March 14, 1996
Harvard
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Switch To Turn On Sleep Found in Brain

HMS studies uncover processes that may relieve the nightmare of insomnia

By William J. Cromie

Gazette Staff

You've had a long, hard day, and you desperately want to fall asleep. But you can't. Your body's tired but your mind won't shut off. You wish you could turn on sleep like you turn off a light.

It's an insomniac's dream that Medical School researchers say could come true. They found a biological sleep switch in the brains of rats. When the switch is "on," they fall asleep. When it's "off," they wake up.

"It almost certainly works the same in humans," says Clifford Saper, James Jackson Putnam Professor of Neurology. "The switch is located in the hypothalamus, a brain structure shared by rats, monkeys, humans, and many other species."

No bigger than a large pea near the center of the grapefruit-sized human brain, the hypothalamus is, by any criteria, an amazing structure. Called the "brain of the brain," it regulates sleep, wakefulness, sex, emotions, eating, drinking, body temperature, heart rate, and hormones.

"It is the one part of the brain you cannot survive without," Saper notes. "Our studies of it are opening up the possibilities of understanding why we sleep and of designing drugs to produce natural sleep and alert wakefulness."

Rats Made Sleepless

Saper and his colleagues at the Medical School's Program in Neuroscience and Beth Israel Hospital are building on work done about 50 years ago in Holland by neurologist Walle Nauta. He found that cutting the front of the hypothalamus of street rats turned them into insomniacs. Surgery on the back of the hypothalamus made them comatose.

While carefully studying the front of the hypothalamus, Saper's team located a clump of cells active only when the animals sleep. Further probing revealed that these cells connect to an area at the back of the hypothalamus known to be involved in keeping rats and humans awake.

The scientists concluded that nerve cells at the front of the structure secrete a chemical that travels along their extensions and turns off activity at the back of the hypothalamus and in other parts of the brain.

When brain cells are turned on, their genes produce a protein known as fos. Wide-awake rats and humans have fos spread throughout their brains. When asleep, however, fos concentrates in a clump of hypothalamic cells much smaller than their name, the ventrolateral preoptic (VLPO) area. At the same time, fos levels drop in other parts of the brain.

"These changes occur after one to two hours of sleep," Saper says.

Cells in the VPLO at the front of the hypothalamus produce a chemical called gamma-aminobutyric acid, or GABA. GABA, in turn, inhibits the activity of brain cells associated with wakefulness.

One possible way to cure insomnia, then, might be to design drugs that "wake up" GABA-producing cells, thereby putting the brain to sleep. That strategy may result in natural sleep, as opposed to the drugged state produced by sleeping pills. The latter, effective only for a limited time, can have serious side effects.

The Clock and the Switch

Now that scientists know how the sleep switch works, the next challenge is to find what turns it on and off. Both biological and behavioral "fingers" appear to be involved.

A day of hard work, a boring meeting, a dull lecture, too much food and wine, absence of stressful or interesting stimuli, even a hot, poorly ventilated room can bring on a snooze.

Sleeping must also be tied to our biological rhythms, that inner clock that synchronizes sleep and wakefulness with the 24-hour, day-night cycle. The minute clump of nerve cells that sets that clock lies only about a tenth of an inch from the front of the hypothalamus.

To be sure that biological rhythms alone do not control the switch, Saper's team reversed the light-dark cycles of lab rats, depriving the rodents of sleep. When they finally let the rats doze off, fos became active in the front of the hypothalamus but not in the clock mechanism, showing that the sleep switch and biological rhythms are separate mechanisms.

"This does not mean the two are independent," Saper explained. "The biological clock probably has a major influence on the working of the sleep switch. We are tracing nerve-cell connections between the two to determine exactly what that influence is."

Saper's team also studies people at autopsy to trace the physical and chemical pathways between the hypothalamus and other parts of the brain. Such basic research must precede any attempt to manipulate the sleeping switch with designer drugs. This work is done with the help of J.E. Sherin, a graduate student in the Department of Neurology, and in collaboration with Priyattam Shiromani, assistant professor of psychology, and Robert McCarley, professor of psychiatry.

Why Do We Sleep?

You can't do this kind of research without asking the big question: Why do we need sleep? If you deprive rats and humans of sleep long enough, they die. How come?

"To rest," is the short answer. But why do we need to rest this way?

"Sleep may be necessary to reset brain circuits that deal with stress and learning," Saper replies.

Genes that turn on while we are awake, including the one that produces fos, handle the stress of living and learning. The hypothalamus connects to many parts of the brain concerned with functions ranging from thinking, to emotions, to fighting and fleeing from danger. These functions often involve stress hormones, which the hypothalmus controls.

"Not being able to reset those circuits -- being deprived of sleep -- is the ultimate stress," Saper declares. "I think of it as erasing the blackboard at the end of the day. If you don't do this, attempting to overwrite new experiences would produce confusion, and disharmony, which would be injurious, even lethal."

 


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