We study the molecular and cellular bases underlying daily behaviors, most notably the daily changes in wake-sleep states. Daily rhythms in wake-sleep are regulated by brain-based pacemaker cells called circadian clocks; sensory inputs, such as photic and temperature; physiologic inputs, such as feeding and metabolic state; and are central to many diseases, such as Parkinson’s, Alzheimer’s and sleep disorders. Our overarching goal is to discover novel pathways that regulate wake-sleep states and how these pathways respond to changes in the environment. To achieve these goals, we are using the powerful genetics available in Drosophila in combination with biochemical, proteomic, evolutionary, cell culture, behavioral, and histochemical approaches.
For many years our lab focused on elucidating the mechanisms underpinning circadian clocks. We identified novel clock genes and how they function. Many of the genes and mechanisms identified in Drosophila showed remarkable conservation with those in mammals, helping explain several human sleep disorders. Indeed, the seminal work based on Drosophila circadian biology was recognized with a Nobel Prize in 2017.
In more recent years we have been using Drosophila as a model system to understand mechanisms governing sleep and arousal states. As with circadian studies, Drosophila, with its ease of genetics, rapid behavioral assays and more simplified brain, offers a ground-breaking frontier in sleep research. Our initial sleep studies were aimed at investigating how daily wake-sleep behavior is regulated by changes in temperature. As we all know, it is difficult to sleep on hot nights, but warm temperatures increase the drive for a midday siesta. Drosophila melanogaster shows the same behavior. Recently, we discovered a new sleep-arousal gene that we call daywake (dyw), which led to a novel model for how siesta levels are modulated by ambient temperature (Yong and Edery, 2019, Current Biology). The dyw gene encodes a hormone-binding protein and acts as an anti-siesta gene that is upregulated by cold-enhanced splicing of an intron found in the nearby clock gene, period (per). To the best of our knowledge this trans-splicing mechanism has not been reported previously and suggests a novel gene-expression paradigm. In addition to better understanding how dyw functions in sleep/arousal/thermal adaptation, several in-house screens have led to the identification of novel genes regulating the balance between sleepiness and wakefulness. We also integrate natural populations that differ in wake-sleep behavior into our studies, giving our work an evolutionary and ‘real-world’ perspective. Although nocturnal sleep is clearly important, daytime sleep in humans is genetically-based and plays a role in learning, memory, well-being and disease prognosis. We anticipate that our studies aimed at characterizing new wake-sleep genes, and the interdependency of brain function and physiology, will shed important insights into the role of sleep in health and disease.
