Assistant Professor of Neurology and Neuroscience
McKusick-Nathans Institute of Genetic Medicine
289 Rangos Building
Johns Hopkins University, School of Medicine. Baltimore, MD 21205
Phone: (410) 502-7511
Genetics and Circuitry Underlying Sleep
Although we spend a significant portion of our lives asleep, why we sleep remains a mystery. Despite the apparent evolutionary drawbacks of sleeping for hours every day, sleep is conserved throughout the animal kingdom. It was recently discovered that fruit flies sleep, and we use Drosophila as a genetically tractable model organism to dissect the genetic and cellular basis of sleep. In addition, we are studying the impact of sleep on neurodegenerative diseases in both flies and humans.
Genetics of Sleep
We have been conducting large-scale forward genetic screens to identify novel genes that regulate sleep. sleepless is one of the shortest sleeping mutants identified, and we determined that the Sleepless protein is a novel molecule that regulates Shaker potassium channels. These findings highlight the importance of downregulating neuronal excitability in sleep. In humans, a similar situation occurs in Morvan’s syndrome, a condition where patients have, among other symptoms, profound insomnia and generally have potassium channel autoantibodies. Sleepless also resembles certain snake neurotoxins, and along with a related molecule, Lynx-1 (which regulates nicotinic acetylcholine receptors), may define a novel family of proto-toxin like molecules that regulates different ion channels.
Circuitry of Sleep
Drosophila is also an outstanding system for the functional dissection of neuronal circuitry. Flies have about 100,000 neurons in the brain, which is large enough to mediate complex behaviors, but small enough to potentially catalog at the single cell level. We are working to identify neuronal circuits that regulate sleep and arousal in flies, as well as how circadian and homeostatic processes influence these circuits. Recently, we identified a single pair of dopaminergic neurons that promotes wakefulness by signaling to and inhibiting the dorsal fan-shaped body, a structure that promotes sleep in flies. These studies suggest that mutually inhibitory wake and sleep promoting circuits (“flip-flop switches”) are an evolutionarily conserved mechanism to promote fast and complete state switching between wake and sleep.
Sleep and Neurodegeneration
Patients with Alzheimer’s disease have impaired sleep and circadian rhythms. Moreover, recent work in mice suggests that poor sleep can accelerate the disease process, by increasing amyloid plaque burden. We are studying the relationship between sleep and amyloid in fly models of Alzheimer’s disease as well as in humans and are working to determine the mechanisms by which lack of sleep can enhance amyloid plaque formation.
Liu, Q., Liu, S., Kodama, L., Driscoll, M., and Wu, M.N. (2012). Two Dopaminergic Neurons Signal to the Dorsal Fan-shaped Body to Promote Wakefulness in Drosophila. Curr. Biol. (in press).
Wu, M.N.* (co-first author), Joiner, W.J.*, Dean, T.*, Smith, C., Yue, Z., Hoshi, T., Sehgal, A.S., and Koh, K. (2010). Sleepless Regulates Shaker Expression, Localization, and Function. Nature Neurosci. 13, 69-75. PMID:20010822
Koh, K.*, Joiner, W.J.*, Wu, M.N.* (co-first author), Yue, Z., Smith, C., and Sehgal, A.S. (2008). Identification of Sleepless, a Sleep Promoting Factor. Science 321, 372-376. PMID:18635795
Wu, M.N., Koh, K., Yue, Z., Joiner, W.J., and Sehgal, A.S. (2008). A Genetic Screen for Sleep and Circadian Mutants Reveals Mechanisms Underlying Sleep Regulation in Drosophila. Sleep 31, 465-472 PMID:18457233