Mei Zhen

calcium imaging, electrophysiology, motor behaviour, optogenetics, genetics, neural development, machine learning, automated tracking, electron microscopy. We investigate how neural circuits enable motor behaviors. Using the C. elegans motor circuit as a model, we combine the classic genetics studies, optogenetics, electrophysiology and electron microscopy to answer the following questions: 1) How is the anatomic ensemble of the motor circuit regulated at the molecular and cellular level; 2) How does the C. elegans motor circuit generate rhythmic movement pattern; 3) Do any of the molecular determinants for cholinergic and GABAergic motor neuron development play conserved roles in other nervous systems? C. elegans is an excellent experimental system for these studies: Its compact and fully sequenced genome, as well as the fast life cycle, allows for the application of powerful forward and reverse genetic tools; The connectivity of its simple nervous system has been deduced by EM reconstructions; the transparency of the animal, and the small number of neurons and synapses allow live imaging at single neuron and single synapse resolution; Physiology tools - in vivo calcium imaging and intracellular recording, are now available, expanding the horizon of functional analyses of nervous system development and function; Lastly, C. elegans exhibits a limited repertoire of motor behaviors that can be precisely quantified through automated tracking systems. Approaches: 1. In collaboration with the Litchman and Samuel groups (Harvard University), we are using cutting-edge, automated EM technique to reconstruct the wiring of the C. elegans developing nervous system. 2. We developed an array of fluorescent markers that allow us to examine the axon and synapse morphology of C. elegans neurons. We perform genetic screens to identify C. elegans mutants that exhibit defective polarization and synapse morphology. Our subsequent molecular genetic characterization of these mutants leads to the identification of key regulators of neuronal development. 3. We developed state-of-art movement tracking, electrophysiology, calcium imaging and optogenetics tools to interrogate the functional connectivity of the C. elegans neuromuscular system. Through these tools, we have demonstrated the presence of action potentials in C. elegans body wall muscles, and the role of a small group of premotor interneurons in controlling the directionality of C. elegans’ movement. 4. We are using the C. elegans GABAergic neurons and GABAergic NMJs to model human mental disorders.