How stressors during pregnancy impact the developing fetal brain

The maternal microbiome and immune system have both independent and synergistic effects on fetal brain health - changes in the mother’s immune system have been linked to an increased risk of neurodevelopmental disorders in children. A new study, published today in Nature Neuroscience, expands our understanding of this “gut-immune axis” by mapping the impact of stressors during pregnancy – namely changes in the microbiome and activation of the immune system - on the neuroimmune landscape of the developing fetal brain.

The research team, led by Brian Kalish, MD, Physician in Medicine in the Division of Newborn Medicine at Boston Children’s Hospital, discovered notable sex-specific responses, including vulnerability for a specific immune pathway in the male brain that could be a potential target for early intervention.

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

The team integrated in situ spatial transcriptomics (MERFISH) with single cell RNA-seq data. This dual-modality approach enabled them to (1) create a developmental cell atlas of immune gene expression in the embryonic mouse brain during mid- and late-gestation; (2) map the spatial location of neurodevelopmental-relevant genes in the developing brain; (3) reveal sex-specific responses of the developing brain to maternal gut-immune disruptions; (4) nominate a specific pathway – known as the CXCL12/CXCR7 signaling pathway - as an important mediator of abnormal neural differentiation.

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