Developmental and postnatal determinants of microglia diversity and functions – MICROXIGNAL

Microglia cells (MGCs) are brain resident phagocytes, which are recognized modulators of brain development, plasticity and neurodegeneration. Recent genomic analyses revealed high heterogeneity of MGC populations during brain development or in pathological conditions. Such heterogeneity may underlie the pleiotropic activities of these cells, but the underlying cellular and molecular determinants remain largely unknown. Identifying such determinants is essential for better understanding of MGC diversity and future therapeutic targeting of microglial subtypes in diseases associated with MGC dysfunction, including Alzheimer disease, multiple sclerosis or depression. The overarching goal of this project is to better understand the mechanisms of developmental and pathological heterogeneity of MGCs and their impact on brain functions.
We hypothesize that some of the pathology-related MGC phenotypes, like senescence, may result from abnormal programming of myeloid cells during early developmental steps. Alternatively, senescent MGCs may emerge as a result of abnormal extrinsic signaling from surrounding cells. We will address such hypotheses by monitoring MGCs’ heterogeneity both at pre- and post-natal stages using single cell transcriptomic analyses in new genetic mouse models relevant for studies of MGC development, as well as MGC senescence. Functional relevance of MGC heterogeneity will be addressed by investigating brain plasticity and animal behavior in such models, as well as in a mouse model of chronic stress relevant for studies of depression. Significance of obtained data for human biology will be inferred from in vitro studies of differentiation of wild type and mutant human induced pluripotent stem cells (iPSCs) to MGCs. Detailed genomic analyses should allow to identify relevant differentiation programs and corresponding functional phenotypes like senescence, phagocytic activity or inflammatory response.