Developmental Crosstalks between Microglia, Blood-Brain Barrier and Maternal Microbiota

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 the brain.

Structural or functional BBB deficits are found in many brain diseases, from neurodevelopment to neurodegeneration, thus understanding how the BBB develops holds critical significance for both biologists and clinicians.

Yet, we still lack fundamental knowledge on how interactions between different cellular populations in coordination with environmental signals contribute to BBB construction during early development.To tackle this issue, we will focus on the core components of the BBB -pericytes and endothelial cells- and microglia, the brain resident macrophages.

Microglia play key roles in circuit assembly and we have shown that prenatal microglia, which are in close apposition to the vasculature, respond in a sex-specific manner to signals derived from the maternal microbiota.Here, we will study the developmental crosstalk between microglia and BBB in both male and female embryos by investigating (i) how pericytes influence prenatal microglia; (ii) the spatiotemporal heterogeneity of BBB closure and implication of microglia; and (iii) the impact of maternal microbiota on BBB formation and crosstalk with microglia.

Our approach leverages multidisciplinary and state-of-the-art techniques in newly developed murine models of microglia depletion and in utero antibiotic treatment, including two-photon live imaging, single-cell and spatial transcriptomics, in vitro BBB model and comparison to human embryos.

Ultimately, we will establish an integrated framework of BBB formation and BBB-microglia interplay, shedding light on how signals from maternal microbiota shape brain development.

Our findings will provide key insights into normal and pathological brain wiring, paving the way for the identification of potential therapeutic targets.