Microbial Regulation of Microglial Function

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Project Summary/Abstract This proposal is for a four-year research career development program, focused on the study of the microbiome’s contribution to the regulation of microglial maturation and function including experience-dependent synaptic pruning. The candidate has already been appointed an Instructor in the Department of Medicine at Weill Cornell Medical Center. The proposal is a natural extension of the candidate’s previous research into microglial-neuronal interaction, synaptic plasticity, and behavioral outcomes in mice. It outlines a plan for the candidate to achieve his goal of becoming an expert in the microbial regulation of critical central nervous system processes, extending the training of the candidate in two dimensions, which are reflected in the mentorship of Drs. Conor Liston and David Artis: 1. Identification of microbially-derived signals that alter the maturation and function of microglia, and 2. Alterations in microglial function that regulate experience-dependent synaptic refinement. The proposed experiments and multi-faceted training plan will impart the candidate with a unique combination of skills that will position him to transition into a successful independent career as a physician-scientist studying the contribution of peripheral organ system dysfunction to alterations in cognitive function and affective states. Alterations in the microbiota have been associated with multiple neuropsychiatric disorders in small-scale human correlational studies, and animal studies utilizing germ-free (GF) mice lacking a microbiota from birth, or animals rendered acutely dysbiotic by antibiotic treatment have demonstrated defects in the normal physiology of multiple CNS regions and cell populations including synapse-level changes in the context of experience. Amongst affected cell populations, the CNS tissue-resident macrophage known as microglia have been shown by us and others to be heavily altered in the absence of a normal microbiota. Given the known importance of microglia in regulating the formation, stability, and plasticity of synapses within both the developing and adult mouse brain, they likely represent an important conduit through which microbiota-derived signals regulate normal experience- dependent synaptic plasticity and ultimately animal behavior. The goal of my proposal is to investigate the role of the microbiota in modulating microglial function in the adult brain. Specifically, this proposal investigates how changes to the microbiome alter microglial-neuronal interaction by: 1. Identifying the microbially-derived small molecule signals by which the microbiome alter mouse and human microglial maturation and function in vitro; 2. Testing the role of these metabolites in regulating microglial-dependent synaptic refinement in a model of experience-dependent plasticity. Collectively, these experiments provide novel insight into the role of the microbiome and its metabolites in regulating microglial function including synaptic refinement.