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Key points
- Mental health problems can be a legacy of a past generation’s trauma, encoded in the genome and inherited.
- Epigenetic inheritance fine-tunes gene readout to maximize success in the environment we experience.
- The negative effects of maternal separation could potentially respond to medication, a new animal study finds.
- The research was conducted on mice and the effect on humans is not yet known.
Is it possible that psychological trauma that your grandparents suffered long before you were born could have been passed down through generations to reappear as mental health issues that afflict you?
New experimental research by a team of investigators in Canada and Italy suggests the answer is yes. Mental health problems can be a legacy of a past generation’s trauma, encoded in the genome and inherited by future generations. But the same study finds that we may not need to be condemned to this fate; pre-clinical animal evidence suggests that a common drug has the potential to erase the inherited "biological memories" of psychological trauma (at least in mice).
What Is Epigenetics?
The genetic code we inherit cannot be changed by experiences in life, but whether or not a certain gene is read out or remains locked up is regulated by molecular markers that earmark which genetic sequences of DNA become activated. Those molecular markers can be influenced by life experience, and through this process called "epigenetics," certain gene sequences that we inherit can be "redacted" or "highlighted" to modify which genes go to work in our bodies.
The purpose of this epigenetic regulation is to fine-tune DNA readout to optimize our abilities for success in the environment we encounter. But those epigenetic markers can be passed down to future generations. Since a particular epigenetic modification helped the parents survive and pass on their genes, that alteration may confer an advantage to their progeny, too.
Psychological trauma in early life—for example, being separated from parents—often leads to persistent mental health issues. A tragic example is the profound effects on Romanian orphans who suffered severe neglect. Early maternal separation in studies on experimental animals increases anxiety-like behavior and other defensive reactions including increased sensitivity to pain. Other emotional, cognitive, and neuropsychiatric stress-related disorders, including depression, autism, posttraumatic stress disorder, and dementia, can also result from early life stresses.
What the Study Found in Mice
In this new study, researchers removed mouse pups from their mothers one day after birth and placed them with a new female mouse whose own pups had just been removed. This procedure of fostering the offspring with an adopted new mother was repeated every day for four days. Previous research with this well-established model confirms that there were no differences in maternal care or feeding by the surrogate lactating females, but the early life stress has adverse effects on the pups that were separated from their biological mother.
As expected, in the new study, pups experiencing this early life stress developed enhanced pain sensitivity and increased hyperventilation, both of which are regarded as defensive responses to stress. These changes can be assessed quantitatively, by measuring the mouse's pain threshold and hyperventilation.
Pain threshold is tested harmlessly by mild probing with fibers of calibrated stiffness or by shining a focused light beam on the mouse’s paw, raising the temperature gradually until the mouse flicks its paw away. Hyperventilation is assessed by measuring respiration rate upon raising the concentration of carbon dioxide in the air. When carbon dioxide levels increase, normal mice begin breathing more rapidly, but mice that had experienced early life stress respond by hyperventilation beyond normal levels.
The researchers found that both the increased sensitivity to pain and hyperventilation when challenged with higher carbon dioxide levels developed in the pups separated from their mothers after birth, but these traits were also passed on to their offspring through two subsequent generations. Although difficult to prove by experiments on humans for ethical reasons, there is some reason to believe that similar effects could happen to human babies who are separated from their mothers in early life.
The researchers were able to pinpoint one of the genes responsible for the inherited increased hyperventilation. When carbon dioxide dissolves in the bloodstream, it forms carbonic acid. The body senses the increased acidity in the blood using acid-sensing proteins encoded by the gene Asic.
Upon examining DNA for epigenetic markers in the brains of these mice who were separated from their mothers in early life, the researchers detected well-established markers (called histone marks) on several genes, including Asic. Further analysis confirmed higher levels of RNA that encodes the ASIC acid-sensing channel in the brain region controlling respiration (medulla oblongata) in the adult mice that had experienced maternal separation as pups. Synthesis of RNA is how DNA is read out to make new proteins. The same enhanced readout of the Asic gene was evident in two subsequent generations of mice that had been reared normally by their biological mothers.
Effect of Amiloride
Reasoning that if the acid-sensing property of the ASIC channel could be dialed back in the mice separated from their mothers, then the hyperventilation resulting from early life maternal separation should also be checked. This would benefit not only the mice separated from their mothers but also the subsequent offspring, because the epigenetic markers would presumably not form on the Asic gene.
To test that theory the researchers gave the mice a drug, amiloride, commonly used to inhibit this acid-sensing channel, and found that hyperventilation caused by maternal separation was prevented, not only in the mice receiving the single dose of the drug, but also in their two subsequent generations of offspring.
These same acid-sensing channels are in sensory neurons that detect pain, and the single dose of amiloride after maternal separation also alleviated the heightened sensitivity to pain in the immediate offspring and their two subsequent generations.
In humans, variations in the Asic gene are associated with panic disorder. A simple amiloride nasal spray could, in theory, be used therapeutically to help people with panic disorder, pain hypersensitivity, and other conditions, the researchers conclude. Though these animal studies are far from conclusive, they suggest the possibility that treating human infants experiencing early-life maternal separation with the same nasal spray could also block the effects—which may similarly continue to subsequent generations.
However, even if that turned out to be the case, would it be a good thing or a bad thing? This is something to ponder considering that nature has devised an epigenetic means of inheritance to promote survival in the specific environments we are born into, be they nurturing or stressful, and which descendants are also more likely to experience.
