Depressive, impulsive and antisocial symptoms caused by severe chronic stress during childhood are transmitted epigenetically from one generation to the next.
Epigenetic inheritance of the negative impact of stressful events across generations
Depressive, impulsive and antisocial symptoms caused by severe chronic stress during childhood are transmitted epigenetically from one generation to the next. This has now been demonstrated by researchers at the University of Zurich and ETH Zurich.
In human, chronic severe stress or traumatic experiences during childhood can lead to various psychological and mental disorders in adult life, such as borderline personality disorder and bipolar depression. A study carried out by a team under the supervision of the neuroscientist Isabelle Mansuy has used mice to demonstrate that such negative experiences can also have an impact on following generations. Mansuy holds a double professorship at the University of Zurich and ETH Zurich.
Stress during childhood, problems during adulthood
The scientists used mice as an experimental model, and exposed newborn pups to chronic and unpredictable maternal separation for two weeks. They also exposed the mother to additional unpredictable stress during the separation. This procedure was designed to induce extremely severe stress in the young mice, and is thought to simulate neglect and traumatic upbringing that children sometimes experience in uncaring, negligent or violent families. The young mice reacted so dramatically to the separation that they became depressive and impulsive as adult, and had social problems.
In particular, these animals were unable to deal appropriately with unfamiliar or adverse situations, and easily lost control of their behavior. For example, they lost their natural sense of caution when exploring new territories, and were no longer able to evaluate the potential risk of unfamiliar situations. They also reacted with apathy and despair in adverse conditions, and did not struggle for life in contrast to mice that grew up in normal conditions.
The traumatized mice retained these altered behaviours during their entire life and strikingly, «transmitted» these behaviours to their offspring. The researchers even provided evidence that transmission was across three generations, and that the offspring of that offspring was also affected.
Epigenetics determines behaviour
However, these behavioural changes are not attributable to mutations in the genetic make-up of the traumatized mice, since the genome is fixed and cannot be modified by stress. The researchers demonstrated that instead, stress interferes with the epigenome, in particular with the profile of methylation of certain genes in the brain and the sperm of male mice. This epigenetic plasticity is based on changes in chromatin structure, that alters the expression of the affected genes. In a way «Stress confuses the methylation machinery in the germline of the stressed pups, and the confusion persists and is transmitted», explains Isabelle Mansuy.
Methyl, a small molecule comprising one carbon and three hydrogen atoms, is attached to one of the four components of DNA, namely cytosine, on certain genes. This subtle modification does not alter the sequence of the DNA itself, but controls its activity.
Too many or not enough methyl groups
So far the scientists have identified five genes which methylation is perturbed due to stress in early life. However, the changes are not equally dramatic in all the genes identified. «The degree, direction and location of the abberant methylation varies from gene to gene», emphasizes Mansuy. In some cases, too many methyl residues are wrongly added while in others, several are missing,
The epigenetic transmission of such behavioural defects has been suspected since a long time, but Mansuy’s team is the first to establish it at a molecular level across several generations. The group even already went one step further. Collaborating with Roche, the pharmaceutical company in Basel, it identified many other genes that are controlled epigenetically and are linked to behavioural disorders.
May be applicable for humans
«The symptoms displayed by the disturbed mice are also prominent in patients suffering from borderline personality disorder, depression or schizophrenia», says Isabelle Mansuy. As a result, it is possible to conclude that the results of these studies in mice may also apply to humans.
The researcher is now considering expanding the examination of this epigenetic phenomenon to humans. To do this, she will need tissue samples from individuals and their children to identify potential methylation candidates in the epigenome. «I am convinced that we will also find cases of abberant methylation in human tissue», says Professor Mansuy.
The findings made by Isabelle Mansuy and her research team are highly relevant for medicine. They are astonishing but difficult to accept for some people in the research community who are reluctant to admit that acquired behaviors can be inherited. Nonetheless, this concept is supported by multiple clinical observations which had remained not understood until now. Isabelle Mansuy states: «Our findings are solid and we confirmed them multiple times.» The team worked for more than eight years on this project, and provided all the possible evidence that the phenomenon is true. Some of the work was published in the journal Biological Psychiatry.