Epigenetic effects of stress hormones during adolescence
Recent studies show that stress during adolescence can increase the risks of psychological disorders in adults.
It has been observed that mice that were exposed to higher stress levels during adolescence, and thus that have more stress hormones-- like cortisol-- circulating in their blood, were more prone to developing mental illnesses derived from genetic factors.
The results of this study pave way for new opportunities in prevention and treatment of some severe neuropsychological disorders such as depression or schizophrenia.
Akira Sawa, a professor of psychiatry and behavioral sciences at Hopkins Medicine headed the study recently published in Science. Sawa and his team investigated the effect of external stressors on adults that are already at risk.
Sawa prepared a group of genetically modified rats that were predisposed to certain mental illnesses and a group of healthy rats as a control. Interestingly, the genetically modified rats showed no deviation in behavior, thus living without any sign of mental illness. However, when they applied certain external pressures to stress them out, the modified rats experienced lasting abnormal behaviors.
The experiment was designed to recreate social isolation, which can be a hard part during teenage years. Sawa isolated mice, both modified and healthy, from its group for three weeks. After three weeks, they were examined for certain abnormalities in behavior and physical performances like swimming.
While healthy rats acted as nothing had changed and swam capably, the modified rats expressed hyperactivity and were also not able to swim. Furthermore, When each of the mice rejoined their group, the modified mice continued to act abnormally, suggesting a long lasting effect of stress during adolescence.
Sawa explains that genetic risk factors are important but not sufficient for the development of mental illness; it is important that an environmental stressor must also be present to trigger the unusual behavior.
The onset of mental illness in these experiments was caused by an excess of circulating cortisol. This stress hormone is secreted by the adrenal gland during the body’s flight-or-fight response, a role that our sympathetic nervous system is responsible for. Additionally, mice also displayed a decrease in dopamine levels in the frontal cortex. Dopamine is responsible for higher brain functions such as cognition, motivation and reward behavior.
In order to determine whether or not the decrease in dopamine levels was associated with the unusual cortisol levels, the researchers administered RU486.
This compound, also known as the abortion pill, is a cortisol antagonist: it prevents cortisol from being active in the cells by blocking the receptors. The symptoms faded away and the dopamine levels were restored.
Why did the mice get better? To answer this question, Sawa and his team looked at the tyrosine hydroxylase (Th) gene. High levels of cortisol had an epigenetic effect on the gene that decreased its activity. This concomitantly led to a decrease in production of an enzyme that regulates dopamine levels.
Epigenetic modifications, unlike mutations that change the sequence of DNA, do not alter the DNA language, but instead add chemical compounds on the sequence. In this case, a methyl group was added to the gene, which prevented it from being fully active, resulting in low dopamine levels. Blocking the cortisol receptors allowed the gene to return to its normal state.
“We are going to look at other genes, not only Th, but also other genes that could cause a decrease in dopamine. We are trying to find other genes that are epigenetically affected,” Sawa said. He also explains that there is a need to develop drugs that are also cortisol antagonist that do not have all the side effects that RU486 has.