Project Summary: Overall “What is the function of glial cells in neural centers? The answer is still not known, and it may remain unsolved for many years to come until scientists find direct methods to attack it.” (Ramon y Cajal, 1901). This prophecy turned out to be accurate. Astrocytes, one of the most abundant cell types in the brain, have long been thought of as primarily passive support cells. Over the past two decades, studies indicate that astrocytes play pivotal roles in nervous system development, function, and diseases. However, a major unresolved issue in neuroscience is how astrocytes integrate diverse neuronal signals under healthy conditions, modulate neural circuit structure and function at multiple temporal and spatial scales, and how aberrant excitation and molecular output influences sensorimotor behavior and contributes to disease. The overall goal of this U19 Team-Research BRAIN Circuit Program proposal is to address this fundamental issue by developing a deeper mechanistic understanding of astrocytes’ roles in neural circuit operation, complex behaviors, and brain computation theories. Two overarching questions will be addressed: 1) How do astrocytes temporally and spatially integrate molecular signals from the diverse types of local and projection neurons activated during sensorimotor behaviors. 2) How do astrocytes convert this information into functional outputs that modulate neural circuit structure and function at different spatial and temporal scales. A multidisciplinary, comprehensive effort is proposed to address these questions that can only be completed through close collaboration between researchers with unique and complementary expertise. An innovative multi-scale approach integrating functional, anatomical, and genetic analyses with theoretical modeling will be leveraged. This approach involves quantitative behavioral assays, large-scale imaging of cellular and molecular dynamics, targeted cell-type-specific manipulations, high- throughput omic techniques, genetic profiling, protein engineering, machine learning, and computational modeling. By integrating experimental and theoretical approaches, molecular, cellular, and circuit mechanisms will be determined through which astrocytes influence neural circuits and contribute to complex behaviors and brain computation theories. The experimental and data analysis tools developed as part of this project will be invaluable for the broader neuroscience community.

Project Narrative: Overall The human brain contains roughly equal numbers of neuronal and non-neuronal cells. A major unresolved issue in understanding brain function is how the non-neuronal cells integrate neuronal molecular signals, modulate neural circuit structure and function at multiple temporal and spatial scales, and mediate changes in information processing, perception, and behavior. This project will employ a broad range of experimental and theoretical approaches to identify core principles of the bi-directional communication between neuronal and non-neuronal cells in various brain regions and how disrupting this regular communication transforms perception and action in health and disease.