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

Introduction

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.

Research Gap

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.

Focus of the Study

To tackle this issue, we will focus on the core components of the BBB:

• Pericytes
• Endothelial cells
• 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.

Objectives

Here, we will study the developmental crosstalk between microglia and BBB in both male and female embryos by investigating:

1. How pericytes influence prenatal microglia.
2. The spatiotemporal heterogeneity of BBB closure and the implication of microglia.
3. The impact of maternal microbiota on BBB formation and crosstalk with microglia.

Methodology

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
• Comparison to human embryos.

Expected Outcomes

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.