Multifactorial development of microglia and its dysregulation

Microglia, the resident macrophages of the central nervous system (CNS), provide immune protection and contribute to brain development and homeostasis by constantly sensing and interacting with their environment. They are implicated in numerous neurological disorders and thus fully understanding how they are regulated could allow therapies that can circumvent these disorders. Many factors play a role in the proper development and function of microglia, however it is still unclear how these factors modulate microglia exactly. Furthermore, prenatal stress such as maternal inflammation activation (MIA) has been shown to affect the behaviors of offspring. In our study, we observe that microglia development involves distinct phases of differentiation, distinguishable by specific transcriptomic signatures. Comparing male and female mice confirmed the sexual dimorphism in microglia, which is more apparent in adults, where females were more immunologically responsive. Using germ-free (GF) mice, the absence of microbiota had a stage and sex-dependent effect on microglia: microglia were found to be significantly perturbed in male embryos or female adults. Comparing human fetal microglia with murine microglia revealed a common gene signature and their importance in neuronal regulation before birth. In all, our study showed that proper microglia development is dependent on multiple factors including both intrinsic or extrinsic factors. These findings have major implications for our understanding of microglia contribution to health and disease.​Doctor of Philosophy (SBS