MicroBBB

Brain functioning can be influenced by body ecosystem signals conveyed through the vasculature and regulated by the blood-brain barrier (BBB), a selective and modulable barrier that controls which substances and cells enter or exit the brain. Vasculature or BBB defects have been reported in many brain diseases, from neurodevelopment to neurodegeneration but we still lack knowledge on their causal interplay. Understanding how BBB develop and interact with brain cells in health and disease is thus essential for both neurobiologists and clinicians. Microglia, the brain resident macrophages, colonize very early on during prenatal life the embryonic brain in which there are in close apposition to the vasculature, but to what extent they interact and regulate each other’s development and function is unclear. To tackle these issues, we will study the developmental crosstalk between microglia and BBB components at a molecular, cellular and functional level in both females and males. In particular, we will characterize (i) the kinetics and underlying mechanisms of BBB component assembly and their interaction with microglia; (ii) how microglia impact on vascular cells maturation, function and BBB closure; and (iii) how pericytes drive microglial states, maturation and homeostasis. We will use multi-disciplinary approaches in newly developed murine model of microglia depletion, including two-photon live imaging, single-cell and spatial transcriptomics and comparison to human embryos. We will ultimately establish an integrated framework of BBB formation and BBB-microglia crosstalk during fetal life. Our findings will provide key insights into both normal and pathological brain wiring and open research avenues for the identification of therapeutic targets.