Question: what鈥檚 the best way to keep a lab rat awake? Answer: put it on a turntable wired to rotate slowly whenever the rat鈥檚 brain waves suggest the beginning of sleep. If the rat starts to nod off, it has to wake up and walk against the spin to avoid bumping into a stationary wall.
For the first week or so, nothing really terrible seems to happen. But keep the rat on the turntable for much longer than a week and it starts to deteriorate. Sores break out for no apparent reason. Thyroid hormones fall. The rat鈥檚 metabolic rate increases even as its body temperature mysteriously drops. Eventually, about 21 days into the marathon, the rat will die. That鈥檚 only about three days longer than it might have lasted without food or water.
Conclusion: sleep, that peculiar biological state that consumes 20 or more years of our lives, is almost as necessary as eating and drinking.
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If only it were that simple. Even when the hapless rat dies from lack of sleep, researchers have a hard time working out exactly what killed it. And in the human realm, a few people get by on so little sleep you begin to doubt its necessity. One 57-year-old man studied by Canadian researchers in the 1970s slept less than 2 hours a night for more than 25 years. One night he overslept in the researchers鈥� lab, sluggardly snoozing for a full two and a half hours. Next day he was groggy and performed poorly.
But for all its slippery complexity, sleep is one enigma scientists are hellbent on solving. A bewildering number of theories have come and gone over the years. But a clear division is now opening up between two main camps.
On one side are researchers who believe sleep is mainly a tactic for conserving energy and recharging energy stores. On the other are those who think sleep is when the brain goes 鈥渙ff-line鈥� to do jobs it can鈥檛 so easily do when we鈥檙e fully conscious-like process information acquired over the course of the day, wash out unwanted memories, or even exercise synapses that don鈥檛 get much of a look-in during the day.
Others simply say, a plague on all your theories, let鈥檚 decide what鈥檚 sleep is for after we鈥檝e studied what really happens to brain cells and their DNA during sleep. And in between all this are researchers who think the enigma may have many meanings. 鈥淚鈥檓 really not convinced that sleep has a universal function that is common to all mammals,鈥� says Jim Horne, who runs the sleep lab at the University of Loughborough in Leicestershire. 鈥淪leep has a variety of functions.鈥�
Indeed, perhaps we should really talk about 鈥渟leeps鈥�. For sleep itself involves the brain cycling between two very different states. Slow-wave sleep, which dominates the first few hours, is characterised by slow, rhythmic delta waves of electrical activity that are synchronised across much of the brain. The second state is known as rapid eye movement or REM sleep. Unlike the slow-wave variety, REM sleep is a time of frenetic brain activity. On an EEG, the brain waves are rapid and disorganised, much as they are when awake. This is when we are most likely to dream, and, except for the jerky eye movements that give REM its name, the body鈥檚 muscles go flaccid, keeping us from acting out these dreams.
As different as these sleep states are, however, they have one obvious thing in common-an immobile body. And this is the characteristic some researchers choose to concentrate on. Sleep is simply a mild form of hibernation, a process everyone agrees is for energy conservation, argues Ralph Berger, a sleep researcher at the University of California at Santa Cruz. Sleepy animals often curl up in energy-saving postures, and sleep as we know it best is unique to birds and mammals, both of which spend large amounts of energy warming their bodies. What鈥檚 more, birds and humans sleep more when they are short of food.
But let鈥檚 look at the numbers. A sleeping person uses 15 to 20 per cent less energy than a couch-potato, a mere saving of around 120 kilocalories over an 8-hour night. Is it worth being unconscious for so many hours just to save the equivalent of a slice of bread? Maybe not. Then again, maybe our sleep patterns are a throwback to our early, shrew-like beginnings. Smaller animals enjoy much greater savings from sleep, because their metabolic rates are much higher-and because they can鈥檛 sit still while awake.
And smaller mammals do indeed sleep more than larger ones, according to a study by Harold Zepelin, a psychologist at Oakland University in Rochester, Michigan. Bats, for example, catch almost 20 hours of shuteye in a typical day, and many ground squirrels sleep 15 hours or more. In contrast, elephants and cattle get about 4 hours, horses 3, and giraffes, the champion insomniacs of Zepelin鈥檚 study, may make do with less than 2 hours sleep. Cats are the exception-no surprise here-with even lions and tigers spending the majority of the day asleep. This laziness may have to do with a predator鈥檚 uncertainty about when the next meal will come along, says Zepelin.
But there are some things energy conservation simply cannot explain. Hibernating rodents, for example, warm their bodies back to normal temperature several times each winter and then sleep away much of these 鈥渁ctive鈥� periods. Why? If sleep were only for conserving energy, the animals would do better to forgo it and quickly return to hibernation. Why, too, should sleep deprivation have such mind-fogging and even lethal consequences, even where food is plentiful?
The explanation must lie within the brain. 鈥淎ny human being who sleeps would say instinctively that sleep is restorative,鈥� says Joel Benington, a neurobiologist at St Bonaventure University, New York state. But what exactly does sleep restore? The simplest explanation is that the brain somehow 鈥渢ires itself out鈥� in wakefulness and needs to 鈥渞ecover鈥�. And indeed, Horne finds that the frontal lobes of the cerebral cortex-the most active part of the brain during wakefulness, and the site of our most complex and distinctively human thought processes-are the first to suffer during sleep deprivation.
But in what sense does the brain tire itself out? Over the past couple of years an answer has begun to emerge from research into a molecule called adenosine.
Adenosine is the A in ATP, the energy molecule that cells use as their ready cash. It is also a molecular messenger, which acts on receptors to damp down nerve cell activity. This effect is particularly strong in the 鈥渁rousal centres鈥� of the brainstem that keep an organism awake, according to experiments by Robert Greene, a neurobiologist at the Brockton Veterans Administration Medical Center at Harvard. Caffeine, the favourite drug of sleep-deprived people, seems to work by blocking adenosine receptors.
In fact, according to research in another Brockton lab, adenosine鈥檚 release in the body may even provide the main chemical signal to sleep. Robert McCarley鈥檚 team has documented adenosine鈥檚 role in the sleep cycle of cats in great detail. When the researchers injected adenosine into the arousal centres of their brainstems, the cats had more slow-wave and REM sleep. By sampling fluid from the brainstem, the researchers also showed that adenosine levels rise gradually during waking, and fall again during sleep. 鈥淭hat was the final piece of the puzzle in identifying adenosine as a sleep factor,鈥� says Greene.
Insomniacs on the lookout for a 鈥渘atural鈥� sleeping pill will be disappointed, however. Adenosine-like compounds given as drugs do make people sleepy-but they also lower blood pressure.
Nor does any of this explain why we need something like adenosine to 鈥渢urn down鈥� the brain in the first place. One idea, from Benington and Craig Heller of Stanford University, is that the brain needs time out to replenish its emergency reserves of energy. The brain鈥檚 staple fuel is the glucose carried in the bloodstream. But, like muscle fibres, it keeps a small reserve of glucose locked up as glycogen. If the brain draws on this reserve during waking, suggest Benington and Heller, the fuel store may need to be recharged during sleep. And adenosine-which is released by energy-starved cells-may trigger and control the recharging.
Of course, something different must be going on during the frenzy of brain activity that is REM sleep. Benington and Heller think that the brain uses REM activity to recover from the biochemical rigours of slow-wave sleep. They have done experiments showing that the brain鈥檚 need for REM sleep builds up during slow-wave sleep-and not, as you might expect, during wakeful periods. During slow-wave sleep, potassium ions leak out of brain cells, causing the cells to become unresponsive to normal electrical inputs. The purpose of REM sleep, Heller and Benington suggest, is to give brain cells a chance to recover potassium ions before the deficit causes a metabolic upset. Block the potassium leak with a drug and rats lose their need for REM sleep.
Both researchers stress that their glycogen hypothesis needs more work. Later this year, Heller hopes to begin the crucial experiments to see if glycogen levels in the brain fall during waking and rise again in slow-wave sleep. But even if the results turn out unfavourably, Benington still thinks energy metabolism must be the key to sleep. 鈥淚 would hate for this particular glycogen hypothesis to turn out wrong and have people turn away from energy metabolism in general,鈥� he says.
Some researchers, however, have already rejected energy metabolism as the principal reason for sleep. They argue that sleep has a much more sophisticated function, helping the brain to process memories.
At Trent University in Peterborough, Ontario, for example, Carlyle Smith and his coworkers have spent the past decade and a half documenting a link between sleep-especially REM sleep-and memory. Lab rats, for example, spend more time than usual in REM sleep during the days immediately after they have been laboriously trained to avoid a shock. Psychologists鈥� other favourite experimental animals-college students-show something similar. In the week after cramming for exams, students experience unusually frantic REM activity in their sleep. And depriving either rats or students of REM sleep after a period of learning hinders their ability to remember what they learned. Somehow, says Smith, REM sleep must help to 鈥減ackage鈥� memories for long-term storage in the brain.
And this packaging occurs at precise intervals after the learning period. In one experiment, rats learned to run through a connecting door between two cages whenever a light flashed to avoid an electric shock. After this training period, some rats were immediately deprived of REM sleep for 4 hours. Other rats were deprived of REM for 4 hours later that day. When Smith retested the rats, he discovered some intriguing differences. Rats robbed of REM sleep 9 to 12 hours after training remembered how to avoid the shock only half as well as rats that got their full complement of REM. Rats deprived 17 to 20 hours after training also showed slightly poorer memory. But rats robbed of REM sleep at other times performed just as well as those that got all the sleep they wanted.
In later experiments, Smith learned that the timing of the REM sleep 鈥渨indow鈥� varies depending on the complexity of the task. The window for learning the location of a submerged resting-place in a pan of murky water comes 4 to 8 hours after training. But windows come earlier when rats have more information to learn, as though the brain were in a hurry to process the information before it starts to leak away.
Humans have these REM sleep windows for learning, too, says Smith-though only for procedural memory (remembering 鈥渉ow鈥�), not for the simpler declarative memory (remembering 鈥渨hat鈥�). For example, people who miss the REM sleep window remember less about how to do logical puzzles requiring the manipulation of symbols according to arbitrary rules. But loss of REM sleep for a night or two never interferes with the ability to memorise paired lists of words or names. Presumably, these simpler tests require less sophisticated brain power and so less processing during REM sleep.
The twist is that there may also be crucial 鈥渓earning windows鈥� in slow-wave sleep. Since the 1950s, researchers have known a good night鈥檚 sleep helps in learning physical skills such as trampolining. 鈥淲hen you come back the next day, you are miraculously better. When there鈥檚 sleep deprivation, you don鈥檛 get that magic boost,鈥� says Smith.
In lab studies, people deprived of the second half of their night鈥檚 sleep fail to show the usual improvement in one simple physical task the next day-using a stylus to track a moving point on a computer screen. But Smith found that REM deprivation alone can鈥檛 explain that failure. Nor can loss of deep sleep, which mostly takes place during the first half of the night. This leaves only light slow-wave sleep, dominant during the second half of the night, as the likely window for 鈥渓earning鈥� the stylus task.
Across the continent in Tucson, Arizona, researchers may have caught a glimpse of one mechanism by which sleep aids memory processing. Using an ingenious system of electrodes implanted in the brain of a rat, Bruce McNaughton and his colleagues at the University of Arizona are tracking the firing patterns of individual neurons as rats learn to find food in a simple 鈥渕aze鈥�-actually just a rectangular or triangular racetrack. The experiments focus on the behaviour of neurons in the hippocampus, a brain structure that plays a part in the laying down of new memories, especially those dealing with location and space. McNaughton鈥檚 team has found that particular combinations of 鈥減lace cells鈥� in the hippocampus fire at specific locations on the track. The rat鈥檚 journey is encoded as a sequence of such combinations.
Action replay
That alone would be an interesting bit of neurobiology. But McNaughton also finds that the brain replays that same sequence of place-cell firings during sleep shortly after the rat leaves the track. The researchers suspect the replay strengthens synaptic connections and thus helps to fix the experience in long-term memory in the cerebral cortex.
Using the same technique, Gina Poe, a researcher in McNaughton鈥檚 lab, finds that important information processing may also occur during REM sleep. During waking and REM sleep in rats, cells of the hippocampus keep up a steady 5 to 10 hertz brain-wave pattern called the theta rhythm. Other researchers have shown that this theta rhythm is important for reshaping connections between neurons. Synapses that fire at the peak of each theta wave become stronger, while those that fire in the theta troughs become weaker. That鈥檚 likely to mean the rhythm has a role in learning, since remodelling synapses is, in essence, how the brain soaks up new information and throws out old. But what role for the theta rhythm?
Poe鈥檚 results from lab rats provide a clue. During REM sleep, cells that store newly learned 鈥渕aze information鈥� tend to fire at theta peaks. That could help to strengthen those memories. In contrast, cells that store familiar information tend to fire in the troughs, which may wash out the older memories. Since the hippocampus serves as a short-term memory store, this 鈥渉ouse-cleaning鈥� makes sense. 鈥淒uring slow-wave sleep, memories are being replayed to the cortex and consolidated there,鈥� suggests Poe. 鈥淒uring REM sleep, you鈥檙e either strengthening memories that have not yet been fully consolidated or weakening memories that have already been encoded in the cortex, so the synapses in the hippocampus can be used for other memories.鈥�
The link to memory has its sceptics. Unlike rats, they point out, humans do not produce a prominent theta rhythm. And people who go short on sleep should suffer no major memory impairments, but don鈥檛. 鈥淚 don鈥檛 believe this information-consolidation hypothesis one bit,鈥� says Priyattam Shiromani, a Brockton neuroscientist. 鈥淎n animal with no REM should be the stupidest animal on the planet. Dolphins have no REM, and they鈥檙e pretty smart.鈥�
If sleep does play some role in memory, it must be subtle enough to be overlooked in everyday life. But perhaps it stars in some other crucial aspect of brain wiring. James Krueger, a physiologist at the University of Tennessee Medical School in Memphis, thinks that the brain takes itself off-line during sleep so it can exercise important, but rarely used, neural pathways. The synapses that connect nerve cells follow the 鈥渦se em or lose em鈥� rule. But there鈥檚 a problem: many pathways don鈥檛 get used regularly in waking life. For example, circuits that help the body cope with extreme conditions in the environment, such as an abnormally high CO2 concentration, might be maladaptive under normal circumstances, he says. But safely confined to sleep, and unplugged from the waking world, the brain can exercise these synapses without acting out the behaviour. Unlike most other sleep hypotheses, Krueger鈥檚 explains why we must be unconscious when we sleep. It also explains why sluggards who stare blankly at a TV all day need just as much sleep as hot-shot executives.
The theory has very little data to back it up so far, Krueger admits. He knows that interleukin-1, a messenger molecule in the bloodstream that accumulates during waking and encourages the sleep to begin, also affects the formation of synapses. And a Russian study on cats by Ivan Pigarev, at the Russian Academy of Sciences in Moscow, hints that the brain鈥檚 normal firing pathways may change dramatically during sleep, when neurons in the visual cortex mysteriously begin to respond to nerve signals from the gut. 鈥淭here鈥檚 a night-and-day reorganisation in terms of where the neuronal traffic鈥檚 going,鈥� says Krueger. The point of which is to give unusual neural connections a workout in sleep.
Ideally, of course, Krueger would like to find direct evidence that little-used synapses are strengthened during sleep. This research might prove impossible with complex mammalian brains, so Krueger is now turning to insects, which enter a state with all the behavioural characteristics of sleep. 鈥淲e don鈥檛 have a chance of seeing anything like a mammalian EEG, because their brain is organised totally differently, so we鈥檙e going to look at it at a biochemical level,鈥� says Krueger. He hopes to track individual nerve cells to see how they respond to insect interleukin-1 and other sleep-controlling and synapse-shaping molecules. This direct approach, he thinks, will give a much clearer test of his theory.
But even then it will be be only one of many ideas that muster a little experimental support. Is the real purpose of sleep synaptic remodelling, memory consolidation, glycogen replenishment, energy conservation, or-as Jim Horne and a few others believe-some combination of them all?
鈥淭hat there is no consensus probably means that we should look for more data,鈥� says Giulio Tononi, a neuroscientist at the Neurosciences Institute in San Diego, reputedly one of the best minds working on the subject. Instead of proposing yet another theory of sleep, Tononi and his coworkers are using a molecular technique called differential display to look at every gene that is expressed in brain cells-some 5000 to 10 000 of them-to find those that are more active during sleep than waking or vice versa. With the genes in hand, they hope to learn their function and eventually work out the function of sleep itself. 鈥淚t is a huge endeavour-but it is also hypothesis-free. We are not at the start assuming that the function of sleep is this or that,鈥� says Tononi.
Early returns look good. The researchers have already confirmed that several so-called immediate early genes, such as c-fos and nerve growth factor-induced A, vary significantly between waking and sleeping. Since these genes act as switches to control the activation of other genes, Tononi is hopeful that many other genes will also turn out to track the sleep rhythm, and initial results indicate that they do.
Sooner or later, Tononi鈥檚 experiments -or those of some other researcher elsewhere-will yield clear and convincing evidence to help resolve the tangle of theories on the function of sleep. Until then, however, Tononi plans to keep his head down, well below the parapet. 鈥淚 am agnostic,鈥� he says. 鈥淚 have my personal preferences, but I keep them for myself.鈥�
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Help, there are spiders on my shoes
Forget bad concentration and tetchiness. Long bouts of sleeplessness can seriously warp the mind as well.
In the first recorded experiment, in 1896, psychologist Allen Gilbert stayed awake for 90 hours in his lab at Iowa University. By the second night, Gilbert鈥檚 floor appeared, in his words, to be 鈥渃overed with a greasy-looking molecular layer of rapidly moving or oscillating particles鈥�. The greasy layer swelled to a foot above the floor, leaving Gilbert floundering as he tried to walk on it.
In 1959, Peter Tripp, a New York disc jockey, was closely monitored by psychologists as he stayed awake for 201 hours. After four days he had trouble recalling the alphabet. Hallucinations and paranoia quickly followed. At one point Tripp thought spiders were spinning webs on his shoes. Yet each night, curiously, he managed to summon up the energy and concentration to do his radio show.
Randy Gardner, a 17-year-old high school student in San Diego, showed a similar ability to concentrate on highly motivating tasks when he stayed awake for 11 days in 1964. On the final night of his record-breaking 鈥渁wakathon鈥�, Gardner beat sleep researcher William Dement 100 times at pinball. He then slept 15 hours and awoke feeling fine.
In general, The longer you stay awake, the fainter your alpha rhythms-brain waves that dominate during the day-become. Eventually, the brain starts producing the rhythms of stage 1 sleep even though you鈥檙e still awake. But really prolonged sleep deprivation results in abnormal, seizure-like brain rhythms.
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Boozing to forget
Many people turn to alcohol to help them fall asleep. But be warned: more than two or three drinks late in the evening can do more harm than good.
The problem is twofold. First, alcohol packs a delayed punch. It may put you to sleep quickly, but later in the night the body metabolises much of the alcohol into aldehydes, which can lead to fitful sleep in the wee hours-or even none at all. Second, and more insidiously, alcohol suppresses REM sleep, thought to be important for the processing of memories in the brain. As little as 0.6 grams of ethanol per kilogram of body weight-the equivalent of just over two pints of beer for an average-sized person-knocks out about half of the normal amount of REM sleep in the first half of the night, says Carlyle Smith of Trent University in Peterborough, Ontario.
Smith鈥檚 experiments confirm that even this comparatively small amount of alcohol can interfere with memory. Student volunteers learnt a logic puzzle that involves assembling a set of symbols into a sequence according to a complex set of rules. After the students got the hang of the puzzle, some were given alcohol either that night or two nights later. The following week, Smith retested all the students to see how well they remembered the puzzle. Students who took alcohol on the night of their learning period performed 30 per cent worse than normal. Even those volunteers who didn鈥檛 drink until two days after learning the test suffered significant memory loss.
College students who knock back a few pints after a hard evening of studying may obliterate much of their hard-won knowledge, says Smith. It鈥檚 something he can detect among his own psychology classes. Smith lets students practise the logic puzzle late one week, then sends them home for the weekend. The next week, he tests them to see how well they remember the task. 鈥淚 can always pick out a group who have stayed up way beyond their bedtime or had a lot of alcohol. It鈥檚 worse if they鈥檝e done both.鈥�
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Bugnaps
DO cockroaches catnap? It depends who you ask-or rather, how you define sleep. For some researchers, slow and rhythmic brainwave activity is the only sure indicator of sleep. Since insects have little in the way of a brain, much less slow-wave activity, they must by definition be sleepless.
But cockroaches and bees will sink into a state that has all the other hallmarks of sleep. They become oblivious to gentle stimuli. Their postural muscles relax and their antennae droop. And if forcibly aroused every time they drop off, the insects need a longer period of 鈥渟leep鈥� afterwards to make up for the loss.
Nobody knows whether this state is akin to mammalian sleep. But if it is, it means that sleep arose very early in evolution.
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Snoozing with half a brain
DOLPHINS spend the night half-asleep. First the right half of their brains goes to sleep, then the left. In fact, the two hemispheres of a dolphin鈥檚 brain trade off, like sentries in a military camp, several times in the course of a night, according to brainwave recordings by Lev Mukhametov of the Academy of Sciences in Moscow. While one hemisphere is in deep, slow-wave sleep, the other is always alert. And when experimenters keep dolphins awake to prevent the right (or left) brain from taking its usual turn, only that side builds up a sleep debt. This bizarre sleep pattern has now been seen in several dolphin and whale species and some seals. It may ensure that some part of the brain is always alert to control breathing in their watery environment. Indeed, dolphins stop breathing entirely if given drugs that put both sides of the brain to sleep at once.