Increased risk for anxiety may begin before birth, shaped by infection or stressful events during pregnancy, according to a new preclinical study from researchers at Weill Cornell Medicine. While scientists have long known that maternal difficulty during pregnancy may raise a child's risk for psychiatric illness, the biological pathways between these prenatal experiences and later mental health have been unclear.
The study , published Sept. 10 in Cell Reports, focuses on a region of the brain called the ventral dentate gyrus (vDG), part of the hippocampus that helps a person assess threats in the environment. The researchers discovered that adversity in the womb configured a small percentage of these brain cells to be overly active when faced with a threatening situation, creating 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, who co-led the research. "This mechanism may help explain the persistent stress sensitivity and avoidance seen in some individuals with innate anxiety."
Lasting Imprints from the Womb
To mimic adverse conditions in the womb, the researchers used a mouse model that develops abnormal immune activity during pregnancy. When tested, their genetically normal offspring grew up to show classic signs of anxiety, such as avoiding open spaces and over-responding to stress. But how does an inflammatory environment in the womb cause lasting changes in the brain that may lead to anxiety?
The team analyzed DNA methylation patterns in individual neurons of the vDG. These chemical tags help control which genes are turned on and off. They also used single-cell RNA sequencing to map the genes that were activated abnormally. These changes are called "epigenetic" because they don't alter the actual genetic code but affect how cells read and use that code.
Surprisingly, the researchers uncovered thousands of sites where DNA methylation was altered, especially in regions that act as "on-off switches" for genes controlling synapses—the connections that allow neurons to communicate. They observed that some neurons were more affected than others.
When the mice were exposed to a threatening environment, the most heavily reprogrammed neurons became hyperactive. These neurons exhibited both altered DNA methylation and abnormal expression of genes related to synaptic function.
"Overall, these epigenetic changes are instructing 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, who co-led this research. "The neurons show too much activity, ultimately contributing to the mice perceiving the environment as more threatening than it actually is."
Reprogramming Behavior
The researchers then monitored these neurons in real time. In control mice, activity in the vDG remained steady when moving from safe to risky areas of a maze. But in mice exposed to prenatal adversity, activity surged as soon as they started thinking about transitioning from safety into a threatening space. This "ramping up" of activity appears to encode an exaggerated perception of danger, driving avoidance and anxious behavior. "The mice seem to anticipate the danger, so the increased activity of the neurons is not a consequence of going into the threatening environment, but precedes it," Dr. Pleil said.
This study provides one of the clearest mechanistic links yet between prenatal environment, epigenetic change and psychiatric risk, but is only a starting point. The researchers plan to tease out more mechanistic details.
"A mouse may have almost 400,000 cells in the vDG, but only a few thousand are impacted during pregnancy. Next, we really want to understand why these certain cells are epigenetically programmed," said Dr. Toth.
A better understanding of this mechanism may help guide the search for similar epigenetic signatures in people, which could serve as early biomarkers of risk. The specific synapse-related genes that are abnormally programmed in these "primed" neurons may also potentially lead to therapeutic targets.
The findings underscore the importance of maternal health during pregnancy—not just for physical outcomes like birth weight, but also for shaping long-term brain function.
This research was supported by grants from the National Institutes of Health, 5R01MH117004, 5R01NS106056 and R01AA027645.
