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Sleep Enhances Removal of the Brain’s Waste

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We know that a good night’s sleep makes us feel energized and refreshed. New research appears to indicate that one of sleep’s primary functions is the increased removal of metabolic waste from the brain, which accumulates during our hours of wakefulness.

All the information-processing and thinking that we do when we’re awake result in different kinds of waste products being generated by the brain’s cells. This debris has to be eliminated daily or it will build up. Brain waste build-up has been linked to diseases involving progressive loss of neurologic function, including Alzheimer’s disease.

Until recently, the only known way for the brain to clear its metabolic refuse was by breaking down waste products and reusing them in individual cells.

But in 2012, researchers from the University of Rochester Medical Center in New York reported about a newly discovered method by which the brain “empties out the trash,” and which appears to be the brain’s primary method for disposing of waste.

From the neck down, cellular metabolic waste is transported from the body’s cells by a yellowish fluid that bathes and surrounds cells continuously. This waste-bearing interstitial (or inter-cellular) fluid seeps through walls of the semi-permeable vessels in the lymphatic system; these vessels are located in many places of the body (but not in the head), and they keep the fluid from building up. Once inside the lymphatic vessels, the used “lymph,” as the fluid is now called, goes to the kidneys and liver, where wastes are filtered out.

But the lymphatic system does not extend to the brain. In the brain, waste also accumulates in interstitial fluid. So, how does the brain get rid of it?

Using modern, microscopic imaging methods, study author Maiken Nedergaard, MD, DMSc, and her colleagues experimented on the brains of mice, whose brains are similar in many respects to the human brain. Using real-time imaging, researchers examined the brains while the mice were awake, asleep, or out under anesthesia.

The researchers found that when mice were asleep, the brain’s interstitial space — the space between cells — more than doubled, increasing by 60 percent, compared to when the mice were awake. The same increase in inter-cellular space was seen when the mice were under anesthesia.

So, whether the animals had fallen asleep naturally or the sleep had been artificially induced, the volume of interstitial space was 60 percent greater than when they were awake and alert, meaning that brain cells make themselves smaller when the brain is on sleep mode.

Researchers were unable to determine which specific types of cells get smaller, but they discovered that the neurotransmitter epinephrine, also known as adrenaline, was communicating with cells and controlling their shrinkage.

Nedergaard and her team observed another curious event, which always happened when the interstitial spaces got bigger: a corresponding increase of cerebrospinal fluid would enter the newly expanded intercellular spaces, and it would displace a lot of the interstitial fluid.

Interstitial fluid is always present in brain and body tissues; it is produced when the heart’s systolic force, generated after a heart beat, pushes water out of capillaries and into surrounding interstitial spaces. In addition to removing waste, interstitial fluid bathes neurons and body cells with nutrients from the blood, and it transports hormones from the blood to cells, which command cells to do specific things.

Cerebrospinal fluid, or CSF, looks like water, and it envelopes and cushions the brain and the spinal cord; it is made in the choroid plexus. The different sections of choroid plexus are located in the brain’s four ventricles, which are spaces and structures situated in the center of the brain and its bottom center.

Choroid plexus tissue is made up of many capillaries that are surrounded by a layer of cells through which fluid from the blood is filtered; this fluid becomes CSF.

Many substances are added to and taken from CSF as it is made. In addition to its important role as a buffer for the brain and the spinal cord, CSF carries nutrients and hormones to remote parts of the brain. And like the brain’s and the body’s interstitial fluids, CSF also removes metabolic waste, including excess hormones, from the brain. Cerebrospinal fluid, then, serves to maintain a regulated, nourished, clean environment in the brain.

As interstitial spaces widen when the brain goes into sleeping mode, CSF floods the brain’s interior spaces and the subarachnoid space, a capillary-filled layer located one layer away from the cerebral cortex, above the pia mater. Once the CSF has delivered nutrients and swept waste in its trajectory, it is then recycled when it’s absorbed back into the bloodstream by nodes that sit on top of the brain, protruding from the subarachnoid space. Used CSF absorption also occurs in upper sections of the lymphatic system.

Dr. Nedergaard referred to the exchange of “dirty” interstitial fluid for clean, fresh cerebrospinal fluid as the “glymphatic system.”

More recently, Nedergaard, in conjunction with researchers from Oregon Health and Science University and New York University, published findings of another related study: the greater influx of cerebrospinal fluid in the brain when the brain is sleeping also leads to stepped-up removal of amyloid-beta proteins. These are protein fragments that can accumulate at connecting points between neurons; they can obstruct electric impulse transmission between neurons and interfere with the release of neurotransmitters that neurons use to communicate with one another. Amyloid proteins are known to accumulate in the brains of people with Alzheimer’s disease and other neurodegenerative disorders.

The researchers had a strong clue that the “glymphatic system” is much more active when the brain is asleep, based on the fact that the amount of energy used by the brain is known not to decrease a lot in the sleep state. They later concluded that the increased release of CSF during sleep requires substantial energy expenditure; brain cleaning, then, may use too much energy to be performed while we’re awake, when the brain is using up a lot of fuel to process input from our senses and for our conscious thinking.

Through a number of experiments with mice, the researchers found that the exchange of used interstitial fluid in the brain for fresh cerebrospinal fluid was almost 10 times greater when the mice were asleep. Sleeping brains removed twice as much debris, including amyloid-beta proteins, than when the brains were awake.

Researchers concluded that interstitial space shrinkage in the awake state automatically restricts CSF flow into the brain, and thus reduces drastically the level of cleaning that can occur when we’re awake. Nedergaard concluded that the restorative properties of sleep may be tied to the clearance of metabolic waste that accumulates during wakefulness.

The research team’s latest findings were recently published in Science magazine.

By Lisa Pecos

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