The recognition of behaviorally distinct sleep stages in Drosophila melanogaster uncovers previously obscured homeostatic and circadian control of sleep
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Understanding the mechanisms underlying homeostatic sleep regulation is a central unmet goal of sleep science. Our understanding of such regulation in mammals has required recognizing distinct sleep stages. Drosophila melanogaster is an important genetic model system for understanding sleep. Since the discovery of sleep-like states in the fly 25 years ago, the field has treated sleep as a unitary state consisting of any inactivity lasting 5 minutes or longer, despite convergent work suggesting the existence of multiple sleep stages. Here, we establish that three distinct sleep stages in flies can be classified based on simple inactivity duration criteria. We show that the daily initiation of these sleep stages is temporally distinct, with long sleep occurring immediately following the largest daily period of wakefulness. We show that rebound in response to mechanical sleep deprivation is present only in long sleep and comes at the expense of shorter sleep stages. Deprivation-induced decreases in shorter sleep stages obscure homeostatic sleep rebound when sleep is measured using traditional methods. We observe distinctly timed ultradian oscillations of fly sleep stages, reminiscent of mammalian sleep cycles. Our results indicate that the field’s unitary definition of fly sleep has outlived its usefulness and call for the re-examination of sleep regulation in the fly using methods that reflect the unique relationships among sleep stages and their homeostatic and circadian control. The recognition of these sleep stages will be necessary to fully realize the promise of the Drosophila model system for identifying conserved genetic mechanisms underlying such regulation.
Significance
The fact that sleep episodes comprise distinct stages in humans and mammalian model systems has been a fundamental discovery in sleep science. This recognition enabled researchers to study the physiological underpinnings of sleep stages and examine the comorbidities and consequences associated with disrupted sleep. The mechanisms underlying sleep homeostasis remain an open problem, and the fruit-fly Drosophila melanogaster continues to be a powerful genetic and neurobiological model to study sleep regulation. Despite recent convergent evidence for distinct sleep stages in the fly, the field continues to treat sleep as a unitary state consisting of any inactivity lasting five minutes or longer. This practice likely obscures important aspects of sleep regulation in the fly, limiting its impact on our understanding of sleep regulation. Inspired by recently developed wearable technologies, which score sleep stages based on motion detection and accelerometry, we asked if distinct fly sleep stages can be identified based on durations of inactivity bouts, and, if so, whether stages of fly sleep are differentially regulated by the two major processes governing sleep: sleep homeostasis and circadian timekeeping. We show that discrete sleep stages can be identified and have distinct relationships amongst each other and to homeostatic sleep regulatory and circadian control centers. Importantly, we find that sleep deprivation produces increases in longer, deeper sleep stages while producing decreases in shorter sleep stages. These opposing responses to deprivation obscure homeostatic sleep responses when the traditional, unitary definition of sleep is used, a reality that has likely hampered the identification of homeostatic regulatory mechanisms in the fly. We concluded that using the simple behavioral criterion we describe here to differentiate sleep stages will be critical for understanding homeostatic and circadian sleep regulation in Drosophila , which remains an important model organism for the discovery of mechanisms of sleep regulation.
