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Sleep Drives Metabolite Clearance from the Adult Brain

Published on Oct 18, 2013in Science 41.04
· DOI :10.1126/science.1241224
Lulu Xie4
Estimated H-index: 4
(URMC: University of Rochester Medical Center),
Hongyi Kang6
Estimated H-index: 6
(URMC: University of Rochester Medical Center)
+ 9 AuthorsRashid Deane45
Estimated H-index: 45
(URMC: University of Rochester Medical Center)
Cite
Abstract
The conservation of sleep across all animal species suggests that sleep serves a vital function. We here report that sleep has a critical function in ensuring metabolic homeostasis. Using real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice, we show that natural sleep or anesthesia are associated with a 60% increase in the interstitial space, resulting in a striking increase in convective exchange of cerebrospinal fluid with interstitial fluid. In turn, convective fluxes of interstitial fluid increased the rate of β-amyloid clearance during sleep. Thus, the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake central nervous system.
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  • References (46)
  • Citations (1238)
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References46
Newest
Published on Jun 28, 2013in Science 41.04
Nedergaard M1
Estimated H-index: 1
Published on Mar 1, 2013in Journal of Clinical Investigation 12.28
Jeffrey J. Iliff24
Estimated H-index: 24
(UR: University of Rochester),
Hedok Lee14
Estimated H-index: 14
(SBU: Stony Brook University)
+ 3 AuthorsHelene Benveniste37
Estimated H-index: 37
(SBU: Stony Brook University)
The glymphatic system is a recently defined brain-wide paravascular pathway for cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange that facilitates efficient clearance of solutes and waste from the brain. CSF enters the brain along para-arterial channels to exchange with ISF, which is in turn cleared from the brain along para-venous pathways. Because soluble amyloid β clearance depends on glymphatic pathway function, we proposed that failure of this clearance system contributes to a...
Published on Feb 1, 2013in The Journal of Comparative Neurology 3.24
Justin P Kinney5
Estimated H-index: 5
(HHMI: Howard Hughes Medical Institute),
Josef Špaček22
Estimated H-index: 22
(Charles University in Prague)
+ 3 AuthorsTerrence J. Sejnowski126
Estimated H-index: 126
(UCSD: University of California, San Diego)
The extracellular space (ECS) is an arena for signaling between neighboring cells on the nanometer and micron scale, and the geometry of the ECS affects this signaling. For example, the ECS provides a reservoir of ions used to support currents in electrically active neurons (Hodgkin and Huxley, 1952). During periods of high neuronal activity, change in extracellular ion concentration depends on local ECS volume (Moody et al., 1974; Bellinger et al., 2008). Activation of metabotropic receptors an...
Alexander S. Thrane10
Estimated H-index: 10
(URMC: University of Rochester Medical Center),
Vinita Rangroo Thrane7
Estimated H-index: 7
(URMC: University of Rochester Medical Center)
+ 3 AuthorsErlend A. Nagelhus32
Estimated H-index: 32
(University of Oslo)
Calcium signaling represents the principle pathway by which astrocytes respond to neuronal activity. General anesthetics are routinely used in clinical practice to induce a sleep-like state, allowing otherwise painful procedures to be performed. Anesthetic drugs are thought to mainly target neurons in the brain and act by suppressing synaptic activity. However, the direct effect of general anesthesia on astrocyte signaling in awake animals has not previously been addressed. This is a critical is...
Published on Nov 1, 2012in Neurochemical Research 2.78
John O’Donnell2
Estimated H-index: 2
(UR: University of Rochester),
Douglas Zeppenfeld1
Estimated H-index: 1
(UR: University of Rochester)
+ 1 AuthorsSalvador Pena1
Estimated H-index: 1
(UR: University of Rochester)
Norepinephrine (NE) is a neuromodulator that in multiple ways regulates the activity of neuronal and non-neuronal cells. NE participates in the rapid modulation of cortical circuits and cellular energy metabolism, and on a slower time scale in neuroplasticity and inflammation. Of the multiple sources of NE in the brain, the locus coeruleus (LC) plays a major role in noradrenergic signaling. Processes from the LC primarily release NE over widespread brain regions via non-junctional varicosities. ...
Published on Aug 15, 2012in Science Translational Medicine 17.16
Jeffrey J. Iliff24
Estimated H-index: 24
(URMC: University of Rochester Medical Center),
Minghuan Wang6
Estimated H-index: 6
(URMC: University of Rochester Medical Center)
+ 8 AuthorsSteven A. Goldman88
Estimated H-index: 88
(URMC: University of Rochester Medical Center)
Because it lacks a lymphatic circulation, the brain must clear extracellular proteins by an alternative mechanism. The cerebrospinal fluid (CSF) functions as a sink for brain extracellular solutes, but it is not clear how solutes from the brain interstitium move from the parenchyma to the CSF. We demonstrate that a substantial portion of subarachnoid CSF cycles through the brain interstitial space. On the basis of in vivo two-photon imaging of small fluorescent tracers, we showed that CSF enters...
Published on Jul 25, 2012in The Journal of Neuroscience 6.07
Megan Larson7
Estimated H-index: 7
(UMN: University of Minnesota),
Mathew A. Sherman12
Estimated H-index: 12
(UMN: University of Minnesota)
+ 4 AuthorsSylvain Lesné25
Estimated H-index: 25
(UMN: University of Minnesota)
Recent evidence has emphasized soluble species of amyloid-β (Aβ) and tau as pathogenic effectors in Alzheimer9s disease (AD). Despite the fact that Aβ, tau, and α-synuclein (αSyn) can promote each other9s aggregation, the potential contribution of soluble αSyn to AD pathogenesis is unknown. Here, we found an approximate twofold increase over controls in soluble αSyn levels in AD brains in the absence of Lewy body cytopathology. Importantly, soluble αSyn levels were a quantitatively stronger corr...
Published on Oct 1, 2011in Computing and Visualization in Science
Charles Nicholson12
Estimated H-index: 12
(NYU: New York University),
Padideh Kamali-Zare2
Estimated H-index: 2
(NYU: New York University),
Lian Tao7
Estimated H-index: 7
(NYU: New York University)
The extracellular space (ECS) consists of the narrow channels between brain cells together with their geometrical configuration and contents. Despite being only 20–60 nm in width, the ECS typically occupies 20% of the brain volume. Numerous experiments over the last 50 years have established that molecules moving through the ECS obey the laws of diffusion but with an effective diffusion coefficient reduced by a factor of about 2.6 compared to free diffusion. This review considers the origins of ...
Published on Sep 14, 2011in The Journal of Neuroscience 6.07
Kaoru Yamada11
Estimated H-index: 11
(WashU: Washington University in St. Louis),
John R. Cirrito44
Estimated H-index: 44
(WashU: Washington University in St. Louis)
+ 8 AuthorsVirginia M.-Y. Lee170
Estimated H-index: 170
(UPenn: University of Pennsylvania)
Although tau is a cytoplasmic protein, it is also found in brain extracellular fluids, e.g., CSF. Recent findings suggest that aggregated tau can be transferred between cells and extracellular tau aggregates might mediate spread of tau pathology. Despite these data, details of whether tau is normally released into the brain interstitial fluid (ISF), its concentration in ISF in relation to CSF, and whether ISF tau is influenced by its aggregation are unknown. To address these issues, we developed...
Cited By1238
Newest
Published on May 8, 2019in Acta neuropathologica communications
Alex J. Smith18
Estimated H-index: 18
(UCSF: University of California, San Francisco),
Tianjiao Duan (UCSF: University of California, San Francisco), A. S. Verkman125
Estimated H-index: 125
(UCSF: University of California, San Francisco)
Redistribution of the water channel aquaporin-4 (AQP4) away from astrocyte endfeet and into parenchymal processes is a striking histological feature in mouse models of Alzheimer’s disease (AD) and other neurological conditions with prominent astrogliosis. AQP4 redistribution has been proposed to impair bulk Aβ clearance in AD, resulting in increased amyloid deposition in the brain; however, this finding is controversial. Here, we provide evidence in support of a different and novel role of AQP4 ...
Published on Feb 5, 2019in Fluids and Barriers of the CNS
Richard F. Keep64
Estimated H-index: 64
(UM: University of Michigan),
Hazel C. Jones5
Estimated H-index: 5
,
Lester R. Drewes34
Estimated H-index: 34
(UMN: University of Minnesota)
This editorial focuses on the progress made in brain barrier and brain fluid research in 2018. It highlights some recent advances in knowledge and techniques, as well as prevalent themes and controversies. Areas covered include: modeling, the brain endothelium, the neurovascular unit, the blood–CSF barrier and CSF, drug delivery, fluid movement within the brain, the impact of disease states, and heterogeneity.
Published on Dec 1, 2019
Barbara Oakley11
Estimated H-index: 11
(UR: University of Rochester),
Terrence J. Sejnowski126
Estimated H-index: 126
(UR: University of Rochester)
Learning How to Learn (LHTL) is currently one of the world’s most popular massive open online course (MOOC), with nearly 2.5 million registered learners in its first 4 years. Here, we “reverse engineer” the design of the course’s videos to show how creative application of well-known principles of multimedia learning in an MOOC context appear to have fueled the course’s popularity. Gaps in knowledge of multimedia learning are also noted. There have been some 50 years of experience researching eff...
Published on Dec 1, 2019in Fluids and Barriers of the CNS
Jeffrey Tithof (UR: University of Rochester), Douglas H. Kelley12
Estimated H-index: 12
(UR: University of Rochester)
+ 1 AuthorsJohn H. Thomas30
Estimated H-index: 30
(UR: University of Rochester)
Background Periarterial spaces (PASs) are annular channels that surround arteries in the brain and contain cerebrospinal fluid (CSF): a flow of CSF in these channels is thought to be an important part of the brain’s system for clearing metabolic wastes. In vivo observations reveal that they are not concentric, circular annuli, however: the outer boundaries are often oblate, and the arteries that form the inner boundaries are often offset from the central axis.
Published on Apr 12, 2019in Scientific Reports 4.01
Liam M. Koehn1
Estimated H-index: 1
(University of Melbourne),
Katarzyna M. Dziegielewska36
Estimated H-index: 36
(University of Melbourne)
+ 5 AuthorsMark D. Habgood26
Estimated H-index: 26
(University of Melbourne)
Many pregnant women and prematurely born infants require medication for clinical conditions including cancer, cardiac defects and psychiatric disorders. In adults drug transfer from blood into brain is mostly restricted by efflux mechanisms (ATP-binding cassette, ABC transporters). These mechanisms have been little studied during brain development. Here expression of eight ABC transporters (abcb1a, abcb1b, abcg2, abcc1, abcc2, abcc3, abcc4, abcc5) and activity of conjugating enzyme glutathione-s...
Published on Mar 6, 2019in Fluids and Barriers of the CNS
Lori Ray (MSU: Montana State University), Jeffrey J. Iliff24
Estimated H-index: 24
(OHSU: Oregon Health & Science University)
+ 0 AuthorsJeffrey J. Heys19
Estimated H-index: 19
(MSU: Montana State University)
Background Despite advances in in vivo imaging and experimental techniques, the nature of transport mechanisms in the brain remain elusive. Mathematical modelling verified using available experimental data offers a powerful tool for investigating hypotheses regarding extracellular transport of molecules in brain tissue. Here we describe a tool developed to aid in investigation of interstitial transport mechanisms, especially the potential for convection (or bulk flow) and its relevance to inters...
Published on Dec 1, 2019in Scientific Reports 4.01
Vegard Vinje (Simula Research Laboratory), Geir Ringstad10
Estimated H-index: 10
(Oslo University Hospital)
+ 4 AuthorsKent-Andre Mardal21
Estimated H-index: 21
(University of Oslo)
Current theories suggest that waste solutes are cleared from the brain via cerebrospinal fluid (CSF) flow, driven by pressure pulsations of possibly both cardiac and respiratory origin. In this study, we explored the importance of respiratory versus cardiac pressure gradients for CSF flow within one of the main conduits of the brain, the cerebral aqueduct. We obtained overnight intracranial pressure measurements from two different locations in 10 idiopathic normal pressure hydrocephalus (iNPH) p...
Published on Mar 5, 2019in Nature Communications 11.88
David Zada5
Estimated H-index: 5
(BIU: Bar-Ilan University),
Irena Bronshtein11
Estimated H-index: 11
(BIU: Bar-Ilan University)
+ 2 AuthorsLior Appelbaum18
Estimated H-index: 18
(BIU: Bar-Ilan University)
Sleep is essential to all animals with a nervous system. Nevertheless, the core cellular function of sleep is unknown, and there is no conserved molecular marker to define sleep across phylogeny. Time-lapse imaging of chromosomal markers in single cells of live zebrafish revealed that sleep increases chromosome dynamics in individual neurons but not in two other cell types. Manipulation of sleep, chromosome dynamics, neuronal activity, and DNA double-strand breaks (DSBs) showed that chromosome d...
Published on Feb 21, 2019in Molecular Neurodegeneration 8.27
Korey Kam4
Estimated H-index: 4
(ISMMS: Icahn School of Medicine at Mount Sinai),
Ankit Parekh (ISMMS: Icahn School of Medicine at Mount Sinai)+ 22 AuthorsAnna E Mullins (ISMMS: Icahn School of Medicine at Mount Sinai)
Background Based on associations between sleep spindles, cognition, and sleep-dependent memory processing, here we evaluated potential relationships between levels of CSF Aβ42, P-tau, and T-tau with sleep spindle density and other biophysical properties of sleep spindles in a sample of cognitively normal elderly individuals.
Published on Feb 27, 2019in Molecular Neurodegeneration 8.27
Tirth K. Patel4
Estimated H-index: 4
(WashU: Washington University in St. Louis),
LeMoyne Habimana-Griffin2
Estimated H-index: 2
(WashU: Washington University in St. Louis)
+ 9 AuthorsPatrick W. Sheehan1
Estimated H-index: 1
(WashU: Washington University in St. Louis)
Background Alzheimer’s disease is characterized by two main neuropathological hallmarks: extracellular plaques of amyloid-β (Aβ) protein and intracellular aggregates of tau protein. Although tau is normally a soluble monomer that bind microtubules, in disease it forms insoluble, hyperphosphorylated aggregates in the cell body. Aside from its role in AD, tau is also involved in several other neurodegenerative disorders collectively called tauopathies, such as progressive supranuclear palsy (PSP),...