Sleep is one of the few major whole-organ phenomena for which no function and no underlying mechanism have been conclusively demonstrated. Sleep could result from global changes in the brain during wakefulness or it could be regulated by specific loci that recruit the rest of the brain into the electrical and metabolic states characteristic of sleep. Here we address this issue by exploiting the genetic tractability of the fruitfly, Drosophila melanogaster, which exhibits the hallmarks of vertebrate sleep. We show that large changes in sleep are achieved by spatial and temporal enhancement of cyclic-AMP-dependent protein kinase (PKA) activity specifically in the adult mushroom bodies of Drosophila. Other manipulations of the mushroom bodies, such as electrical silencing, increasing excitation or ablation, also alter sleep. These results link sleep regulation to an anatomical locus known to be involved in learning and memory.

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

Neuronal stressors such as hypoxia and firing of action potentials at very high frequencies cause intracellular Na+ to rise and ATP to be consumed faster than it can be regenerated. We report the cloning of a gene encoding a K+ channel, Slick, and demonstrate that functionally it is a hybrid between two classes of K+ channels, Na+-activated (KNa) and ATP-sensitive (KATP) K+ channels. The Slick channel is activated by intracellular Na+ and Cl- and is inhibited by intracellular ATP. Slick is widely expressed in the CNS and is detected in heart. We identify a consensus ATP binding site near the C terminus of the channel that is required for ATP and its nonhydrolyzable analogs to reduce open probability. The convergence of Na+, Cl-, and ATP sensitivity in one channel may endow Slick with the ability to integrate multiple indicators of the metabolic state of a cell and to adjust electrical activity appropriately.