Glymphatic modulation of sleep dependence
Abstract
We have recently described a macroscopic pathway in the central nervous system – the glymphatic system - that facilitates the clearance of interstitial waste products of neuronal metabolism. Glymphatic clearance of macromolecules is driven by cerebrospinal fluid (CSF) that flows into brain along para-arterial spaces and through the brain parenchyma via support from astroglial aquaporin-4 water channels. The glymphatic circulation constitutes a complete anatomical pathway; para-arterial CSF exchanges with the interstitial fluid, solutes collect along para-venous spaces, and then drain into the vessels of the lymphatic system for ultimate excretion by the kidney or degradation in the liver. The glymphatic system is regulated by the sleep-wake cycle and is primarily active during sleep, raising the question as to whether glymphatic clearance of neurotoxic waste products during sleep explain why all species, including humans, spend a large fraction of their lives sleeping and why lack of sleep impairs cognitive function. Manipulation of the glymphatic clearance is therefore of considerable interest, as it may define entirely new approaches for enhancing sleep quality and reducing or delaying the need for sleep. The glymphatic system also represents a novel and unexplored target for preventing the harmful effects of sleep deprivation, which is known to accelerate the progression of neurodegenerative diseases. The proposed experiments will in Aim 1 define the astrocytic and neuronal membrane transporters and pumps that drive glymphatic fluxes of water and solutes during sleep using transcriptome analysis. Aim 2 will use whole body gamma counter for detection of radiolabeled tracer to track glymphatic influx and efflux. The movement of radiolabeled tracers (125I-amyloid- ?) will be compared in control mice and following pharmacological inhibition of the main transporters and pumps expressed by astrocytes, including NKCC1 (Na-K-Cl cotransporter 1). Aim 3 will use pharmacological tools to increase glymphatic clearance during sleep. These experiments will be combined with EEG/video recordings to evaluate whether a transient increase in glymphatic clearance can reduce or eliminate the need for rebound sleep. We are particularly interested in defining whether manipulation of glymphatic clearance can reduce the homeostatic need for sleep and/or improve the cognitive deficits in mice exposed to sleep deprivation. The proposed experiments take advantage of the expertise in the glymphatic system, at the University of Rochester Medical Center.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 12, 2016
- Source ID
- N000141512016
Entities
People
- Maiken Nedergaard
Organizations
- Office of Naval Research
- United States Navy
- University of Rochester