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.

U19 Program Narrative The proposed studies will explore the hypothesis that activation of neurons increases transport of cerebrospinal fluid (CSF) in the perivascular spaces and in the ventricles via neurovascular coupling-mediated arterial dilation. We hypothesize that the transient changes in blood volume, that are most pronounced during sleep, act as a driving force for reciprocal transport of CSF. Studies linking neural activity, blood and CSF transport in the mouse and human brain will use an array of imaging approaches across multiple temporal and spatial scales, and will be unified in a computational fluid flow model.