It has long been recognised by psychologists that the negative effects of trauma experienced by parents can also be detected in their children, but the molecular mechanisms underlying this effect are only now being identified. A research team led by Isabelle Mansuy, professor of neuroepigenetics at the University of Zurich and ETH Zurich, has tested the degree to which the beneficial effects of stress can be passed to following generations in mice.
Prof. Isabelle Mansuy | Isabelle Mansuy is a French-born molecular biologist. She studied in Strasbourg, received her PhD in Basel and worked at Columbia University in the lab of Eric Kandel, Nobel laureate of 2000. Today Mansuy is a professor at the University of Zurich and at the ETH Zurich. Her main research interest is neuro-epigenetics.
The researchers subjected newborn male mice to traumatic stress by removing them from their mother at irregular and frequent intervals, and by severely stressing the mothers in addition. They used standardised tests to analyse the behaviour of these pups after they had grown up, as well as their offspring, always comparing it to the behaviour of control mice not subjected to stress. They observed that the offspring of the stressed mice handled complex tasks more efficiently than the control group.
For example, one test revealed that the offspring of stressed fathers adapted better to changing rules to earn a drink reward when they were thirsty: they were able to react more flexibly. In another test, the mice had to poke their nose into a hole when prompted by a light signal to get water, but only after a pre-determined delay of 6, 12 or 18 seconds. The stressed mice and their offspring performed the task better than the control mice at the long time interval of 18 seconds, which was especially challenging. This result was interpreted as evidence for improved goal-oriented behaviour in difficult situations. Since the fathers were kept apart from their offspring and the mothers, the young animals cannot have learned this behaviour. Rather, they must have inherited it via molecular pathways.
To determine how this behaviour is expressed and transmitted to the next generation, the researchers examined the activity of a gene, a mineralocorticoid receptor gene previously implicated in flexible behaviour. Mansuy’s team discovered that 'epigenetic' marks, which determine how much a gene is expressed, were altered on this gene, both in the brain and sperm of the stressed mice. The altered marks were passed on to the next generation probably through the sperm, and may be partly responsible for the altered behaviour. The mineralocorticoid receptor in question binds signal messengers like the stress hormone cortisone that initiates a signalling cascade in neurons.
"Our results show that environmental factors change behaviour and that these changes can be passed on to the next generation," explains Mansuy. This finding – that not only a parent's susceptibility to psychological disorders can be passed on to its offspring, but also its improved goal-oriented behaviour – might prove to be of value to clinical practice. Doctors could help post-trauma patients suffering from depression to build on these strenghts. The implication of the mineralocorticoid receptor gene could also be a good starting point for future medical therapies.
"We are not in any way suggesting that early-childhood trauma is somehow positive," says Mansuy. But she adds that her study on mice demonstrates how extreme stress can affect the brain and behaviour across generations - negatively, but positively.
(© ETH Zurich, AcademiaNet)