Sleep is an essential process conserved from flies to humans. The importance of sleep is underscored by its tight homeostatic control. Here, through a forward-genetic screen, we identify a novel gene, sleepless, required for sleep in Drosophila. sleepless encodes a brain-enriched, glycosylphosphatidylinositol-anchored protein. Loss of SLEEPLESS protein causes an extreme (>80%) reduction in sleep. Furthermore, a moderate reduction in SLEEPLESS protein has minimal effects on baseline sleep, but markedly reduces recovery sleep following sleep deprivation. Genetic and molecular analyses reveal that quiver, a mutation that impairs Shaker-dependent K + current, is an allele of sleepless. Consistent with this finding, Shaker protein level is reduced in sleepless mutants. We propose that SLEEPLESS is a signaling molecule that connects sleep drive to lowered membrane excitability.Insufficient and poor quality sleep is an increasing problem in industrialized nations. Chronic sleep problems diminish quality of life, reduce workplace productivity, and contribute to fatal accidents (1). Although the biological needs fulfilled by sleep are unclear (2), they are likely to be important because sleep is conserved from flies to humans (3-7), and prolonged sleep deprivation can lead to lethality (8-10). Identifying mechanisms that control sleep may lead to novel approaches for improving sleep quality.Sleep is regulated by two main processes: circadian and homeostatic (11,12). The circadian clock regulates the timing of sleep, whereas the homeostatic mechanism controls sleep need. Homeostatic pressure to sleep increases with time spent awake and decreases with time spent asleep. Homeostatic control is thought to influence sleep under normal (baseline) conditions as well as recovery (rebound) sleep following deprivation. However, the molecular mechanisms underlying homeostatic regulation of sleep remain unclear.A powerful approach to unraveling a poorly understood biological process is to conduct unbiased genetic screens to identify novel molecules required for that process. The Drosophila model for sleep is well-suited for such an approach, which proved invaluable for elucidation of the molecular basis of the circadian clock. Although several Drosophila genes have been implicated in sleep regulation (for example, 13-15), only one of these, the gene encoding the Shaker (Sh) K + channel, was isolated as a result of a genetic screen (16). A mutation in this gene causes one of the shortest-sleeping phenotypes known, validating the use of screens and suggesting that control of membrane excitability is a critical requirement for # This manuscript has been accepted for publication in Science. This version has not undergone final editing. Please refer to the complete version of record at http://www.sciencemag.org/. Their manuscript may not be reproduced or used in any manner that does not fall within the fair use provisions of the
Most animals sleep more early in life than in adulthood, but the function of early sleep is not known. Using Drosophila, we found that increased sleep in young flies was associated with an elevated arousal threshold and resistance to sleep deprivation. Excess sleep results from decreased inhibition of a sleep-promoting region by a specific dopaminergic circuit. Experimental hyperactivation of this circuit in young flies results in sleep loss and lasting deficits in adult courtship behaviors. These deficits are accompanied by impaired development of a single olfactory glomerulus, VA1v, which normally displays extensive sleep-dependent growth after eclosion. Our results demonstrate that sleep promotes normal brain development that gives rise to an adult behavior critical for species propagation and suggest that rapidly growing regions of the brain are most susceptible to sleep perturbations early in life.
Summary Endogenous circadian rhythms are thought to modulate responses to external factors, but mechanisms that confer time-of-day differences in organismal responses to environmental insults/therapeutic treatments are poorly understood. Using a xenobiotic, we find that permeability of the Drosophila “blood”-brain barrier (BBB) is higher at night. The permeability rhythm is driven by circadian regulation of efflux and depends upon a molecular clock in the perineurial glia of the BBB, although efflux transporters are restricted to subperineurial glia (SPG). We show that transmission of circadian signals across the layers requires gap junctions, which are expressed cyclically. Specifically, during nighttime gap junctions reduce intracellular magnesium ([Mg2+]i), a positive regulator of efflux, in SPG. Consistent with lower nighttime efflux, nighttime administration of the anti-epileptic phenytoin is more effective at treating a Drosophila seizure model. These findings identify a novel mechanism of circadian regulation and have therapeutic implications for drugs targeted to the central nervous system.
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