Saturday, November 12, 2011 - 0 comments

Waking Up

By : Tim Beardsley in Washington, D.C.

Finding a purpose for sleep has been as elusive as rest to an insomniac, but researchers are getting much closer.

hope to understand the mechanisms of sleep
disorders, which afflict millions of people.
Sleep may well be “a gentle thing, beloved from pole to pole,” as Samuel Taylor Coleridge observed. For physiologists, it remains a biological mystery of the first order. Why should mammals and birds spend such a large part of their lives unresponsive and, worse, vulnerable? Although denying an animal sustenance produces bodily changes that are readily measured, nobody understands what harm is done to an animal—or a person —deprived of sleep. Yet something clearly goes terribly wrong. Researchers have known for more than a decade that a rat prevented from sleeping will lose the ability to maintain body heat and die in about three  weeks, leaving no clues in the form of physiological damage. For humans, sleep deprivation undermines thinking, but science has no explanation.

There are, however, plenty of theories—and thus plenty of enmity in the field. Sleepers lower their metabolic rate, thereby conserving energy. But this does not explain why we lose consciousness. Most researchers believe sleep benefits the brain, perhaps by giving neurons a chance to recuperate. Some, pointing to the fervid neuronal activity during the bouts of REM (rapid-eye movement) sleep that punctuate our nights, suggest we doze to consolidate memories. Others propose that dreams are mental junk being eliminated: we sleep to forget. Although it is too soon to proclaim the conundrum of sleep solved, findings are illuminating processes that seem to control it. At the same time, investigators are refining their ideas about the benefits of slumber for the brain. Understanding its purposes may ultimately help the millions of people who suffer from sleep disorders, which range in severity from the merely irritating to the fatal.

The starting point for many investigations into the control of sleep has been the hypothalamus, a platformlike structure in the brain that has long been known to have an important role. Damage to the back part of the hypothalamus causes somnolence, suggesting that when intact, it maintains alertness. Damage near the front part, in contrast, induces insomnia, indicating that the spur to sleep is there. Investigators have long looked for a controlling circuit for slumber that operates between the two halves of the hypothalamus.

The hypothalamus also plays a part in temperature regulation, and some physiologists have speculated that sleep evolved out of a more primitive thermostat. Last year M. Noor Alam, Dennis McGinty and Ronald Szymusiak of the Department of Veterans Affairs Medical Center in Sepulveda, Calif., found the first evidence of neurons that fill both functions. The team discovered neurons in the front part of the hypothalamus of cats that fire more rapidly when they are warmed by two degrees Celsius—and automatically increase their firing rate while the animal sleeps. The researchers suggest that these neurons are part of the body’s thermostat and that they are responsible for controlling naturally occurring non-REM sleep.

A related discovery was reported earlier this year by Jonathan E. Sherin, Priyattam J. Shiromani, Robert W. McCarley and Clifford B. Saper of Harvard Medical School. These workers uncovered evidence that clusters of neurons in part of the front hypothalamus of rats—a site called the ventrolateral preoptic (VLPO)—seem to be activated when the animal is not awake. The researchers tracked the levels of a gene product that appears to be present whenever a cell is busy: the busy signal in these neurons was greater in animals that had slept more.

Sherin and his colleagues then took another step. They had previously suspected that neurons in the VLPO region send extensions to the rear part of the hypothalamus. By injecting what is called a retrograde tracer into the suspected target region in the rear of the hypothalamus and then following the diffusion of the tracer, they proved that the sleep-active neurons in the VLPO area did indeed project to the back part of the hypothalamus, where they wrap around their target cells. The pathway “probably is playing a major role and may play a critical role in helping sleep,” according to Saper.

Evidence from two quite different avenues of inquiry is consistent with the idea that a crucial piece of the  puzzle resides in that region. One is narcolepsy, which affects 250,000 Americans, causing them suddenly and unpredictably to lose muscle control and fall asleep. Any emotionally laden event—even hearing a joke—can trigger such attacks. Neurologists have supposed that some specific type of brain damage must underlie the condition, but nobody has been able to pinpoint it.

Until now. Jerome M. Siegel of the University of California at Los Angeles studied the brains of narcoleptic Doberman pinschers and found destruction of cells in the amygdala, a region involved in emotional responses. Damage to these areas could explain the symptoms of narcolepsy, Siegel suggests. Moreover, neurons run from the amygdala to the front part of the hypothalamus. It is therefore possible, others observe, that cell death in the amygdala might somehow influence the VLPO, bringing on drowsiness and the loss of muscle control characteristic of REM sleep.

Another VLPO clue comes from studies of circadian rhythms, described roughly as a 24-hour cycle of sleep and waking. Recognized as providing one cue for sleep in animal studies, the circadian clock resides in a part of the hypothalamus called the suprachiasmatic nucleus. And the suprachiasmatic nucleus sends neuronal projections to the VLPO, Saper reports. This pathway could be what directs signals about the time of day from the suprachiasmatic nucleus to the VLPO region.

Details of the neural circuitry that turn on sleep beg the question of what sleep is ultimately for. No damage to the brain prevents sleep indefinitely, notes James M. Krueger of the University of Tennessee. Therefore, Krueger argues, the final explanation must involve a benefit to neural functioning. And he asserts that the benefit is closely linked to the immune system.

Krueger points to experiments conducted by Carol A. Everson, also at Tennessee, showing that rats deprived of sleep have high numbers of bacterial pathogens that are normally suppressed by the immune system. Everson says there is little doubt that the bacteria eventually kill the rats. The exhausted, dying rats fail to develop fever, which would be the normal response to infection. Prolonged sleep deprivation, then, apparently dangerously suppresses the immune system. In humans, even moderate sleep deprivation has a detectable influence on immune system cells.

Further, the effect of sleep on the immune system is not a one-way street: the immune system affects sleep in return. Infections are well known to cause sleepiness, and Krueger has shown that several cytokines, molecules that regulate immune response, can by themselves induce slumber. In addition, cytokines have direct effects on neural development. Krueger and his colleagues have recently demonstrated that in rats, a gene for one cytokine becomes more active in the brain during sleep. He suggests that cytokine activity during sleep reconditions the synapses, the critical junctions between neurons, thereby solidifying memories. The  cytokines also keep the immune system in shape. Neural pathways like the one in the VLPO region, according to Krueger, may simply coordinate a process that arises at the level of small groups of neurons.

Many physiologists still regard Krueger’s ideas as speculative—but later this year Krueger says he will present hard data indicating that cytokines are involved in normal sleep. Genetically engineered mice that lack receptors for two important cytokines, interleukin-1 and tumor necrosis factor, sleep less than usual, Krueger says. So these and related cytokines may well trigger normal sleep in healthy animals, not just the sleepiness of infection and fever.

Whether cytokines, heat-sensitive neurons and the VLPO area indeed hold the key to understanding sleep is a question for the future. But one thing is clear: sleep researchers have never before had so many tantalizing leads or such a full agenda.


Post a Comment