Project Summary/Abstract: We are using the small nematode C. elegans as an experimentally tractable model to study the molecular roles of conserved genes in neuronal, circuit, and behavioral plasticity. We aim to study the generation of behavior at a level and scope not possible in other organisms, including parallel analysis of many genes across multiple behaviors and circuits. This includes the goal of understanding the contribution and interactions of genes, and even single isoforms of genes, in behavior. By focusing on conserved orthologs of genes associated with neurodevelopmental and neuropsychiatric disorders, characterized by changes in behavior, we hope to expand our understanding of the role of genes in behavior. Our molecular dissection of gene function in single neurons between and across behavioral circuits has led to identification of novel molecular mechanisms and genetic interactions in experience-dependent neuronal plasticity and behavioral plasticity. Here we focus on synaptic cell adhesion molecule (sCAMs) genes, including neurexins and neuroligins, which are extremely complex and redundant gene families in vertebrates. The complexity and diversity of vertebrate neurons, circuits, and sCAM genes have prevented simultaneous analysis at the genetic, molecular, circuit, and behavioral resolution we hope to achieve. We propose to use C. elegans as a tractable experimental system to simultaneously investigate the molecular and circuit mechanisms of many synaptic adhesion genes in multiple behaviors. Our research plans over the coming years are to expand the list of sCAM genes we are studying in depth to gain a more nuanced and complete picture of the molecular coordination of sCAM genes in behavior. Using a suite of modern genetic and neuroscience techniques we plan to 1) Identify networks of sCAM genes involved in multiple foraging behaviors, 2) Define the cellular, subcellular, molecular, and temporal requirements of each identified sCAM gene, and 3) Characterize the impact of each sCAM gene on the structure and functional connectivity of a foraging circuit, all at single neuron resolution. Our top-down approach relies heavily on using behavior as a readout of gene and circuit function, with the hope this will provide a unique window into the genetic and molecular basis of behavior. Successful completion of our work will result in a deeper understanding of the principles of neuronal circuit formation, function, and behavioral output with implications across basic and disease-focused disciplines. C. elegans are not only a uniquely tractable experimental model for the resolution of experiments we propose, but also provide an inclusive experimental system to train/mentor undergraduates, graduate students, and postdocs at all levels of experience.