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BME PhD Thesis Defense: "High-Throughput and High-Resolution Functional Imaging Methods to Identify Mechanisms of Variable Neural Excitability in E. Elegans" by Kyra R. Burnett

Wednesday, March 27, 2019
9:00 am to 10:00 am
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The human brain contains billions of neurons which form trillions of connections that drive complex cognitive and behavioral functions. Investigating the fundamental mechanisms that regulate functional connectivity has improved our understanding of the brain and neurological disorders such as epilepsy, schizophrenia, and autism. Current gold-standard neuroimaging technologies have allowed researchers to observe patterns of neural activity at the network level; however, much less is known about the underlying mechanisms of variability in brain function. To study these important neural dynamics at the cellular level, we used the model organism C. elegans because of its simple and highly conserved neural anatomy, complete connectome, genetic tractability, and compatibility with non-invasive imaging techniques. Using our high-throughput microfluidic stimulation and neural imaging techniques, we found that a single chemosensory neuron (AWA) has variable neural responses to the same natural odor stimulus, butyl acetate, across 52 genetically identical animals. With this approach, we screened neural responses from hundreds of animals in 12 genotypes andidentified that specific ion channels and synaptic pathways are responsible for regulating this variable neural excitability. Further, we identified multiple neurons that respond reliably to this natural odor using standard multi-neural imaging techniques and concluded that the chemosensory neuron ASE is a primary detector of butyl acetate. Overall, we identified a few novel regulatory pathways that mediate variable neural excitability at the cellular level in C. elegans. Additionally, to investigate how these short time-scale (minute) regulations occur across multiple neurons and throughout long durations (hours), we developed a new and more efficient approach to simultaneously perturb neural circuit function while broadly observing variable neural excitability in vivo. For successful high-resolution imaging of cellular activity, I developed a versatile hydrogel encapsulation technique that keeps animals immobilized and healthy during long-term functional recordings. With this, we were able to reliably and precisely stimulate a single neuron using a red-shifted channelrhodopsin, Chrimson, while also observing calcium responses in up to 30 additional neurons in individual animals. Overall, this work elucidated several mechanisms that can regulate sensory-level neural circuit variability in C. elegans, and provided new in vivo imaging methods, tools, and approaches to advance our understanding of neural circuit function.

Defense Committee:

Dirk Albrecht, PhD, Associate Professor, Biomedical Engineering, WPI (Thesis Advisor)
Karen Troy, PhD, Associate Professor, Biomedical Engineering, WPI (Chair)
Raymond Page, PhD, Professor of Practice, Biomedical Engineering, WPI
Luis Vidali, PhD, Associate Professor, Biology and Biotechnology, WPI
Mark Alkema, PhD, Associate Professor, Neurobiology, University of Massachusetts Medical School
Department of Biomedical Engineering
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