Establishing a balance between the activities of competing neuronal circuits is essential to the coordination of behaviors. We propose to investigate the developmental strategies that ensure the establishment of this balance in the nervous system. Studies of the vertebrate embryonic nervous system have shown that correlated activity patterns the structure and output nascent circuits through mechanisms akin to learning. The scale and complexity of vertebrate brains has made it challenging to identify the rules which govern this learning or the mechanisms which drive optimization of the circuit toward a balanced output. The small size and invariance of the Caenorhabditis elegans nervous system make it possible to study these processes with specificity not possible in vertebrates. Using the development of one of the first functional circuits in the C. elegans embryo as a model, I will study how functional balance is established in the developing nervous system and identify the developmental mechanisms that ensure the robustness of this balance. To accomplish this goal, I propose the following specific aims: 1) To identify the models of IL1 neuron function in the patterning of embryonic head movement. 2) To automate and improve an approach for controlling transgene expression with single cell resolution by infrared laser-induced heatshock. And 3) To determine the mechanisms by which the IL1 circuit establishes and maintains a balanced output to produce coordinated movements. To enable this, I have developed a real-time cell tracking system which automates the identification of targeted cells during embryonic development and can control the conduct of single cell optical perturbations such as laser ablation as described in a recently published paper in Developmental Cell or, as will be developed in Aim 2, single cell heatshock. I have also developed an automated image analysis pipeline which allows me to track and measure movement patterns in the early embryo with which I have identified the neuronal origins of patterned head movement and, using genetic mutants of neuronal function, shown that this patterning is defined by neuronal input. I believe that this work will provide important insights into the patterning of the embryonic nervous system with implications for our understanding of the circuit-level origins of some neurodevelopmental disorders. In order to expand my training as a biologist and complement my broad technical training and expertise, I will carry out the mentored phase of this award as a postdoctoral Research Associate in the laboratory of Dr. Zhirong Bao, an expert on C. elegans embryonic development, and under the mentorship of a well-accomplished advisory committee comprised of experienced biologists and neuroscientists. I have designed a structured plan to further my scientific training and support my career development to prepare for an independent career. The Sloan Kettering Institute and the tri- institutional community at Weill Cornell Medical College and The Rockefeller University provide an unparalleled intellectual environment to support my scientific growth and progress towards independence.
The generation of coordinated behaviors requires a balance in the output of competing neuronal circuits. By studying the developmental regulation of this balance in the C. elegans embryo, our goal is to understand these processes at the level of the individual neuron and synapse. Through this, we hope to better understand how related processes may function or fail in human development and disease.
