Severe childhood stress may increase a person’s risk of anxiety, depression, and other mood disorders when stressful experiences occur later in life. Researchers from Washington University School of Medicine in St. Louis and Princeton University have identified an epigenetic mechanism that may help explain how early-life trauma produces lasting changes in the brain.
The study suggests that childhood adversity can alter gene activity by changing how brain cells package DNA. These changes may increase the activity of stress-related genes, leaving the brain more reactive and less resilient when it encounters future challenges.
The findings were published August 7 in the journal Neuron.
“We have discovered a novel biological process that links experiences of childhood adversity with long-term vulnerability to mental illness,” said Dr. Megan Creed, associate professor of anesthesiology at Washington University School of Medicine and a co-author of the study. “This discovery reveals the physical scars left by trauma experienced during development inside brain cells and provides scientists with a concrete biological target for developing new treatments and interventions.”
How childhood stress changes DNA packaging
More than half of children worldwide experience some form of significant stress during childhood, including domestic abuse, exposure to violence, substance misuse in the home, or other traumatic events. Experiencing four or more adverse childhood experiences is associated with a substantially higher risk of physical and mental health problems later in life.
To investigate how early-life stress affects the developing brain, researchers focused on the ventral tegmental area, a region containing dopamine-producing neurons. Dopamine is a chemical messenger involved in processing important experiences, including reward, motivation, and adversity. When stress causes these neurons to become abnormally active, reward processing may be disrupted, potentially increasing vulnerability to anxiety and depression.
The scientists examined the epigenome within these dopamine-producing neurons. The epigenome consists of molecular markers that help regulate whether genes are switched on or off, influencing how cells respond to their environment.
Katherine Jensen-Peña, Ph.D., assistant professor at the Princeton Neuroscience Institute and senior and co-corresponding author of the study, compared cellular DNA to a long, coiled molecule. DNA is wrapped around proteins called histones, which determine how tightly or loosely the genetic material is packed. When DNA is tightly compressed, genes are less accessible and are more likely to remain inactive. When the structure loosens, genes become easier for the cell to activate.
SETD7 primes brain cells for future stress
The researchers found that young mice exposed to stress had higher levels of an enzyme called SETD7 in their dopamine-producing neurons than mice raised in typical conditions. SETD7 adds a chemical marker known as H3K4me1 to the DNA packaging system. According to Jensen-Peña, this marker helps open the genetic structure, making brain cells more sensitive to signals from their environment.
To determine whether SETD7 could directly drive these changes, the scientists increased the enzyme’s levels in young mice that had not experienced early-life stress. As the mice matured, their dopamine neurons developed a more open DNA structure, allowing stress-related genes to become more easily activated.
As adults, these mice also showed reduced stress resilience. Animals exposed to elevated SETD7 levels during early development had more reactive dopamine neurons and displayed more anxiety-related behavior than mice whose SETD7 levels remained normal.
Blocking molecular “scars” from childhood stress
The researchers next tested whether reducing SETD7 activity after early-life stress could prevent these long-term effects. Limiting SETD7 prevented excessive H3K4me1 marking and helped keep the DNA structure more tightly closed. As a result, the mice did not develop abnormal sensitivity to stress later in life.
Even after experiencing stress during both early development and adulthood, mice with reduced SETD7 activity behaved similarly to animals that had not experienced early-life stress. They remained social and exploratory, while activity in their dopamine neurons stayed within normal levels.
The findings suggest that SETD7-related changes in DNA packaging may create a lasting molecular memory of childhood adversity. They also identify specific biological pathways that could be studied as potential targets for future therapies and early interventions.
“There are currently no treatments specifically designed for the effects of childhood stress on the brain, in part because we do not have a clear understanding of which molecular mechanisms to target,” Jensen-Peña said. “This study is exciting because it reveals a clear mechanism and helps explain why the effects of stress can be latent and pervasive. If supportive care, therapy, or social resources can buffer children during sensitive periods of development, we may be able to protect the epigenome, prevent genetic risks from becoming locked in an open state, and give the developing brain a greater opportunity to build natural resilience.”
Source: www.sciencedaily.com