HMN 2026: How Immune stress during pregnancy changes how fetal brain cells communicate

Research led by the SickKids Research Institute in Toronto and the University of Pennsylvania, has found that immune-related genes vary by location and cell type across the developing mouse brain before birth. Maternal immune activation and maternal microbiome depletion shifted parts of that immune signaling pattern, with differences observed between male and female embryos.

Immune molecules, including cytokines, chemokines, and cognate receptors, are critical regulators of synapse development, cellular communication, and neural precursor cell migration in the developing brain. During development, nerve cells are born in one area, move to their destinations, and settle into stacked layers, especially in the cortex. Those layers line up in an ordered way, with different types of neurons ending up in different layers.

Changes to the maternal immune system and microbiome have been linked to abnormal fetal neurodevelopment, influencing neurogenesis, cell fate, and precursor cell migration. Knowledge of immune signaling networks within the developing brain is needed to understand the mechanisms of how the mother’s stressors impart influence.

In the study, “Spatial transcriptomics of the developing mouse brain immune landscape reveals effects of maternal immune activation and microbiome depletion,” published in Nature Neuroscience, researchers used multiplexed error-robust fluorescence in situ hybridization (MERFISH) to measure immune activity in embryonic mouse brains during mid and late gestation to see how maternal immune activation and maternal microbiome depletion altered those patterns.

Embryonic mouse brain single-cell RNA sequencing data supported identification of spatially restricted cell populations, followed by cell clustering, differential gene expression analyses, and ligand–receptor analyses.

MERFISH profiled embryonic male and female brains from maternal immune activation, maternal microbiome depletion, and saline solution-treated mothers using the same custom panel focused on cytokine and chemokine signaling.

After quality control filtering, analyses included 2.1 million cells with a median of 511 molecules detected per cell.

Brain slices from embryos were stained to mark deep-layer cortex cells and to count dividing cells. Male embryos from maternal immune activation and maternal microbiome depletion groups showed a thicker deep-layer band and fewer dividing cells in a key growth zone than males from saline-injected controls. No clear change showed up in female embryos of the microbiome depletion group.

Adult offspring later took a social interaction test and an open-field test at eight to 12 weeks. Social behavior differed in males from maternal immune activation and maternal microbiome depletion groups, while overall time spent interacting and total distance traveled stayed similar across groups.

Time spent in the center of the open field dropped in males exposed to maternal immune activation and maternal microbiome depletion, with similar movement speed across groups.

Male and female responses diverged

Gene activity shifted in different ways in male and female embryos after maternal immune activation. Several genes tied to growth and division in early brain-building cells, Nes and Mki67, dropped in males across multiple precursor populations.

Male embryos also showed higher activity of Neurod1, Neurod2, and Neurog2, genes tied to neural development, in intermediate precursor cells and dorsal radial precursors. Females did not show the same rise.

Maternal microbiome depletion produced gene activity changes that tracked more closely across sexes. Immune-related genes rose in precursor populations such as ventral radial precursors, intermediate precursor cells, and transit amplifying precursors.

A key mechanism found

CXCL12 is a chemokine, an immune signaling molecule that cells use for cell-to-cell communication in the developing brain and CXCR7 is a receptor that can bind CXCL12.

Ackr3, a gene that encodes the receptor CXCR7, and Cxcl12, a gene that encodes CXCL12, shifted after both maternal immune activation and maternal microbiome depletion. Findings suggested a potential common mechanism tied to neural progenitor abnormalities.

Cells rearrange in the cortex

Distances between different cell populations shifted after maternal immune activation. After maternal immune activation, some cell groups that usually sit closer together were farther apart.

Brain precursor cells linked to later glial development were farther from developing inhibitory neurons, and early brain-building cells in ventral and dorsal regions were farther from blood-vessel lining cells.

Microglia also changed position relative to developing neuron populations. Shorter distances appeared between microglia and migratory excitatory neurons, intermediate precursor cells, and corticothalamic projection neurons in maternal immune activation males compared with control males.

Comparisons between maternal immune activation males and maternal immune activation females also showed closer spacing between microglia and several cell types, including corticothalamic projection neurons, immature and migratory neurons.

Chromatin accessibility differed between males and females. Researchers infer that baseline sex differences in chromatin accessibility may prime how the developing brain responds to maternal gut–immune perturbations.

Connections made

The research connects maternal immune activation and maternal microbiome depletion with sex-specific shifts in immune gene expression, ligand–receptor signaling, and cell spacing within the embryonic brain. Specifically, CXCL12 and CXCR7 signaling stood out as an important mediator of abnormal neural differentiation and migration after maternal immune activation and maternal microbiome depletion.

Future gain-of-function and loss-of-function experiments are suggested to test for neuronal migration changes and later-life behavioral outcomes.

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