How sleep clears your brain: Slow waves, glymphatic waste removal, and synaptic down-selection
Abstract
In this MURI application, a team of researchers at the University of Rochester and the University of Wisconsin-Madison propose a project entitled, ÒHow sleep clears your brain: Slow waves, glymphatic waste removal, and synaptic down-selection.Ó The application is submitted to the Department of Defense Multidisciplinary Research Program of the University Research Initiative in response to ARO Announcement # W911NF18S0003, FY2018 MURI Topic #9. We propose that sleep clears the brain and restores cognitive function through a process of two flows: neuronal flow and fluid flow. During non-rapid-eye-movement (NREM) sleep, slow-wave activity (SWA) and the underlying neuronal ON/OFF activity flow along neural pathways, clearing excess synapse strength; while the underlying ionic movements responsible for ON/OFF activity (depolarization-repolarization) promote the glymphatic fluid flow that clears metabolic waste, including amyloid-beta and tau. This proposal combines two novel and complementary hypotheses explaining the need for sleep across all species, including humans: (1) the synaptic strength that builds up during wakefulness is preferentially downregulated during NREM sleep (the synaptic homeostasis hypothesis, SHY); and (2) the metabolic waste that builds up during wakefulness can only be cleared during NREM sleep (the glymphatic model). Both excess synaptic strength and metabolic waste are the unavoidable price to pay to sustain high neuronal activity and plasticity during wakefulness, because synaptic plasticity requires neuronal activity, but neuronal activity generates metabolic waste. We further hypothesize that the mechanisms of both flows are causally linked because SWA drives changes in ions that promote fluid flow in the direction from frontal to posterior cortex. To establish the role of SWA in neuronal and fluid flow, we will combine 2-photon and wide-field optical imaging of glymphatic tracers, particle-tracking and front-tracking velocimetry, SWA imaging, high-density recordings of neural activity using silicon probes, and quantification of synaptic down-selection using molecular and ultrastructural markers of synaptic strength. We will create a brain-wide hydraulic network model of glymphatic fluid flow and test this model by increasing or decreasing SWA activity on global and local scales using several approaches, including optogenetics and chemogenetics. Understanding how brain fluid flow interacts with synaptic homeostasis and neural circuit mechanisms will provide new, transformative insight into the restorative function of sleep and the detrimental effects of sleep deprivation or circadian dysregulation on cognitive performance. Our goal is to provide a basis for the development of glymphatic manipulations that can enhance performance and prevent or delay the onset of neurodegenerative diseases. Prof. Maiken Nedergaard will serve as the principal investigator and will direct the overall project, coordinate activities and semi-annual meetings, and maintain contact with the DOD Research Office. She will also be responsible for collection of all data requiring optical imaging of glymphatic function and Ca2+ in vivo. Profs. Douglas Kelley and John Thomas will oversee the detailed fluid-dynamic modeling and development of the global hydraulic-network model, and interpret the imaging of neuronal Ca2+ activity in different brain states in mice. Profs. Chiara Cirelli and Giulio Tononi will oversee the high-density recordings of neural activity, opto/chemogenetic manipulation of SWA, analysis of synaptic homeostasis using multiple alternative approaches, and cognitive measures. The entire team of researchers will combine the glymphatic flow measurements with imaging of cortical activity in mice and chronic recordings of cortical neuronal activity in order to test the predictive capabilities of the fluid-dynamic and hydraulic-network models.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 29, 2019
- Source ID
- W911NF1910280
Entities
People
- Maiken Nedergaard
Organizations
- Army Contracting Command
- United States Army
- University of Rochester