PI: Buelow, Hannes E. Project Summary The general body plan of most animals follows a bilateral symmetry. Some organs such as the heart and liver break this gross anatomical symmetry, while other structures such as the brain display a superficial bilaterally symmetric anatomy. Nonetheless, it has been known for a long time that the two hemispheres of the human brain serve distinct functions, and many classical examples in neuroscience and psychology have shown the importance of asymmetry in brain function. For example, higher order cognitive abilities such as language, spatial orientation, attention, and visual processing exhibit left-right (L-R) functional asymmetries in humans. Of note, many neuropsychiatric conditions including autism spectrum disorders, depression, schizophrenia, and post-traumatic stress disorder display defects in brain laterality, further underscoring the importance of lateralized brain function. Not surprisingly, neuropsychiatric conditions often have a genetic and, hence possibly, a developmental component. Most of these conditions are also influenced by environmental factors, yet how the environment interfaces with connectivity remains largely unknown. We have identified an asymmetric synaptic connection between two pairs of sensory neurons in the nematode Caenorhabditis elegans that changes in response to experience. Importantly, this connection is controlled cell-non- autonomously from other cells by insulin signaling, which in turn is regulated by experience. This provides a paradigm to investigate, on a molecular level and in single cell resolution, how the environment can change hardwiring of a neural circuit in an experience-dependent manner. The goal of this proposal is to investigate the developmental, plastic and functional aspects of this connection using C. elegans as a model system. In Specific Aim 1, we will determine the mechanisms by which experience changes connectivity. We will determine whether transcription or translation is required and whether neuronal activity is necessary and sufficient, and in which cells. In Specific Aim 2, we will determine the role of insulin signaling in controlling synaptic connectivity. Specifically, we will test which insulin-like agonists and antagonists function in which cells to effect the changes in connectivity; where the receptor functions and in which genetic context. Lastly, in Specific Aim 3, we will determine how changes in connectivity translate into changes in information flow and behavior using whole brain calcium imaging and behavioral experiments. In sum, our research program aims to establish the mechanisms, by which the environment changes synaptic hardwiring and behavior in the context of an asymmetric synaptic connection.