Genetic and molecular regulation of experience-dependent structural plasticity

PROJECT SUMMARY Structural plasticity of neuronal connections is crucial for the wiring and rewiring of neuronal circuits in response to experience during development and in adulthood. Defects in plasticity of neuronal connectivity underlie, exacerbate, or contribute to the pathogenesis of many neurodevelopmental, neuropsychiatric, and neurological disorders, including age-related decline. However, our understanding of the molecular control of structural plasticity across the lifespan and in different neuronal contexts is far from complete, in part due to the lack of an experimentally tractable system to study this complex process at this resolution. The well-defined nervous system of the nematode Caenorhabditis elegans is an ideal system to identify the genes and molecular mechanisms involved with direct comparison of multiple life stages. We propose to exploit a robust model of structural plasticity we discovered in C. elegans to identify and compare the genetic and molecular regulation of experience-dependent structural plasticity across development, adulthood, and aging at single neuron resolution. In Aim #1, we will use the power of C. elegans genetics to screen 20 conserved cell adhesion, scaffolding, and signaling molecules for roles in experience-dependent structural plasticity during both development and in early adulthood. Aim #2 will comprehensively characterize the impact of aging on a neuron, circuit, and behavior in both sexes, and directly measure any changes in the capacity for structural plasticity across adulthood and aging by inducing and inhibiting structural plasticity with opto- and chemo-genetic tools. We will identify the mechanisms that maintain or degrade the capacity for structural plasticity with age, providing novel characterization and understanding of structural plasticity across the lifespan. In Aim #3, we will leverage the model of experience-dependent structural plasticity in C. elegans to gain mechanistic insights into the role of multiple conserved and disease-associated cell adhesion molecules in the regulation of structural plasticity. Using a combination of transgenic rescue experiments and insertion of tags/tools into the endogenous CAM genes, we will define the cellular, molecular, and temporal mechanisms by which CAMs contribute to plasticity. The proposed experiments will directly contribute to our understanding of the mechanisms and conserved genes that regulate experience-dependent structural plasticity. thereby informing its role in brain health, disease, and aging, while potentially identifying novel molecular targets for therapeutic intervention.