Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Sleep Drives Metabolite Clearance from the Adult Brain


Science 18 October 2013: Vol. 342 no. 6156 pp. 373-377

Sleep Drives Metabolite Clearance from the Adult Brain

Lulu Xie, Hongyi Kang, Qiwu Xu, Michael J. Chen, Yonghong Liao, Meenakshisundaram Thiyagarajan, John O’Donnell, Daniel J. Christensen, Charles Nicholson, Jeffrey J. Iliff, Takahiro Takano, Rashid Deane, Maiken Nedergaard

1Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.

2Department of Neuroscience and Physiology, Langone Medical Center, New York University, New York, NY 10016, USA.


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.

Despite decades of effort, one of the greatest mysteries in biology is why sleep is restorative and, conversely, why lack of sleep impairs brain function. Sleep deprivation reduces learning, impairs performance in cognitive tests, prolongs reaction time, and is a common cause of seizures. In the most extreme case, continuous sleep deprivation kills rodents and flies within a period of days to weeks. In humans, fatal familial or sporadic insomnia is a progressively worsening state of sleeplessness that leads to dementia and death within months or years.

Proteins linked to neurodegenerative diseases, including β-amyloid (Aβ),   α-synuclein,   and tau,   are present in the interstitial space surrounding cells of the brain. In peripheral tissue, lymph vessels return excess interstitial proteins to the general circulation for degradation in the liver. Yet despite its high metabolic rate and the fragility of neurons to toxic waste products, the brain lacks a conventional lymphatic system. Instead, cerebrospinal fluid (CSF) recirculates through the brain,   interchanging with interstitial fluid (ISF) and removing interstitial proteins, including . The convective exchange of CSF and ISF is organized around the cerebral vasculature, with CSF influx around arteries, whereas ISF exits along veins. These pathways were named the glymphatic system on the basis of their dependence on astrocytic aquaporin-4 (AQP4) water channels and the adoption of functions homologous to peripheral lymphatic removal of interstitial metabolic byproducts. Deletion of AQP4 channels reduces clearance of exogenous Aβ by 65%, suggesting that convective movement of ISF is a substantial contributor to the removal of interstitial waste products and other products of cellular activity. The interstitial concentration of Aβ is higher in awake than in sleeping rodents and humans, possibly indicating that wakefulness is associated with increased Aβ production. We tested the alternative hypothesis that Aβ clearance is increased during sleep and that the sleep-wake cycle regulates glymphatic clearance.

We used in vivo two-photon imaging to compare CSF influx into the cortex of awake, anesthetized, and sleeping mice. The fluorescent tracers were infused into the subarachnoid CSF via a cannula implanted in the cisterna magna for real-time assessment of CSF tracer movement. Electrocorticography (ECoG) and electromyography (EMG) were recorded in order to continuously monitor the state of brain activity.

Because of the high sensitivity of neural cells to their environment, it is essential that waste products of neural metabolism are quickly and efficiently removed from the brain interstitial space. Several degradation products of cellular activity, such as Aβ oligomers and amyloid depositions, have adverse effects on synaptic transmission and cytosolic Ca2+ concentrations and can trigger irreversible neuronal injury. The existence of a homeostatic drive for sleep—including accumulation of a “need to sleep” substance during wakefulness that dissipates during sleep—has been proposed. Because biological activity is inevitably linked to the production of metabolic degradation products, it is possible that sleep subserves the important function of clearing multiple potentially toxic CNS waste products. Our analysis indicates that the cortical interstitial space increases by more than 60% during sleep, resulting in efficient convective clearance of Aβ and other compounds. The purpose of sleep has been the subject of numerous theories since the time of the ancient Greek philosophers. An extension of the findings reported here is that the restorative function of sleep may be due to the switching of the brain into a functional state that facilitates the clearance of degradation products of neural activity that accumulate during wakefulness.

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