Stress during pregnancy may rewire a baby’s brain for anxiety, a new study found. Adverse prenatal environments change how neurons in the hippocampus develop, leaving offspring more sensitive to threats in adulthood.
Anxiety disorders are the world’s most common mental disorder, according to the World Health Organization (WHO). While it’s a healthy survival tactic to avoid threatening and aversive environments, exaggerated reactions to perceived threats are maladaptive. But are those exaggerated reactions innate or learned?
A new study by researchers from Weill Cornell Medicine (WCM) examined whether exposing a developing baby to an environment that is deemed adverse due to factors such as inflammation and infection is linked to later anxiety.
“Our data reveal prenatal adversity left lasting impressions on the neurons of the vDG [ventral dentate gyrus] linking gestational environment to anxiety-like behavior,” said the study’s co-corresponding author, Professor of Pharmacology Miklos Toth, MD, PhD. “This mechanism may help explain the persistent stress sensitivity and avoidance seen in some individuals with innate anxiety.”
The vDG is a region in the brain’s hippocampus that’s strongly linked to anxiety because of its involvement in emotional processing and responses to stress. The researchers used a mouse model to simulate an adverse gestational environment, specifically maternal immune activation, which mimicked infection or inflammation during pregnancy, and examined what effect that had on the cells in the vDG.
They used a number of methods to investigate, including behavioral testing, electrophysiology to see how neurons fired and communicated, DNA methylation (epigenetics) to see how gene regulation was altered, RNA sequencing to check which genes were turned on or off in specific neurons, and fiber photometry to measure real-time neural activity in safe and threatening environments.
Mouse offspring exposed to stressful, or adverse, conditions during pregnancy showed more anxiety-like behaviors. In these mice, the researchers observed that ventral dentate granule cells (vDGCs) had reduced inhibition, making them more excitable. A stressful gestational environment changed the way certain genes were switched on or off in the neurons of offspring, by altering their chemical markers (DNA methylation). These changes especially affected genes that control how neurons connect and communicate.
Weill Cornell Medicine/Nicole Politowska
When the mice were put into a stressful or anxiety-provoking situation, the brain cells that had these changes were the ones that became most active. In those cells, many of the connection-related genes were seen to be working differently than normal. In their real-time studies of vDGCs, the researchers found that adversity-exposed mice showed increased activity during transitions from safe to threatening environments, suggesting heightened threat perception.
“Overall, these epigenetic changes are instructing certain neurons in the vDG to respond differently in adulthood when faced with unsafe environments,” said Kristen Pleil, PhD, an Associate Professor of Pharmacology at WCM and the study’s other corresponding author. “The neurons show too much activity, ultimately contributing to the mice perceiving the environment as more threatening than it actually is.”
The study has limitations. Obviously, as a mouse study, translation to human subjects is not guaranteed. Effects were variable across neurons; only about 10% to 30% of cells showed major methylation changes. Further, the study did not directly prove which methylation changes caused what transcriptomic changes; that would require further research. The work focused on the vDG, where other hippocampal regions may also be involved.
Nonetheless, the study supports the idea that maternal inflammation or stress during pregnancy can predispose offspring to anxiety disorders later in life. According to the researchers, their study provides one of the clearest mechanistic links yet between the gestational environment, epigenetic changes, and psychiatric disorders.
“A mouse may have almost 400,000 cells in the vDG, but only a few thousand are impacted during pregnancy,” Toth said. “Next, we really want to understand why these certain cells are epigenetically programmed.”
The study was published in the journal Cell Reports.
Source: Weill Cornell Medicine
