Mom’s Immune Health Influences Fetal Brain Development

During pregnancy, as a mother’s body nurtures new life, her health shapes the baby’s development. Shifts in maternal health can trickle to the fetus, leaving lasting effects on the baby’s long-term well-being.

Indeed, maternal microbiome changes and immune activation are linked to the risk of neurodevelopmental disorders in children.^1,2 However, scientists do not fully understand how such maternal stressors tweak immune signaling in developing brains to increase disease risk.

Now, Harvard University neonatologist and neurobiologist Brian Kalish and his team employed spatial transcriptomics to map the neuroimmune landscape in mouse embryos and studied how maternal health shaped it.³ Their results, published in Nature Neuroscience, highlight potential mechanisms underlying neurodevelopmental disorders.

For their study, Kalish and his team obtained brain tissue from 14- and 18-day-old mouse embryos, representative of the mid and late stages in the mouse gestational period of 19 to 21 days. Using an advanced fluorescence in situ hybridization technique, the scientists examined the expression patterns of important immune ligands and receptors in these tissues. Combining this with single-cell RNA sequencing helped them pinpoint the spatial localization of specific genes within particular brain regions.

To characterize dynamic changes to the neuroimmune landscape across the developmental stages, Kalish and his team compared the tissue from 14- and 18-day-old embryos. As brains matured, the researchers observed fewer neural progenitor cells, which likely differentiated into specialized cells. Immature cell types also gave way to more mature cell populations in 18-day-old embryo brains.

“Our study establishes a detailed spatial transcriptomic resource of immune gene networks during a critical window of embryonic brain development,” Kalish said in a statement. “Unlike previous atlases focused on the adult brain, our dataset captures dynamic immune signaling interactions at a stage when the brain is highly vulnerable.”

Equipped with a resource to track changes in the brain, Kalish and his team investigated how maternal gut-immune disruptions influenced neurodevelopment. They either activated the immune systems of female mice by injecting them with a chemical that induces inflammation and cytokine production, or they depleted the animals’ microbiota by treating them with antibiotics.

Compared to embryos from untreated mothers, male—but not female—embryos from mothers with gut-immune disruptions showed reduced neuronal proliferation and abnormal neuronal migration. Consistent with this, male mice born to mothers with immune perturbations displayed abnormal social interaction.

Comparing the neuroimmune landscapes of male embryos from untreated mothers and those with gut-immune disruptions revealed dysregulated expression of the genes encoding chemokine receptor CXCR7 and its ligand CXCLl12. This chemokine network is critical for patterning of the embryonic brain. Overall, their results indicated that the maternal environment programs immune regulation in the developing brain in a sex-specific manner.

“As a neonatologist, this work adds to our understanding early-life environmental factors that may impact neurodevelopmental potential and lends insights for potential interventions,” said Kalish.