Why We Sleep (or can't)

But how does the brain regulate its own state of wakefulness? And what, in fact, is the biological value and meaning of sleep and dreaming? Recent research is beginning to make headway in resolving some of these age-old questions, and we can look forward to some new medications and treatments in the coming years that may relieve one of life's major sources of travail.

Many theories have been proposed, including a famous suggestion by the Nobel Prize winner, Francis Crick, that the purpose of sleep is to allow the brain to "take out the trash" -- to deprogram the miscellaneous events that are not to be stored for long-term memory. Recent studies with animals in our laboratory suggest that he may be right, at least at a molecular level.

To explore the circuits in the brain that participate in sleep, we have homed in on the production of a protein called Fos, made by many nerve cells in the brain when they are active. We find that, during forced wakefulness, progressively more Fos is made by the brain's neuronal circuitry. Even after the animals are allowed to go to sleep, many take some time to "get in the mood," and during that period the Fos system in the brain remains extremely active. However, with the onset of sleep, the Fos protein in the brain disappears very rapidly.

The gene that codes for the Fos protein is a kind of molecular "switch." Nerve cells use this switch to engage much of the housekeeping that is necessary for them to go about their daily tasks. The disappearance of Fos protein with the onset of sleep may mean that it is necessary to turn off these genetic pathways, to allow them to reset, so the nerve cells can be re-engaged the next day anew in a fresh set of tasks. This would fit with our knowledge that continuous engagement of the nervous system results in mental derangement in humans, and, if sufficiently prolonged in animals, may even result in death.

The Slumber System
How, then, does the brain regulate its state of wakefulness? At the turn of the century, it was assumed that the natural state of the brain was awake, and that sleep represented a state of generalized decreased brain activity. However, by the early years of this century, evidence began to accumulate that injuries to the brainstem, the lowest portion of the brain, could cause the forebrain to fall into a sleep-like state, known as coma. This led scientists to speculate that the brain might not be so much "naturally" awake as kept awake by some distinct mechanism, probably in the brainstem.

Over the last few decades, scientists have uncovered a system of pathways within the brain, arising from the brainstem, that stimulate the forebrain and cause it to remain awake. These "wakefulness" pathways consist of nerve cells that communicate using as neurotransmitters a group of chemicals, called monamines, and acetylcholine. The monoamines include norepinephrine, dopamine, serotonin, and histamine. Nerve cells containing these monamines are found in clusters along the brainstem; they send their messages to the forebrain through long branches, or axons, that provide an arousing input to the cerebral cortex, the highest level of the nervous system and the region most closely associated with thought.

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Nerve cell groups and pathway involved in arousal. (By Leigh Corial Design and Illustration, from a drawing by C. Saper.)

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The nerve cells that contain acetycholine are located in the brainstem and the base of the forebrain; they also send axons to the cerebral cortex, and provide a major arousing input to the thalamus, a waystation in the forebrain that controls transmission of sensory information to the cerebral cortex. During wakefulness, both cholinergic and monoaminergic pathways are firing at full speed; injury to these pathways results in coma.

Another finding in the early years of this century was that injury to the base of the brain, at a region called the preoptic area, could produce long-lasting insomnia. Recent studies have identified nerve cells in this area of the brain that are specifically active during sleep. In other words, not only is waking an active state, but sleep also requires activity of special nerve cells to maintain a state of sleep.

In our laboratory we set out to learn precisely how this activity serves sleep, by examining the connections of sleep-active nerve cells in the preoptic area. We found that these cells send their axons to the monamine and acetycholine neurons in the brainstem and the nerve terminals wrap around and encrust the nerve cells in the arousal system. Significantly, the sleep-active nerve cells in the preoptic area contain GABA, an inhibitory neurotransmitter which turns down, or dampens, the firing of other cells. When the sleep-active neurons are firing, we believe that they profoundly inhibit the arousal systems of the brain, and "turn off the lights."

The Dream Machine
The meaning of dreams has fascinated humans since the beginning of time. Even within our own era, psychoanalysts such as Freud constructed elaborate schemes for interpreting them. But where do dreams come from, and what do they signify?

In the 1950's, it was discovered that sleep consists of fluctuations between a state in which the brain shows slowing of its activity, and a very active state in which the electrical responses of the cerebral cortex are difficult to distinguish from waking. Yet, during this "paradoxical sleep," the individual is less arousable than during most of the quiet sleep, and the typical body adjustments that accompany quiet sleep stop completely; the individual is essentially motionless.

Paradoxical sleep is also accompanied by rapid eye movements (and therefore may be called REM sleep), and usually by active dreaming; the individual may experience fluctuations in heart rate and rhythm that make this the time of night when the largest number of heart attacks and strokes occur.

During the onset of paradoxical sleep, the acetycholine neurons in the brainstem fire in bursts. It is thought that this release of acetycholine stimulates the thalamus to cause increased activity of the cerebral cortex. Meanwhile, the release of acetylcholine in the brainstem stimulates eye movements and autonomic responses. The acetylcholine release also causes other neurons to fire and these inhibit the motor system and result in near paralysis.

Cats, in which the paralysis can be selectively prevented during paradoxical sleep, may chase mice and carry out other cat behaviors while they appear to be dreaming. The paralysis during paradoxical sleep, then, may keep us out of trouble. In recent years, we have come to recognize that some people also have a REM sleep behavioral disorder in which they act out their dreams and may behave in a bizarre and sometimes dangerous fashion while they are asleep.

During quiet, or non-REM sleep, people also may dream, but the mental images are more static. It is during the deeper stages of non-REM sleep, in which the body is resting but not paralyzed, that most sleep-walking, bed-wetting, and night terrors occur in children. The natural reduction in these events with aging reflects the fact that, with advancing age, individuals spend less time in deep, non-REM sleep. Elderly people often complain of frequent awakening and sleep that is not sufficiently restful. Most sedative drugs that produce sleep are only a temporary fix, as the long-term effect is to reduce deep non-REM sleep further.

Is There Hope for Me, Doctor?
A remarkably broad range of people have sleep disorders of various types, and finding some way to alter their sleep patterns is an important goal. There are many over-the-counter and prescription sleep medications available. For most people, they afford temporary relief, but do not provide long-lasting help. The main reason for this disappointment is that, as in any area of medicine, it is important to make an accurate diagnosis that can guide effective treatment.

Fortunately, sleep physicians can now train an array of technological advances on defining and treating sleep disorders. Most people with common sleep disorders, such as insomnia or daytime sleepiness, can now be diagnosed accurately, and specific therapy can be given based upon the underlying cause of the problem.

Still, hope springs eternal for a quick fix for sleep difficulties. Melatonin has recently achieved considerable popularity for inducing sleep. Careful studies show that it has minimal effects on the time it takes to fall asleep or total time spent sleeping, though it may allow somewhat deeper sleep. When compared to placebo, the effects are not impressive.

Currently, melatonin is not approved as a medication, but rather is sold as a "food supplement." This means that there is no standardization of dosage and no certification to prevent contaminants. A similar fad surrounding the "food supplement" tryptophan several years ago ended in tragedy when a batch of the unregulated substance contained a contaminant that caused neuromuscular damage in people who took it. At present, taking melatonin for sleep is both without sound basis and potentially dangerous, as the long term effects of it have never been studied adequately.

The remarkable discoveries made over the last few years bode well for new generations of medications that will selectively activate the nerve pathways involved in regulating wakefulness and sleep. As in so many areas of neuroscience, hope for better medications and relief lies in research that helps us understand more clearly the neuronal determinants of sleep. *