A mouse study suggests that changes in DNA packaging can create a molecular memory of trauma that makes the brain more vulnerable to future stress.
Severe stress in childhood can leave effects that emerge years later, increasing vulnerability to anxiety, depression, and other mood disorders when new difficulties arise in adulthood. Researchers at Washington University School of Medicine in St. Louis and Princeton University have now identified a biological process that may help explain how early trauma leaves such a lasting imprint on the brain.
Previous research had established that early-life stress alters gene activity in the brain. The new work, conducted in mice, traces those changes to the way DNA is packaged inside brain cells. This altered packaging leaves genes involved in the stress response easier to activate, potentially lowering the brain’s tolerance for future stress.
The study was published 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.”
Early stress changes how DNA responds
More than half of children worldwide experience early-life stress involving abuse, household dysfunction such as violence or drug use, or other traumatic events. Experiencing four or more such adversities is associated with substantially greater risks of long-term physical and mental health problems in adulthood.
To investigate how stress during development might physically alter the brain and increase later sensitivity to stress, the researchers focused on the ventral tegmental area. This brain region contains neurons that produce dopamine, a chemical messenger involved in processing important environmental experiences, including rewards and adversity. When stress causes these neurons to become abnormally active, reward processing can be disrupted in ways associated with vulnerability to anxiety and depression.
Within these dopamine-producing neurons, the researchers examined the epigenome, a collection of molecular tags that helps control whether genes are switched on or off and therefore influences how cells behave.
Catherine Jensen Peña, PhD, an assistant professor at the Princeton Neuroscience Institute and the study’s senior and co-corresponding author, compared DNA inside cells to a coiled slinky. DNA wraps around proteins called histones, which help determine how tightly the genetic material is packed. When it is tightly compressed, genes are less accessible and remain inactive. When the structure loosens and opens, those genes become easier for the cell to activate.
SETD7 kept stress genes accessible
Young mice exposed to stress had higher levels of an enzyme called SETD7 in their dopamine neurons than mice raised under typical conditions. SETD7 helps add a chemical tag called H3K4me1 to the DNA structure. Peña explained that this mark promotes a more open configuration, making the cell more responsive to signals from its environment.
The researchers then increased SETD7 artificially in young mice that had not experienced early-life stress. Even without that adversity, the animals developed a more open DNA structure in their dopamine-producing neurons, leaving stress response genes easier to activate. As adults, these mice tolerated stress less well, showed more reactive dopamine neurons, and displayed more anxious behavior than mice whose SETD7 levels remained normal throughout life.
The opposite experiment produced a strikingly different result. When researchers prevented SETD7 from adding excessive H3K4me1 after early-life stress, the DNA remained more tightly packed, and the mice did not become hypersensitive to later stress. Despite experiencing stress both early in life and again as adults, mice with reduced SETD7 activity remained as social and exploratory as unstressed animals, while their dopamine neurons maintained normal activity.
“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.”
Reference: “Early-life stress alters H3K4me1 in VTA to prime stress sensitivity” by Hye Ji J. Kim, Luke T. Geiger, Julie-Anne Balouek, Lisa Z. Fang, Mason R. Barrett, Jeremy M. Thompson, Lorna A. Farrelly, Travis Hage, Rixing Lin, Andy S. Chen, Megan Tang, Hao Huang, Anna Buretta, Agatha Chan, Shannon N. Bennett, Benjamin A. Garcia, Ian Maze, Meaghan C. Creed and Catherine Jensen Peña, 7 August 2026, Neuron.
DOI: 10.1016/j.neuron.2026.07.018
This work was supported by grants from the National Institutes of Health (NIH), grant numbers K99MH115096, R00MH115096, R01MH129643 and R01HD106051; New York Stem Cell Foundation, grant numbers R01DA049924, R01DA058755 and R01DA056829; Princeton C.V. Starr Fellowship, grant number R01MH116900; Howard Hughes Medical Institute; CIHR Doctoral Research Award; Alison Cole endowed Mentored Research Training Grant from the Foundation for Anesthesia Education and Research; Peña CJ is a New York Stem Cell Foundation Robertson Investigator. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
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