There’s always one person snoring through the talk you’re trying to listen to at SfN. That person might even be you at some point during this meeting! Whether you are sleepy because of the time change, or because you finished your poster at 3AM, or because you were up late catching up with friends and colleagues, sleep is an essential behavior that is regulated by two independent processes: (1) a circadian clock that regulates the timing of sleep, and (2) a homeostatic mechanism that influences the amount and depth of sleep. Surprisingly, despite significant progress in our understanding of the molecular clock, the mechanisms by which the circadian clock regulates the timing of sleep is poorly understood.
In a recent collaborative study, researchers identified the molecule called WIDE AWAKE as a regulator of sleep onset. Using Drosophila as their model system, they examined thousands of different lines of flies until they found one that fell asleep later than other flies and didn’t sleep very long periods of time. They determined that these flies didn’t have WAKE in a set of arousal-promoting clock neurons, the large ventrolateral neurons, which explains their delay in sleep onset at dusk.
Previous studies in Drosophila have identified Clock and Cycle as transcriptional activators that are core circadian oscillators. Clock and Cycle mutant flies also exhibit profound delays in sleep onset. Interestingly, this impairment can be rescued by restoring WAKE expression in the large ventrolateral neurons of the fly brain!
So how does WAKE work? It turns out that WAKE interacts with GABA receptors and promotes their localization to the plasma membrane of large ventrolateral neurons. Since GABA is an inhibitory neurotransmitter, it seems likely that WAKE is helping to inhibit the large ventrolateral neurons, thus aiding in the transition from wake to sleep. In summary, WAKE acts as a clock output molecule specifically for sleep!
This study is a striking example of the power of fruit flies in identifying the cellular and molecular mechanisms that regulate sleep.
One of the collaborators on this study is Amita Sehgal, who is an HHMI investigator at the University of Pennsylvania. Be sure to catch her Special Lecture at SfN on Sunday, November 16, 2014 8:30-9:40am in Hall D. Her talk is titled, “What Drives Sleep – Wake Cycles: Identification of Molecules and Circuits in Drosophila.”
Liu S., Qili Liu, Masashi Tabuchi, Yong Yang, Melissa Fowler, Rajnish Bharadwaj, Julia Zhang, Joseph Bedont, Seth Blackshaw & Thomas E. Lloyd & (2014). WIDE AWAKE Mediates the Circadian Timing of Sleep Onset, Neuron, 82 (1) 151-166. DOI: http://dx.doi.org/10.1016/j.neuron.2014.01.040
Images courtesy of Sha Liu, Ph.D., first author of this publication and postdoctoral fellow in the Wu Lab at Johns Hopkins School of Medicine.