A new study may explain why some people are more vulnerable to stress and stress-related psychiatric disorders.
Researchers at Duke University have discovered that the addition of a chemical mark atop a gene known for its involvement in clinical depression and post-traumatic stress disorder (PTSD) can affect the way a person’s brain responds to threats.
The study, which appeared in Nature Neuroscience, focused on a molecule known as the serotonin transporter, which regulates the amount of serotonin signaling between brain cells.
In the 1990s, scientists discovered that differences in the DNA sequence of the serotonin transporter gene seemed to give some people exaggerated responses to stress, including the development of depression. That’s why it has become a target for the treatment of depression and other mood disorders, according to researchers.
Sitting on top of the serotonin transporter’s DNA are chemical marks called methyl groups that help regulate where and when a gene is active.
DNA methylation is one form of epigenetic modification being studied by scientists trying to understand how the same genetic code can produce so many different cells and tissues, as well as differences between individuals as closely related as twins, the researchers explained.
“We decided to start with the serotonin transporter because we know a lot about it biologically, pharmacologically, behaviorally, and it’s one of the best characterized genes in neuroscience,” said senior author Ahmad Hariri, a professor of psychology and neuroscience and member of the Duke Institute for Brain Sciences.
“If we’re going to make claims about the importance of epigenetics in the human brain, we wanted to start with a gene that we have a fairly good understanding of.”
The latest experiments are part of the Duke Neurogenetics Study (DNS), which is looking at genes, brain activity, and other biological markers of risk for mental illness in young adults.
For this study, the researchers performed non-invasive brain imaging in the first 80 college-aged participants of the DNS, showing them pictures of angry or fearful faces and watching the responses of a deep brain region called the amygdala, which helps shape our behavioral and biological responses to threat and stress.
They also measured the amount of methylation on serotonin transporter DNA isolated from the students’ saliva.
The study found that the greater the methylation, the greater the reactivity of the amygdala. Increased amygdala reactivity may in turn contribute to an exaggerated stress response and vulnerability to stress-related disorders, the researchers explain.
“To our surprise, even small methylation variations were sufficient to create differences between the students’ amygdala reactivity,” said lead author Yuliya Nikolova, a graduate student in Hariri’s group.
“The amount of methylation was a better predictor of amygdala activity than DNA sequence variation, which had previously been associated with a risk for depression and anxiety,” he noted.
The researchers report they were excited about the discovery but also cautious, because there have been many findings in genetics that were never replicated.
That’s why they jumped at the chance to look for the same pattern in a different set of participants, this time in the Teen Alcohol Outcomes Study (TAOS) at the University of Texas Health Science Center at San Antonio.
Working with TAOS director Douglas Williamson, the researchers measured amygdala reactivity to angry and fearful faces as well as methylation of the serotonin transporter gene in 96 adolescents between 11 and 15 years old. The analyses revealed an even stronger link between methylation and amygdala reactivity, according to the researchers.
“Now over 10 percent of the differences in amygdala function mapped onto these small differences in methylation,” Hariri said. The DNS study found just under seven percent.
Taking the study one step further, the researchers also analyzed patterns of methylation in the brains of dead people in collaboration with Etienne Sibille at the University of Pittsburgh, now at the Centre for Addiction and Mental Health in Toronto.
Once again, they saw that methylation of a single spot in the serotonin transporter gene was associated with lower levels of serotonin transporter expression in the amygdala.
“That’s when we thought, ‘All right, this is pretty awesome,'” Hariri said.
According to Hariri, the work reveals a link: Higher methylation is associated with less reading of the gene. He explained methylation dampens expression of the gene, which then affects amygdala reactivity, presumably by altering serotonin signaling.
“We plan to study how methylation of this specific bit of DNA affects the brain. In particular, this region of the gene might serve as a landing place for cellular machinery that binds to the DNA and reads it,” Nikolova said.
The researchers add they also plan to look at methylation patterns of other genes in the serotonin system that may contribute to the brain’s response to threatening stimuli.
Source: Duke University