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

• 批准号: 10516497
• 负责人: Patrick James Drew
• 金额: $ 249.25万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 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/10516497
• 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; 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; base; cell type; cerebrospinal fluid flow; designer receptors exclusively activated by designer drugs; driving force; experimental study; fluid flow; glymphatic clearance; glymphatic system; hemodynamics; imaging approach; locus ceruleus structure; network models; neural circuit; neural patterning; neuromechanism; neuronal circuitry; neuroregulation; neurovascular; neurovascular coupling; neurovascular unit; non rapid eye movement; novel; optical imaging; optogenetics; particle; programs; relating to nervous system; response; simulation; solute; spatiotemporal; tool; two photon microscopy; wasting

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：本项目旨在确定控制动脉周围神经回路的机制