Why we sleep remains a mystery, and drugs attempting to manipulate the sleep-wake cycle - depending on the consumer's goals, either to induce sleep or wakefulness - have a long history and a large market.
But for whatever reason, sleep is clearly essential for survival, and how we sleep is the subject of three recent papers investigating everything from genetic bases of sleep to the neurotransmitters involved.
In an article appearing in the April 28, 2005, issue of Nature, scientists from the University of Madison at Wisconsin identified a mutant fly that should become the envy of truck drivers and revelers everywhere - it needs only about four to five hours of sleep a day, roughly one-half to one-third as much sleep as its normal cousins, who spend nine to 15 hours of every day snoozing.
The researchers tested those flies, which they dubbed minisleep, on a variety of behavioral tasks, from the so-called geotaxic response (coordinated movement away from gravitational pull) to escape from heat; the flies showed no obvious behavioral deficits. In contrast to wild-type flies, however, they were not impaired on those behavioral tasks after sleep deprivation, though they did show increased sleep after a 24-hour period of sleep deprivation.
The scientists mapped the genetic mutation responsible for minisleep's decreased need for shuteye first to the X chromosome, and then to the Shaker gene, which encodes a voltage-dependent potassium channel.
Apparently, though, the mutation holds no lessons for those who want to get the most out of life by spending as little of it as possible asleep. Though the minisleep flies log less time sleeping on a day-to-day basis, pretty much their only described phenotypic aberration is a shortened life span.
Two other studies, both appearing in the April 21, 2005, issue of Neuron, investigate the roles of the transmitters orexin and adenosine in sleep and wakefulness, respectively.
In the first study, the authors, who hail from the University of Tsukuba, the Japan Science and Technology Corp., and the medical schools of Showa and Fukushima Universities, focused on the orexin system. Orexin is a peptide produced by neurons in the hypothalamus; it keeps animals awake, and an orexin deficiency causes narcolepsy in humans.
The downstream connections of orexin neurons already had been mapped, but little was known about their inputs. The scientists genetically engineered mice to produce a nontoxic fragment of the tetanus toxin as a tracer protein; the tracer was produced only in orexin-containing neurons, and can cross synapses to transfer itself upstream from that origin.
The scientists found that orexin neurons are innervated by cholinergic neurons in the basal forebrain, a cell population that is very active during aroused states. Previous studies already had shown that orexin neurons project to those cells, sending positive signals downstream to help keep them active. The new study showed that the innervation is reciprocal and the relationship between the basal forebrain cholinergic system and the orexin neurons is a self-reinforcing loop that can consolidate wakefulness.
In contrast to their activation by cholinergic forebrain neurons, orexin neurons appear to be inhibited by another group of hypothalamic neurons, as well as a group of neurons in the raphe nuclei. Both those upstream populations are known to be important for maintaining sleep.
"When one group of neurons is active, the other group must be inactive, and vice versa," said Masashi Yanagisawa, a Howard Hughes Medical Institute investigator at UT Southwestern and senior author of the study. "It's a seesaw, or flip-flop, mechanism. That's important because you don't want to be half-asleep. You want to be either completely awake or completely asleep."
Another way to keep from being half-asleep, of course, is to have a cup of coffee, and a separate paper in the same issue of Neuron investigates the relationship between adenosine, glutamate transmission, caffeine, and wakefulness.
Adenosine is something of a fatigue factor; it constantly exerts a weak inhibition on the cholinergic forebrain arousal centers, and prolonged wakefulness, as well as exploratory behavior, and the aftermath of stress, increases that inhibition, suggesting that adenosine facilitates the transition to sleep.
In the current Neuron study, Robert Greene and his colleagues at UT Southwestern used slices of brain stem and forebrain arousal centers culture to study the interplay between excitatory glutamate and adenosine transmission. Applying the usually excitatory NMDA over longer periods led to a decrease in excitatory currents through an increase in adenosine levels, which then stimulated presynaptic adenosine A1 receptors. The effects of NMDA could be blocked by the caffeine analogue cyclopentyltheophylline (CPT).
"Global inputs to the arousal system activate a local adenosine homeostatic mechanism," Greene told BioWorld Today. "And because those arousal systems project widely, those effects are then projected out globally again.
"Three things have to happen for this effect," he added. "NMDA receptors have to be activated, adenosine levels have to go up, and adenosine A1 receptors have to be activated."
The reversal effect of CPT both demonstrated the link between NMDA and adenosine and suggested how caffeine might exert its anti-drowsiness effects.
"We knew that coffee kept us awake," Greene said. "Now we know why: Coffee and tea are blocking the link between the prolonged neural activity of waking and increased levels of adenosine in cells, which is why they prevent us from getting drowsy."