Experiencing severe stress during childhood can make a person more vulnerable to anxiety, depression and other mood disorders when faced with hardships as an adult. Researchers at Washington University School of Medicine in St. Louis and Princeton University have now uncovered how trauma early in life can leave a lasting effect on the brain.
Scientists already knew that stress early on in life changes the activity of genes in the brain. In a new study, the research team discovered that this is due to alterations in how brain cells package DNA, leaving the brain's genetic stress response vulnerable to being turned on easily and reducing tolerance to stress.
The study was published Aug. 7 in Neuron.
"We have uncovered a new biological process linking experience of early-life adversity to this long-term vulnerability to mental illness," said Meaghan Creed, PhD , an associate professor of anesthesiology at WashU Medicine and the study's co-corresponding author. "This finding reveals a physical scar left by trauma experienced during development inside brain cells, providing scientists with a concrete biological target to develop new treatments and interventions."
Stress stretches the genetic slinky
More than half of the world's children are exposed to early-life stress from abuse, household dysfunction such as violence or drug use, or other traumatic experiences. Accumulation of four or more such experiences can trigger much higher risks for long-term mental and physical health challenges in adulthood.
The researchers set out to understand how trauma during early development physically changes the brain to make it more sensitive to stress later in life. They focused on a region of the brain called the ventral tegmental area where brain cells that produce dopamine — a chemical messenger — are responsible for processing important things in the environment, including rewards and adversity. When these brains cells are activated abnormally, which can happen in response to stress, they disrupt how the brain processes rewards, leaving individuals vulnerable to anxiety and depression.
Within dopamine-producing neurons the researchers zoomed in on the epigenome, a set of molecular tags that direct the cell's machinery to turn genes on and off, which in turn affects cells' activity.
Inside cells, DNA is coiled like a slinky, explained Catherine Jensen Peña, PhD, an assistant professor at the Princeton Neuroscience Institute and the study's senior and co-corresponding author. The DNA coils are wrapped around histone proteins that help determine how tightly or loosely the coil is wound. When the genetic slinky is compressed, its genes are turned off. As the DNA slinky stretches and opens, genes are more easily accessible to be turned on.
The researchers found that an enzyme called SETD7 was more abundant in the dopamine neurons of young mice that had experienced stress compared with mice reared in a typical environment. SETD7 helps place a chemical tag — H3K4me1 — on the genetic slinky, marking the structure for uncoiling, which in turn makes the cell more reactive to everything going on in the environment, explained Peña.
The researchers then artificially boosted SETD7 in young, stress-free mice. Even without early-life stress, these mice grew up with a stretched-open DNA structure in their dopamine-producing brain cells, making it easier to turn on the genes that respond to stress. Such mice had a lower tolerance for stress in adulthood. The researchers found that, as adults, the mice that had boosted SETD7 levels when they were young had more reactive dopamine neurons and more anxious behavior compared to mice with normal levels of SETD7 throughout their lives.
Conversely, when the researchers blocked the SETD7 enzyme from adding too much of the H3K4me1 tag after early-life stress, the slinky remained closed, shielding mice from becoming hypersensitive to stress later in life. Despite experiencing both early-life and adult stress, mice with their SETD7 levels dampened were able to remain as social and exploratory as unstressed mice, and their dopamine neurons were active at normal levels.
"There are currently no treatments for what early-life stress does to the brain, partially because we have not had a clear picture of what molecular mechanisms to target," Peña said. "This work is exciting because it reveals a clear mechanism, and also helps explain why the impact of stress is both latent and broad. Additionally, if we can step in with supportive care, therapy or social resources to buffer children during those sensitive windows of development, we may be able to protect the epigenome — preventing the genetic slinky from locking into an open position and perhaps giving the developing brain a chance to build natural resilience."
