The Maternal Gut-Immune Axis Programs the Neuroimmune Landscape of the Developing Brain

Immune molecules, including cytokines, chemokines, and their cognate receptors, are developmentally regulated in the brain and dynamically expressed in the context of neurodevelopmental and neuropsychiatric disease. Here, we employed highly multiplexed in situ spatial transcriptomics to map the expression of major immune ligands and receptors in the developing mouse brain during mid and late gestation. Given the importance of the maternal environment in shaping fetal neurodevelopment, we also determined how the embryonic neuroimmune landscape was altered after maternal immune and microbiome perturbations, with notable sex-specific patterns. We discovered significant changes in the expression of the CXCL12/CXCR7 chemokine network after maternal immune activation and maternal microbiome depletion, suggesting an underlying mechanism for corticogenesis abnormalities. This resource underscores how the maternal environment programs the precise regulation of immune molecules in the developing brain, highlighting sex-specific disease vulnerability. We performed multiplexed error-robust fluorescence in situ hybridization (MERFISH) on n=3 male embryonic day 14.5 (E14.5) and n=3 male E18.5 mouse brains. The MERFISH was also performed on two conditions 1) E14.5 embryonic brain of mice from maternal immune activated mothers, and 2) E14.5 embryonic brain of mice from maternal microbiome depleted mothers. For both conditions embryonic brains were collected from males and females with n=3, and respectively PBS controls were also studied. Coronal sections of the entire brain were used for analysis.