Sleep—an inspiration to poets and scientists alike—moved Shakespeare to write:
Sometimes a thousand twangling instruments
Will hum about mine ears; and sometime voices,
That, if I then had wak’d after long sleep,
Will make me sleep again
Scientists look at sleep’s onset, duration, and return more mechanistically. For years, they have been trying to work out the details of a two-process model of sleep. One process, the circadian clock, controls the onset and offset of sleep; the other process, the sleep homeostat, regulates sleep duration based on the sleep pressure built up during prior wakefulness.
Circadian control has been relatively well characterized—brain structures and neurotransmitters have been implicated in the timing of sleep and wakefulness. The sleep homeostat is less well known. At least one detail, however, has recently come to light. A protein—a newly discovered sleep mutant called redeye—appears to be directly controlled by the homeostatic drive to sleep.
This link to sleep drive was uncovered by researchers affiliated with the University of Pennsylvania’s Perelman School of Medicine and the Howard Hughes Medical Institute. They published their findings February 4 in eLife, in an article entitled “Identification of Redeye, a new sleep-regulating protein whose expression is modulated by sleep amount.”
The article, which cites the difficulties of performing genetic experiments with mammalian models, relied on fruit flies, Drosophila, one of several premier genetic organisms that have been introduced into the sleep field. Work with such organisms suggests that behavioral genetics in lower organisms provides an efficient tool to identify sleep components. Moreover, as the authors insist, at least some of the mechanisms underlying sleep are conserved through evolution.
In detailing their results, the authors wrote: “We conducted a forward genetic screen of chemically mutagenized flies to identify short-sleeping mutants and found one, redeye (rye) that shows a severe reduction of sleep length. Cloning of rye reveals that it encodes a nicotinic acetylcholine receptor α subunit required for Drosophila sleep."
The researchers, led by Amita Sehgal, Ph.D., a neuroscience professor at Perelman, concluded that cycling of the redeye protein is independent of the circadian clock in normal day/night cycles. Instead, this cycling appears to depend on the sleep homeostat. According to the researchers, redeye protein levels are upregulated in short-sleeping mutants as well as in wild-type animals following sleep deprivation. Also, they found that mutant flies had normal circadian rhythms, suggesting that their sleep problems were the result of disrupted sleep/wake homeostasis.
Providing yet more details, the authors indicated that “while rye builds up during sleep deprivation, it does not accumulate gradually over the wake period in a daily cycle. Rather, it displays a marked increase close to the time of sleep onset, suggesting that it is not a central component of the homeostat, but responds to an upstream homeostatic signal, perhaps when that signal reaches a certain threshold.”
Ultimately the researchers want to use the redeye gene to locate sleep homeostat neurons in the brain. Identification of molecules that reflect sleep drive could lead to the development of biomarkers for sleep, and may get us closer to revealing the mystery of the sleep homeostat.