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1/16/96

Stanford researchers suggest how sleep re-charges the brain

STANFORD -- Why do we sleep? The answer seems obvious - to restore ourselves at the end of a long day. However, scientists have surprisingly little information about exactly what is restored during sleep. According to Stanford biologist Craig Heller, "the function of sleep is one of the major unanswered questions in biology."

Heller and a former graduate student may have found the answer to that question, at the level of individual brain cells. They suggest that only during deep, restful sleep can human brain cells replenish the energy stores they deplete during a full day of thinking, sensing and reacting.

Heller, the Lorry I. Lokey / Business Wire Professor of Biological Sciences and associate dean of research at Stanford, and Joel Benington, now a Stanford research scientist, presented their hypothesis in a recent issue of the journal Progress in Neurobiology, in a theory paper based on their research and a review of the scientific literature on neurobiology and sleep. In the journal Brain Research, they present the details of the experimental evidence supporting their ideas, from research they carried out at the Stanford Center for Sleep and Circadian Neurobiology.

Sleep is such a fundamental need that scientists long have known it must be governed by some form of homeostatic control, a feedback mechanism like the controls that keep the body's blood pressure, temperature and other aspects of its internal environment within narrow ranges.

Benington and Heller's experiments have identified a possible controlling agent of this homeostatic feedback, a neurotransmitting chemical, adenosine, that seems to govern how deeply a laboratory rat - and presumably a person - will sleep after a period of wakefulness.

Adenosine is released by brain cells when the cells' demand for energy exceeds available supplies. Heller and Benington speculate that adenosine release is one step in the homeostatic feedback loop, signaling the cells to rest so that the essential element they need - energy - can be replenished. They speculate that the brain's only source of stored energy, glycogen, is depleted in different regions of the brain where energy demands are high during wakefulness, and is then replenished during sleep.

Understanding the biochemical nature of sleep may lead to treatments for some sleep disorders, or allow chronic insomniacs to get enough restful sleep. Heller notes that scientists ultimately may be able to intensify the depth of sleep so a full night's rest could be gained in, say, four hours. Alternatively, the need for sleep could be temporarily "put on hold" when a person needs to stay alert beyond normal physiological limits - for example, during shift work, recovery from jet-lag or combat.

The need for sleep

The need for sleep is so intense, said Benington, "it is virtually impossible to keep a sleep-deprived animal or person awake for very long periods." Other researchers have shown that lack of sleep leads shift workers to fall asleep at the factory bench, and causes thousands of over-tired drivers to fall asleep on the road each year.

The intensity of sleep need led Heller and Benington to the hypothesis that whatever is restored during sleep must be important to the brain's normal functioning.

Glycogen fills the bill.

Although glycogen supplies less than 6 percent of all the fuel needs of brain cells (the rest comes from glucose delivered via the bloodstream), it is necessary because it can be called into use very quickly to meet the needs of highly active cells in localized regions of the brain. Glycogen acts like a spare battery that keeps an electrical appliance running during a temporary power outage. Because the brain does not burn fat, glycogen is the only source of spare energy for neurons.

During normal thinking and reacting, Benington and Heller speculate, the relatively small glycogen stores in the brain gradually are used up, at least in certain regions. At this point, it becomes increasingly difficult for the brain to accommodate demands for sudden increases in regional activity.

Glycogen supplies take time to replenish; unless brain cells stop their constant business of sensing and reacting, it should be difficult to rebuild this energy store. Thus, Benington and Heller say, the individual experiences glycogen loss as a buildup of the need for a good night's sleep.

Glycogen loss also triggers the release of adenosine. Heller and Benington speculate that adenosine release increases when glycogen is depleted, and that adenosine acts as a messenger to the cells, promoting restful sleep.

Benington designed an experiment to test the hypothesis that adenosine is the messenger in the sleep homeostatic feedback mechanism. He showed that its concentration influences brain cells after the onset of sleep, and seems to determine how deeply we sleep.

A chemical similar to adenosine was injected into rats that had already fully replenished their sleep need. The rats returned to deep sleep, as measured by EEG (electroencephalographic) scans. The EEG readings closely mimicked the slow electrical waves typically seen in normal sleep after prolonged wakefulness.

The conclusion was that restorative sleep is promoted by the presence of adenosine or a similar chemical.

Previous findings on the effects of caffeine on sleep fit with Heller and Benington's adenosine hypothesis. Caffeine is known to block the adenosine receptor sites on the brain cells, preventing adenosine from acting on the cell. It masks the need for sleep, but because it does not eliminate that need, caffeine is not a substitute for restful sleep. An extra cup of coffee can combat the drowsiness that comes from sleep need, but it just can't substitute for a good night's sleep.

The clock, the homeostat and REM sleep

What about the circadian rhythm, the familiar biological clock that tells owls to stay awake all night and humans to stay awake all day?

"Circadian control is critical to sleep and wakefulness," Heller said. However,
the sleep-need homeostat works independently from the circadian clock. In fact, Heller and Benington say, the clock is needed to keep humans and other diurnal animals awake during the day - without it, we would fall asleep as soon as our biochemical need for sleep was strong enough.

They cite recent research by Stanford research scientist Dale Edgar that shows that the circadian clock works like an alarm, "ringing" to keep us awake in spite of an increasing need for sleep. Animals without strong day-night schedules, like cats and guinea pigs, sleep in short bursts throughout the day, whenever the sleep homeostat signals a need for rest and energy restoration. Owls and humans sleep when the internal clock stops ringing.

If Heller and Benington's hypothesis is correct, once a person's clock shuts off at night, the sleep-need feedback mechanism takes over to ensure that he sleeps long enough to restore his brain's glycogen stores.

Their research also provides some evidence that a related biochemical homeostat controls REM sleep, the restless rapid-eye-movement sleep that often coincides with dreams. The sleep cycle, the switch between REM and non-REM sleep, normally occurs several times a night in humans, and many more times during the sleep of other mammals. In another set of papers in Progress in Neurobiology and Brain Research, Heller and Benington propose that REM sleep is needed to perform a biochemical task so that the body can return to non-REM sleep.

Non-REM is the deep sleep associated with slow-wave readings on the EEG. Heller and Benington propose that this is the essential part of sleep, where the sleep debt accumulated during waking is restored. Non-REM sleep has biochemical costs: for example, brain cells are kept in this quiet state thanks to a slow leak of positive ions from the cell membrane. Benington and Heller propose that a cycle of REM sleep, when the brain is partly active, may be needed to pump positive ions back into the cells, so another cycle of non-REM sleep can begin.

What about the dreams in REM sleep? Does REM clear the memory banks or consolidate new memories? Does it help us work through deeply seated psychological problems?

If its function were purely psychological, REM sleep would likely show different patterns in different animals. But it seems to make up about 20% of total sleep time in a wide variety of animals. As Heller noted, "You can't tell me a rat is working out his Freudian problems during REM sleep".

Putting the theory to the test

While this is not the only attempt to explain the function of sleep, Heller said it is the most comprehensive and compelling so far.

For example, experimental evidence that sleep need increases when the brain is heated, such as during exercise, has led some researchers to argue that sleep serves as a temperature regulation and recovery process for the brain. This evidence also can be explained by Heller and Benington's hypothesis, since an increase in temperature boosts the brain's metabolic rate. That could cause the glycogen stores to be used more rapidly, eventually resulting in greater sleep need.

However, Benington stressed, a number of outstanding questions about glycogen metabolism in the brain must be answered before the hypothesis can be confirmed. Benington and Heller now are working with Raymond Swanson, a researcher at the Veterans Affairs Medical Center in San Francisco, to directly measure glycogen levels during wakefulness and sleep. They want to test two questions crucial to the hypothesis: Are brain glycogen stores substantially depleted during normal waking behavior? Are they restored only during sleep?

Meanwhile, Heller and Benington's hypothesis has attracted enough attention that they shortly will begin testing the effect on sleep of certain drugs that mimic the effect of adenosine. Such compounds already have been developed by several pharmaceutical companies but until now were intended for other purposes.

Currently, there are no suitable drugs for the treatment of chronic insomnia. People rapidly develop tolerance to existing sleeping medication, leading them to take higher doses and to mix medications. This can result in bad side effects and even worse insomnia when they try to reduce the medications.

Heller and Benington expect that by manipulating the brain's own signaling system for the control of sleep, it may be possible to develop safe, effective medications that will help people achieve a good night's sleep.

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Editor's note: Benington and Heller's theory paper, "Restoration of brain energy metabolism as the function of sleep," was published in the journal Progress in Neurobiology, Vol. 45 (1995), pp. 347-360. Their research report, "Stimulation of A1 adenosine receptors mimics the electroencephalographic effects of sleep deprivation," was published in the journal Brain Research, Vol. 692 (1995), pp. 79-80.