U19NS128613

Neural Circuit Control of Fluid and Solute Clearance During Sleep - 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 vasoconstriction 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.

University Of Rochester

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.273 - Alcohol Research Programs

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

National Institute on Alcohol Abuse and Alcoholism (NIAAA) [HHS - NIH]

Rochester, New York 14642 United States

Single Zip Code

BRAIN Initiative: Team-Research BRAIN Circuit Programs - TeamBCP (U19 Clinical Trial Not Allowed) (RFA-NS-19-003)

Amendment Since initial award the total obligations have increased 272% from $2,492,498 to $9,264,577.