Virtually unique among somatic tissues, the brain and spinal cord lack a lymphatic system. Despite the high metabolic activity and fragility of neural tissue, there exists no effective understanding of the means by which interstitial fluid and waste products are removed from the CNS. Our preliminary analysis, based on in vivo two- photon imaging, shows that low molecular weight tracers delivered to the CSF circulate surprisingly rapidly through the mouse brain, and do so along a surprising anatomical route. This consists of a para-arterial inflow path, a trans-glial intra-parenchymal path of interstitial flow, and a para-venous outflow path. Within the intra- parenchymal pathway, astrocytes support convective fluid currents through the brain interstitial space, as deletion of the astrocytic water channel AQP4 sharply reduces overall tracer flow along these routes. Given the continuous movement of fluid supported by this pathway, and its critical dependence upon astrocytic water transport, we propose that this system - which we designate here the 'glymphatic system'- subserves a function homologous to the peripheral lymphatic system, and is essential for the clearance of metabolic waste products from the CNS.
Aim 1 will use 2-photon in vivo microscopy to assess the spatial dynamics and temporal kinetics of fluorophore-tagged tracer clearance. By systematically comparing the effect of modifications of molecular sizes or surface charge upon tracer clearance, we will define the basic transport properties of the glymphatic system.
Aim 2 will extend the preliminary observation that aged mice exhibit a striking decline in glymphatic system function, and evaluate the role of age-related suppression of arterial wall pulsation and resulting reduced convective inflow along the para-arterial path and global glymphatic fucntion.
Aim 3 proposes that induced knock-out of either astrocytic AQP4 water channels or gap junctions (Cx43/Cx30) will slow parenchymal convective fluid flow and globally suppress tracer clearance.
Aim 4 tests the proposition that suppression of trans-astroglial fluid movement resulting from AQP4 or Cx43/Cx30 deletion will slow clearance of exogenous A? and thereby potentiate age-related amyloid plaque formation. We predict that slowing astrocytic parenchymal fluid flow will accelerate paravascular amyloid deposition, which in a feed- forward manner will further reduce the efficiency of clearance of waste products by the glymphatic system. To our knowledge, these studies represent the first attempt to systematically define the mechanisms involved in the clearance of metabolic waste products from the brain on a whole-organ level. Two-photon imaging of through chronic cranial windows will allow imaging of tracer clearance in real time, whereas transgenic mice with inducible deletion of key astroglial membrane proteins will establish the functional role of astrocytes in glymphatic transport. Combined, these studies will provide fundamental insight into the mechanisms contributing to age-related accumulation of neurotoxic metabolic waste products and define novel, and likely highly important, functional properties of astrocytes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS078304-02
Application #
8411974
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Corriveau, Roderick A
Project Start
2012-01-15
Project End
2016-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
2
Fiscal Year
2013
Total Cost
$326,140
Indirect Cost
$115,046
Name
University of Rochester
Department
Neurology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Ding, Fengfei; O'Donnell, John; Xu, Qiwu et al. (2016) Changes in the composition of brain interstitial ions control the sleep-wake cycle. Science 352:550-5
Rasmussen, Rune; Nedergaard, Maiken; Petersen, Nicolas Caesar (2016) Sulforhodamine 101, a widely used astrocyte marker, can induce cortical seizure-like activity at concentrations commonly used. Sci Rep 6:30433
Xie, Lulu; Kang, Hongyi; Nedergaard, Maiken (2016) A Novel Model of Transient Occlusion of the Middle Cerebral Artery in Awake Mice. J Nat Sci 2:
Achariyar, Thiyagaragan M; Li, Baoman; Peng, Weiguo et al. (2016) Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation. Mol Neurodegener 11:74
Sreetama, S C; Takano, T; Nedergaard, M et al. (2016) Injured astrocytes are repaired by Synaptotagmin XI-regulated lysosome exocytosis. Cell Death Differ 23:596-607
Peng, Weiguo; Achariyar, Thiyagarajan M; Li, Baoman et al. (2016) Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease. Neurobiol Dis 93:215-25
O'Donnell, John; Ding, Fengfei; Nedergaard, Maiken (2015) Distinct functional states of astrocytes during sleep and wakefulness: Is norepinephrine the master regulator? Curr Sleep Med Rep 1:1-8
Iliff, Jeffrey J; Goldman, Steven A; Nedergaard, Maiken (2015) Implications of the discovery of brain lymphatic pathways. Lancet Neurol 14:977-9
Lundgaard, Iben; Li, Baoman; Xie, Lulu et al. (2015) Direct neuronal glucose uptake Heralds activity-dependent increases in cerebral metabolism. Nat Commun 6:6807
Haydon, Philip G; Nedergaard, Maiken (2015) How do astrocytes participate in neural plasticity? Cold Spring Harb Perspect Biol 7:a020438

Showing the most recent 10 out of 71 publications