Ravi Allada, MD
- Professor, Department of Neurobiology
- Interdepartmental Neuroscience
- Weinberg College of Arts and Sciences
The Molecular Genetics of Circadian Rhythms and Sleep
We are interested in the molecular mechanisms underlying circadian rhythms and their links to various clinical disorders, such as insomnia, depression and even cancer(1-4). The origins of our molecular understanding of human circadian rhythms can be traced to genetic studies in the fruit fly, Drosophila melanogaster. Since the cloning of the first clock gene period in Drosophila in the1980s, the cloning of new fly rhythm genes has led to the discovery of their mammalian counterparts, reflecting their remarkable evolutionary conservation. Indeed, a mutation in a human homolog of Drosophila period is responsible for an inherited sleep disorder, advanced sleep phase syndrome (ASPS)(5). Across evolutionary boundaries, transcriptional feedback loops form the core of circadian pacemakers. We believe the most efficient strategy to identify new components of human circadian feedback loops is through a molecular genetic approach in Drosophila. The wealth of genetic tools and short generation time (~10 days) facilitate high throughput phenotype-driven screens that will be required to decipher the functional significance of the human genome. Current efforts in our laboratory are focused on cloning a novel circadian rhythm mutant as well as the identification of molecular and cellular links between central pacemakers and output genes and behaviors. The most prominent circadian behavior is the sleep-wake cycle. Sleep itself is as important as food; animals deprived of sleep live approximately as long (2-3 weeks) as they live without food (6,7). Approximately 60 million Americans experience suboptimal sleep, leading to loss in productivity, health and even fatal accidents(8) Although not for lack of effort, traditional neuroscience approaches have been unable to provide a compelling explanation for our need to sleep. The behavioral state of sleep is principally defined by circadian control, homeostatic regulation and characteristic drug responses. Astonishingly, fruit flies exhibit inactive states with all of these cardinal features (9,10). Flies are active in the day and inactive at night. Deprived of sleep, flies will compensate with extra rest. Fly sleep will even be perturbed by caffeine. It is hypothesized that the accumulation of specific molecules during wakefulness promotes the restorative process of sleep. To identify these molecules, we are screening for mutants that alter the quantity, quality, or pharmacology of sleep in flies.