Molecular and cellular mechanisms underlying circadian rhythms and sleep in Drosophila

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Summary: The environment on Earth is rhythmically changing, and organisms need to adapt to and anticipate these cyclical variations. For us humans, the most striking and impactful environmental cycle is the alternance of day and night, and we organize our activities around it. For example, we usually work and eat during the day, and sleep preferentially at night. Actually, our metabolism, physiology and behavior are all controlled by intracellular molecular timers called circadian clocks, that optimize most of our bodily functions with the time-of-day. When these biological clocks are disrupted, for example in shift workers, the incidence of cancers, metabolic diseases and mood disorders is increased. Circadian clocks are present in most organisms, and the use of potent genetically-tractable models in cyanobacteria, plants, fungi and mammals has shed light on the basic principles underlying circadian rhythms. In all eukaryotes, transcriptional feedback loops modulated by post-translational modifications are at the core of the molecular circadian clock. Drosophila melanogaster has proved to be a particularly potent model for the study of circadian rhythms, and the molecular and neural mechanisms uncovered in fruit flies have been found to be particularly well conserved in mammals. Drosophila is also a very efficient system to study sleep, a key circadian output. Our long-term goals are to understand in detail how Drosophila circadian rhythms are generated and how they are synchronized with the day/night cycle. More recently, we have also studied how sleep is controlled in fruit flies. We propose here to tackle three critical questions. First, we aim to determine comprehensively how post-transcriptional regulatory mechanisms control circadian rhythms. Indeed, while circadian transcriptional and post-translational controls have been characterized in detail, the regulation of circadian rhythms at the mRNA processing and translational levels remains poorly understood. Second, we aim to understand the phenomenon of temperature compensation. This property ensures that the period of circadian clocks is insensitive to ambient temperature and is therefore necessary for these biological timers to be of adaptative value. However, how circadian temperature compensation is achieved remains unclear. Third, we aim to uncover the mechanisms by which glia regulate sleep, with a focus on glial transporters. Indeed, glia is emerging as an important modulator of neural sleep circuits in fruit flies and mammals. These three innovative aims should decisively advance our understanding of circadian rhythms and sleep in Drosophila. Given the conservation of the mechanisms underlying circadian clocks and sleep, and the essential role they play for the well-being and survival of animals including humans, we expect that our work will have broad implications, including for human health.