Mark Wu MD, PhD
Professor of Neurology
Professor of Neurology
Sleep is the only essential behavior whose function remains unknown. In addition, the molecular and cellular mechanisms regulating sleep remain poorly understood. We use the fruit fly, Drosophila melanogaster, as a model system to probe the mysteries underlying sleep. Despite having a relatively simple central nervous system containing ~100,000 neurons, flies exhibit a complex repertoire of behaviors, including courtship, aggression, addiction, learning and memory, and sleep. Their rapid generation time and numerous genome-wide genetic reagents, coupled with in vivo patch clamp electrophysiology and functional imaging of identified neurons, leads to exquisite power and precision in the analysis of the circuits and molecules underlying behavior.
We use a multi-pronged approach in our studies: genetic screens, molecular and immunohistochemical analyses, and electrophysiological and imaging-based techniques. Although it is clear that the circadian clock regulates sleep, how it does so is unknown. Recently, we identified a conserved molecule, named WIDE AWAKE, that plays a critical role in mediating circadian clock-dependent regulation of sleep. WIDE AWAKE translates timing information from the molecular clock to modulate excitability of clock neurons, in order to regulate the timing of sleep. Strikingly, this novel molecule is conserved in mammals, and is specifically enriched in the suprachiasmatic nucleus in mice (their circadian pacemaker), strongly suggesting that the function of WIDE AWAKE will be conserved in mammals. Using these technologies, we are also studying the role of sleep in regulating synaptic plasticity--one of its hypothesized functions.
We also investigate the dopamine networks modulating behavior. Dopamine is a critical neuromodulator that regulates a wide variety of behaviors, and we have been generating novel genetic tools in order to easily isolate few to individual dopamine neurons. Using these tools, we probe the function and activity of highly restricted dopamine circuits in regulating different behaviors, including arousal and feeding. The goal of these studies is to unravel the complex network of interactions between internal states and external stimuli mediated by dopamine.