediating Metabolic Microspheres Modeling Monitor Movement Mus Neurons Opsin Optics Photometry Population Production Property Pump Rodent Role Sensory Shapes Signal Transduction Sleep Smooth Muscle Myocytes Subarachnoid Space Techniques Testing Transport Process Variant Vibrissae Viral Wakefulness Work basal forebrain cell type cerebrospinal fluid flow designer receptors exclusively activated by designer drugs driving force experimental study fluid flow genetic manipulation glymphatic clearance glymphatic system hemodynamics imaging approach locus ceruleus structure network models neural neural circuit neural patterning neuromechanism neuronal circuitry neuroregulation neurovascular neurovascular coupling neurovascular unit non rapid eye movement novel optical imaging optogenetics particle programs response simulation solute spatiotemporal tool transmission process two photon microscopy wasting

项目摘要

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.

项目摘要：该提案旨在确定控制动脉周围神经的神经回路机制脑脊液 (CSF) 泵送以及液体和溶质的类淋巴清除。我们开发了一个合作量化人类和小鼠脑脊液在多个尺度上的运输动态，涵盖分子运输、神经元和神经胶质活动、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全局和局部的血容量变化，这反过来又是 CSF 运输的主要驱动力。我们的模型建立了一个新颖的概念框架，即神经元电路通过对星形胶质细胞和脉管系统的影响来控制清除，打开一系列可测试的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，以确定动脉扩张是如何介导的神经活动，驱动动脉周围脑脊液泵送和跨长度尺度的类淋巴流出。两只小鼠的模型人类根据项目 2-4 中的实验，将推动在这些项目中测试假设。项目 2 将剖析神经活动如何将 Ca2+/cAMP 信号传导至神经血管单元，从而改变血管周围空间的物理尺寸和功能特性。病毒标签组合通过对单个细胞群进行光遗传学刺激，将揭示对脑脊液流量的神经效应，通过测量来测量粒子追踪。该项目还将提供第一个将动脉周围脑脊液流入与类淋巴管溶质清除率。项目 3 将剖析局部神经和全局神经调节驱动因素使用光遗传学和化学遗传学操作来研究 NREM 睡眠期间的血管动力学。此外，本地和睡眠期间的整体动脉动态将被成像，提供有关脑脊液血管泵送的关键信息移动。项目 4 将使用基于 MRI 的新型技术来确定神经活动和大规模流体如何人脑中的流动是相互联系的。通过感觉刺激和成像来驱动局部神经活动跨唤醒状态的自发神经血管和脑脊液动力学，它将测试特定的时空神经活动模式影响清醒和 NREM 睡眠中的血流动力学和脑脊液流量。项目将得到专注于病毒工具、数据科学和管理的核心的支持，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。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hydraulic resistance of three-dimensional pial perivascular spaces in the brain.

大脑中三维软脑膜血管周围空间的液压阻力。

DOI：
发表时间：
2024-01-11
期刊：
影响因子：
0
作者：
Boster, Kimberly A S;Sun, Jiatong;Shang, Jessica K;Kelley, Douglas H;Thomas, John H
通讯作者：
Thomas, John H

Artificial intelligence velocimetry reveals in vivo flow rates, pressure gradients, and shear stresses in murine perivascular flows.

人工智能测速揭示了小鼠血管周围流动的体内流速、压力梯度和剪切应力。

DOI：
发表时间：
2023-04-04
期刊：
影响因子：
11.1
作者：
Boster, Kimberly A S;Cai, Shengze;Ladrón;Sun, Jiatong;Zheng, Xiaoning;Du, Ting;Thomas, John H;Nedergaard, Maiken;Karniadakis, George Em;Kelley, Douglas H
通讯作者：
Kelley, Douglas H

Locomotion Induces Fundamentally Different Patterns of Ca2+ Signaling in Astrocytes and Neurons.

运动会在星形胶质细胞和神经元中诱导出根本不同的 Ca2 信号传导模式。