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Taking Out the Trash

The purpose of sleep remains mysterious. Using state-of-the-art in vivo two-photon imaging to directly compare two arousal states in the same mouse, Xie et al. (p. 373; see the Perspective by Herculano-Houzel) found that metabolic waste products of neural activity were cleared out of the sleeping brain at a faster rate than during the awake state. This finding suggests a mechanistic explanation for how sleep serves a restorative function, in addition to its well-described effects on memory consolidation.

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 and Notes

1
Saper C. B., Fuller P. M., Pedersen N. P., Lu J., Scammell T. E., Sleep state switching. Neuron 68, 1023–1042 (2010).
2
Hobson J. A., Sleep is of the brain, by the brain and for the brain. Nature 437, 1254–1256 (2005).
3
Malow B. A., Sleep deprivation and epilepsy. Epilepsy Curr. 4, 193–195 (2004).
4
Stickgold R., Neuroscience: A memory boost while you sleep. Nature 444, 559–560 (2006).
5
Rechtschaffen A., Gilliland M. A., Bergmann B. M., Winter J. B., Physiological correlates of prolonged sleep deprivation in rats. Science 221, 182–184 (1983). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6857280&dopt=Abstract
6
Shaw P. J., Tononi G., Greenspan R. J., Robinson D. F., Stress response genes protect against lethal effects of sleep deprivation in Drosophila. Nature 417, 287–291 (2002).
7
Montagna P., Gambetti P., Cortelli P., Lugaresi E., Familial and sporadic fatal insomnia. Lancet Neurol. 2, 167–176 (2003).
8
Cirrito J. R., Yamada K. A., Finn M. B., Sloviter R. S., Bales K. R., May P. C., Schoepp D. D., Paul S. M., Mennerick S., Holtzman D. M., Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron 48, 913–922 (2005).
9
Larson M. E., Sherman M. A., Greimel S., Kuskowski M., Schneider J. A., Bennett D. A., Lesné S. E., Soluble α-synuclein is a novel modulator of Alzheimer’s disease pathophysiology. J. Neurosci. 32, 10253–10266 (2012).
10
Yamada K., Cirrito J. R., Stewart F. R., Jiang H., Finn M. B., Holmes B. B., Binder L. I., Mandelkow E. M., Diamond M. I., Lee V. M., Holtzman D. M., In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J. Neurosci. 31, 13110–13117 (2011).
11
Aukland K., Reed R. K., Interstitial-lymphatic mechanisms in the control of extracellular fluid volume. Physiol. Rev. 73, 1–78 (1993).
12
J. J. Iliff et al., A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci. Transl. Med. 4, 147ra111 (2012).
13
Iliff J. J., Lee H., Yu M., Feng T., Logan J., Nedergaard M., Benveniste H., Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J. Clin. Invest. 123, 1299–1309 (2013).
14
Nedergaard M., Garbage truck of the brain. Science 340, 1529–1530 (2013).
15
Bateman R. J., Munsell L. Y., Morris J. C., Swarm R., Yarasheski K. E., Holtzman D. M., Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat. Med. 12, 856–861 (2006).
16
Kang J. E., Lim M. M., Bateman R. J., Lee J. J., Smyth L. P., Cirrito J. R., Fujiki N., Nishino S., Holtzman D. M., Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science 326, 1005–1007 (2009). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=19779148&dopt=Abstract
17
Nicholson C., Phillips J. M., J. Physiol. 321, 225–257 (1981).
18
Nicholson C., Quantitative analysis of extracellular space using the method of TMA+ iontophoresis and the issue of TMA+ uptake. J. Neurosci. Methods 48, 199–213 (1993).
19
Yao X., Hrabetová S., Nicholson C., Manley G. T., Aquaporin-4-deficient mice have increased extracellular space without tortuosity change. J. Neurosci. 28, 5460–5464 (2008).
20
Nicholson C., Syková E., Extracellular space structure revealed by diffusion analysis. Trends Neurosci. 21, 207–215 (1998).
21
Syková E., Nicholson C., Diffusion in brain extracellular space. Physiol. Rev. 88, 1277–1340 (2008).
22
Syková E., Vorísek I., Antonova T., Mazel T., Meyer-Luehmann M., Jucker M., Hájek M., Ort M., Bures J., Changes in extracellular space size and geometry in APP23 transgenic mice: A model of Alzheimer’s disease. Proc. Natl. Acad. Sci. U.S.A. 102, 479–484 (2005).
23
Kinney J. P., Spacek J., Bartol T. M., Bajaj C. L., Harris K. M., Sejnowski T. J., Extracellular sheets and tunnels modulate glutamate diffusion in hippocampal neuropil. J. Comp. Neurol. 521, 448–464 (2013).
24
Deane R., Sagare A., Hamm K., Parisi M., Lane S., Finn M. B., Holtzman D. M., Zlokovic B. V., apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J. Clin. Invest. 118, 4002–4013 (2008).
25
Steriade M., McCormick D. A., Sejnowski T. J., Thalamocortical oscillations in the sleeping and aroused brain. Science 262, 679–685 (1993). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8235588&dopt=Abstract
26
Carter M. E., Yizhar O., Chikahisa S., Nguyen H., Adamantidis A., Nishino S., Deisseroth K., de Lecea L., Tuning arousal with optogenetic modulation of locus coeruleus neurons. Nat. Neurosci. 13, 1526–1533 (2010).
27
Constantinople C. M., Bruno R. M., Effects and mechanisms of wakefulness on local cortical networks. Neuron 69, 1061–1068 (2011).
28
O’Donnell J., Zeppenfeld D., McConnell E., Pena S., Nedergaard M., Norepinephrine: a neuromodulator that boosts the function of multiple cell types to optimize CNS performance. Neurochem. Res. 37, 2496–2512 (2012).
29
McBain C. J., Traynelis S. F., Dingledine R., Regional variation of extracellular space in the hippocampus. Science 249, 674–677 (1990).
30
Parameshwaran K., Dhanasekaran M., Suppiramaniam V., Amyloid beta peptides and glutamatergic synaptic dysregulation. Exp. Neurol. 210, 7–13 (2008).
31
Kuchibhotla K. V., Goldman S. T., Lattarulo C. R., Wu H. Y., Hyman B. T., Bacskai B. J., Abeta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks. Neuron 59, 214–225 (2008).
32
Mattson M. P., Calcium and neuronal injury in Alzheimer’s disease. Contributions of beta-amyloid precursor protein mismetabolism, free radicals, and metabolic compromise. Ann. N. Y. Acad. Sci. 747, 50–76 (1994).
33
A. Borbely, I. Tobler, in Brain Mechanisms of Sleep, D. J. McGinty, Ed. (Raven, New York, 1985), pp. 35–44.
34
Barbera J., Sleep and dreaming in Greek and Roman philosophy. Sleep Med. 9, 906–910 (2008).

Information & Authors

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Published In

Science
Volume 342Issue 615618 October 2013
Pages: 373 - 377

History

Received: 30 May 2013
Accepted: 28 August 2013

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Authors

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Lulu Xie*
Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
Hongyi Kang*
Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
Qiwu Xu
Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
Michael J. Chen
Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
Yonghong Liao
Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
Meenakshisundaram Thiyagarajan
Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
John O’Donnell
Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
Daniel J. Christensen
Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
Charles Nicholson
Department of Neuroscience and Physiology, Langone Medical Center, New York University, New York, NY 10016, USA.
Jeffrey J. Iliff
Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
Takahiro Takano
Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
Rashid Deane
Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
Maiken Nedergaard [email protected]
Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.

Notes

*
These authors contributed equally to this work.
†Corresponding author. E-mail: [email protected]

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Science
Volume 342|Issue 6156
18 October 2013
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Received:30 May 2013
Accepted:28 August 2013
Published in print:18 October 2013
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