Summary: Combining two natural compounds that influence the epigenome, researchers report a promising strategy that reverses PTSD-like symptoms in an animal model and may be translatable to humans.
Source: Bar Ilan University
Exposure to traumatic events can lead to post-traumatic stress disorder (PTSD), a debilitating condition that currently lacks reliable, widely effective therapies. A central question in PTSD research is how a brief trauma can produce long-lasting symptoms in some individuals while others who experience the same trauma remain resilient.
Epigenetic modifications are chemical markers on DNA and associated proteins that regulate gene activity without changing the underlying genetic code. These marks are established during development to guide tissue-specific gene expression, but mounting evidence shows that life experiences and environmental exposures can also alter epigenetic patterns at later stages of life.
Human studies have linked PTSD to changes in DNA methylation measured in blood, suggesting that trauma may leave an epigenetic “signature.” However, it remained unclear whether similar epigenetic alterations occur in specific brain regions tied to PTSD and whether such changes play a causal role in the behavior associated with the disorder.
A research team at Bar-Ilan University led by Prof. Gal Yadid investigated this question using an established animal model of PTSD. Their study focused on epigenetic changes in the nucleus accumbens, a brain region implicated in stress response and emotional regulation. The findings were published in the journal Molecular Psychiatry.
The investigators compared DNA methylation maps in the nucleus accumbens between animals that became susceptible to PTSD-like behaviors after trauma and those that remained resilient. They identified distinct methylation differences, finding an overall decrease in methylation at many genomic sites in susceptible animals. This hypomethylation correlated with reduced expression of the DNA methyltransferase enzyme DNMT3A, which is responsible for adding methyl groups to DNA.
Further analysis of the differentially methylated genes revealed pathway-level changes. One notable group of affected genes is regulated by the retinoic acid receptor (RAR) pathway, including the RAR-related orphan receptor alpha (RORA), a transcription factor activated by vitamin A derivatives. These results suggested that altered activity of DNMT3A and RORA-related pathways could contribute to PTSD-like behavior.
To test causality, the researchers used viral vectors to increase expression of either DNMT3A or RORA specifically in the nucleus accumbens. Restoring these genes reversed PTSD-like behaviors in susceptible animals, while experimental knockdown of DNMT3A or RORA increased susceptibility. Those results support a causal role for reduction of DNMT3A and RORA in producing PTSD-like phenotypes in this model.
Direct gene delivery to human brains is not currently a practical therapeutic approach, so the team explored a pharmacological strategy based on these mechanistic insights. Because DNMT3A promotes DNA methylation, they supplemented the animals with a natural methyl donor, S-adenosylmethionine (SAMe). To activate RORA-related signaling, they treated animals with retinoic acid, a vitamin A–derived ligand that engages retinoic acid receptors.
Combined systemic treatment with SAMe and retinoic acid reversed PTSD-like behaviors in susceptible animals, whereas either compound alone was less effective. This combined, epigenetically focused therapy appears to restore gene regulation patterns altered by trauma, addressing the underlying molecular changes rather than just providing temporary symptom relief.
The study highlights a novel, potentially translatable approach to PTSD treatment that targets epigenetic dysregulation. Because SAMe and vitamin A derivatives are relatively well tolerated as nutritional supplements or pharmaceuticals, the authors suggest this combinatorial epigenetic therapy could offer a low-toxicity option to reverse trauma-induced genomic changes associated with PTSD. Further research will be needed to evaluate safety, dosing, and efficacy in humans.
About this PTSD research news
Source: Bar Ilan University
Contact: Press Office – Bar Ilan University
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Original Research: Open access. “Reduction of DNMT3a and RORA in the nucleus accumbens plays a causal role in post-traumatic stress disorder-like behavior: reversal by combinatorial epigenetic therapy” by Gal Warhaftig, Noa Zifman, Chaya Mushka Sokolik, Renaud Massart, Orshay Gabay, Daniel Sapozhnikov, Farida Vaisheva, Yehuda Lictenstein, Noa Confortti, Hadas Ahdoot, Avi Jacob, Tzofnat Bareli, Moshe Szyf & Gal Yadid. Molecular Psychiatry
Abstract
Reduction of DNMT3a and RORA in the nucleus accumbens plays a causal role in post-traumatic stress disorder-like behavior: reversal by combinatorial epigenetic therapy
Post-traumatic stress disorder (PTSD) is a trauma-related disorder with serious functional impact and limited reliable treatments. Although peripheral blood studies have associated PTSD with epigenetic alterations, it has remained unclear where such changes occur in the brain and whether they causally contribute to PTSD symptoms.
Using an animal PTSD model, the authors identified distinct DNA methylation signatures in the nucleus accumbens that distinguish susceptible from resilient animals. Susceptible animals showed widespread hypomethylation at genomic CG sites that correlated with reduced expression of DNMT3A. Pathway analysis of differentially methylated sites highlighted enrichment in retinoic acid–related pathways and LXR/RXR signaling, implicating RORA activation.
Functional experiments demonstrated that restoring DNMT3A or RORA expression in the nucleus accumbens reversed PTSD-like behaviors, while reducing expression of these factors increased susceptibility. Translating these findings pharmacologically, systemic treatment with the global methyl donor S-adenosylmethionine (SAMe) together with retinoic acid reversed PTSD-like behaviors in susceptible animals.
These results support a novel, epigenetically targeted therapeutic strategy for PTSD that may be translatable to humans.