Neuroscience has entered an era of rapid advancement, with the advent of new tools to manipulate neuronal activity, and to reveal neuroanatomy with unprecedented depth and precision. By harnessing these technical power and applying them to appropriate animal models, it is possible to gain a full understanding of circuit property that determines animal behaviors.
We study how motor circuits develope and generate behaviors. We utilize C. elegans, a genetic model that allows investigation of intact circuits in behaving animals, with molecular, cellular and synaptic resolution. Its simple nervous system - 220 neurons at birth and 302 in adults - makes it possible to compare circuit mechanisms that drive motor behaviors at different developmental stages.
Approaches and Goals: We combine electron microscopy, genetics, optogenetics, real-time calcium imaging and electrophysiology to study the C. elegans motor circuit development and function at cellular, synaptic and molecular resolution. These tools and insights allow us to apply C. elegans as a model to reveal deficits underlying human neurological disorders.
1) How does the motor circuit develop? All nervous systems undergo postnatal growth, but there is little understanding on how this process affects circuit development and behavior adaptation. The C. elegans nervous system undergoes expansion across larval stages. Its small number makes it possible to determine wiring differences of the entire nervous system. In collaboration with the Samuel and Lichtman groups, we are applying cutting edge EM technology to reconstruct the motor circuits at different developmental stages.
2) How does the motor circuit generate movements? We address this question using two approaches. Genetics: through analyzing C. elegans mutants with distinctive changes in motor behaviors, we identify molecular regulators, and their sites of function (neurons and their connections) that reveal the necessary circuit components for motor behaviors. Neurophysiology: through correlating behaviors with motor circuit activity revealed by calcium imaging, quantifying behavioral changes upon optogenetic manipulation of motor circuit components, and defining the nature of neuronal communications by electrophysiology, we assign the function of each motor circuit component and its connectivity to behaviors.
3) C. elegans models for neurological disorders. Through genetic screens with synapse markers and motor behaviors, we have identified new regulators for neuronal signaling that are associated for human neurological disorders. We also apply the developed tools for quantitative functional assessment of neurons, synapses, circuits and behaviors to pinpoint underlying cellular and circuit defects of C. elegans disease models.