Researchers have put ample effort into identifying genes that help explain why cancer or heart disease run in some families. But scientists still don't know if some genes can explain why the children and grandchildren of people who've survived traumatic events are more likely to experience mental illnesses than the general population. If there is a gene, or set of genes, that make the children of survivors more likely to develop depression and schizophrenia, scientists have yet to find it. Now, new research suggests that many scientists might have been looking in the wrong place.
A group of European researchers have discovered that early life traumatic events can alter a non-genetic mechanism governing gene expression in the sperm cells of adult mice. And they think that this finding, published today in Nature Neuroscience, explains why the offspring of these mice exhibit the same depressive-like behaviors that their parents do.
Early childhood trauma
The idea that altered gene expression can be passed down is controversial
People who experience early childhood trauma, like abuse or war, often exhibit a number of hormonal imbalances. The mechanisms involved are poorly understood, but most scientists agree that traumatic events alter gene expression, which then causes misregulations in a number of biological processes. But whether these changes can actually be passed down to offspring is a controversial question, because it would imply that acquired traits — traits that aren't actually encoded in DNA, but rather arise following certain experiences — are somehow being passed down through generations.
"Despite all the studies on the subject, there are still no known genes for depression and borderline personality disorder," says Isabelle Mansuy, a geneticist at the Swiss University ETH Zurich and co-author of the study. This is why Mansuy suspects that environmental factors, in addition to genes, explain why the effects of trauma are inherited in certain families.
To study this effect, Mansuy and her colleagues put male mouse pups and their mothers under repeated and prolonged periods of intense stress. They did so by periodically and unpredictably removing the pups from their mothers for hours at a time. Despite evidence that mothers can also pass down symptoms of trauma, researchers focused on the male pups, because they produce a lot of sperm and breed with many females.
Following these prolonged periods of stress, the traumatized mice exhibited altered behaviors, including diminished fear responses to open spaces and bright lights, and a number of depressive-like symptoms. These behavioral changes, Mansuy says, are the result of changes in the number of non-coding microRNAs — tiny snippets of genetic material that don't encode proteins — in the blood and brains of the mice. Under normal circumstances, she says, microRNAs regulate gene expression. But the trauma that these mice experienced resulted in the over-expression of microRNAs in the brain and an abnormal dip the production of certain proteins. "This," Mansuy says, "makes animals do things wrong."
Trauma in the un-traumatized
After the pups of the traumatized male mice were born, scientists monitored their behavior. As expected, these pups showed the same symptoms of trauma that their fathers did, despite having never undergone traumatic events themselves. And these symptoms were even apparent in a third generation of mice.
Symptoms despite having never undergone trauma
When researchers looked at the sperm of the traumatized mice, they discovered that the microRNAs in these sperm cells were also present in abnormally high numbers. "This means that germ cells — sperm in males and oocytes in females — are very sensitive to environmental conditions in early life," Mansuy says, "and early childhood trauma has consequences not only for the brain but also for the germ cell line."
Unfortunately, researchers don't know how the changes in microRNAs go from being present in the brain to being present in sperm. Figuring that out will require a lot more research. "The stress of the trauma that the pups undergo most likely does many things," Mansuy says. She posits that there might be one common factor linking the brain to these various effects, including the number of microRNAs in sperm. "It could be a stress hormone, a neuropeptide, or cytokines ... we really don't know. Perhaps it's a change in the blood."
And even though the third generation of mice exhibited maladaptive behaviors, the second generation didn't appear to produce sperm with excessive quantities of microRNAs. "The alteration of microRNAs doesn't persist beyond the second generation," Mansuy says, "so it's possible that the alteration is transferred into another non-genetic mark before the third generation."
Finally, Mansuy and her team were unable to demonstrate a direct link between the altered sperm microRNAs and the altered behaviors in the second and third generations of mice. So, they validated their findings indirectly by injecting sperm microRNAs from traumatized males into the oocytes of female mice. This allowed them to reproduce the same pattern of trauma symptoms in the resulting offspring that they had witnessed in the pups of the traumatized males.
The medical community is slowly becoming aware of transgenerational trauma
Eva Jablonka, a molecular biologist at Israel's Tel Aviv University who did not participate in the study, said in an email to The Verge that this study is "extremely valuable." It gives "a more detailed mechanistic explanation of a phenomenon that for a long time was supposed to be biologically impossible," she said. Mansuy and her team are now studying the effect of these short RNAs in humans. She notes that much more research is needed before scientists can start working on diagnostic tests or drug therapies. And, according to Jablonka, the medical community is only now becoming aware of these kinds of transgenerational effects.
Still, this study offers yet another argument for changing the way scientists approach trauma. "Epidemiological studies need to be re-thought," Jablonka said. These effects are "enormously important" because they indicate that altering the stress condition of a child isn't sufficient to ensure that the next generation will be ok. To achieve that result, she said, "we also have to counter the parental effects that were transmitted."