Infection or stressful events during pregnancy may heighten the risk of anxiety in children, according to new research from Weill Cornell Medicine. The preclinical study, published September 10 in Cell Reports, identifies how early disruptions in the womb can leave lasting imprints on the developing brain.
While scientists have long recognized that maternal challenges during pregnancy can increase psychiatric risk in offspring, the biological pathways connecting prenatal experiences to later mental health have remained unclear. This study sheds light on one of those mechanisms.
Researchers focused on the ventral dentate gyrus (vDG), a brain region within the hippocampus that plays a central role in assessing threats. They found that adversity during pregnancy reprograms a subset of vDG neurons, making them overly active in threatening situations and fostering a vulnerability to anxiety.
“Our data reveal prenatal adversity left lasting imprints on the neurons of the vDG, linking gestational environment to anxiety-like behavior,” said Dr. Miklos Toth, the Arleen B. Rifkind, M.D. Professor in the Department of Pharmacology at Weill Cornell Medicine and co-lead author. “This mechanism may help explain the persistent stress sensitivity and avoidance seen in some individuals with innate anxiety.”
Tracing Lasting Imprints
Using a mouse model of abnormal immune activity during pregnancy, the researchers observed that genetically normal offspring developed classic anxiety-related behaviors, such as avoiding open spaces and overreacting to stress.
Through DNA methylation analysis and single-cell RNA sequencing, the team uncovered widespread epigenetic changes—chemical tags that affect how genes are read without altering the genetic code. Many of these changes occurred in regions that control synaptic function, affecting how neurons communicate.
When exposed to threats, the reprogrammed neurons displayed abnormal hyperactivity, encoding an exaggerated perception of danger and fueling avoidance behaviors.
“These epigenetic changes instruct certain neurons in the vDG to respond differently in adulthood when faced with unsafe environments,” explained Dr. Kristen Pleil, associate professor of pharmacology at Weill Cornell Medicine and co-lead author. “The neurons show too much activity, ultimately contributing to heightened anxiety-like behavior.”
Toward Future Applications
Although only a small fraction of the roughly 400,000 neurons in the vDG were altered, these changes had profound behavioral effects. Future research will investigate why certain cells are particularly vulnerable and whether similar patterns exist in humans.
A better understanding of these mechanisms may open the door to early biomarkers of anxiety risk and new therapeutic targets aimed at reversing or preventing maladaptive programming in the brain.
The findings also highlight the crucial importance of maternal health during pregnancy, not only for physical outcomes but also for shaping the brain’s long-term resilience to stress.
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