Small DNA modifications predict brain's threat response

An artist's conception shows how molecules called methyl groups attach to a specific stretch of DNA, changing expression of the serotonin transporter gene in a way that ultimately shapes individual differences in the brain's reactivity to threat. The methyl groups in this diagram are overlaid on the amygdala of the brain, where threat perception occurs. Credit: Annchen Knodt, Duke University

The tiny addition of a chemical mark atop a gene that is well known for its involvement in clinical depression and posttraumatic stress disorder can affect the way a person's brain responds to threats, according to a new study by Duke University researchers.

The results, which appear online August 3 in Nature Neuroscience, go beyond genetics to help explain why some individuals may be more vulnerable than others to stress and stress-related psychiatric disorders.

The study focused on the , a molecule that regulates the amount of serotonin signaling between brain cells and is a major target for treatment of depression and mood disorders. In the 1990s, scientists discovered that differences in the DNA sequence of the seemed to give some individuals exaggerated responses to stress, including the development of depression.

Sitting on top of the serotonin transporter's DNA (and studding the entire genome), are chemical marks called groups that help regulate where and when a gene is active, or expressed. 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.

In looking for methylation differences, "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," Hariri said.

This work is part of the ongoing Duke Neurogenetics Study (DNS), a comprehensive study linking genes, brain activity and other biological markers to risk for mental illness in young adults.

The group 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.

The team also measured the amount of methylation on serotonin transporter DNA isolated from the participants' saliva, in collaboration with Karestan Koenen at Columbia University's Mailman School of Public Health in New York.

The greater the methylation of an individual's serotonin transporter gene, the greater the reactivity of the amygdala, the study found. Increased amygdala reactivity may in turn contribute to an exaggerated stress response and vulnerability to stress-related disorders.

To the group's surprise, even small methylation variations between individuals were sufficient to create differences between individuals' 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 risk for depression and anxiety.

The team was excited about the discovery but also cautious, Hariri said, 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 group again measured amygdala reactivity to angry and fearful faces as well as methylation of the serotonin transporter gene isolated from blood in 96 adolescents between 11 and 15 years old. The analyses revealed an even stronger link between methylation and amygdala reactivity.

"Now over 10 percent of the differences in amygdala function mapped onto these small differences in methylation," Hariri said. The DNS study had found just under 7 percent.

Taking the study one step further, the group 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, 'Alright, this is pretty awesome,'" Hariri said.

Hariri said the work reveals a compelling mechanistic link: Higher methylation is generally associated with less reading of the gene, and that's what they saw. He said methylation dampens expression of the gene, which then affects amygdala reactivity, presumably by altering serotonin signaling.

The researchers would now like to see 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 group also plans to look at of other genes in the serotonin system that may contribute to the brain's response to threatening stimuli.

The fact that serotonin transporter methylation patterns were similar in saliva, blood and brain also suggests that these patterns may be passed down through generations rather than acquired by individuals based on their own experiences.

Hariri said he hopes that other researchers looking for biomarkers of mental illness will begin to consider methylation above and beyond DNA sequence-based variation and across different tissues.

More information: "Beyond genotype: serotonin transporter epigenetic modification predicts human brain function," Yuliya S. Nikolova, Karestan C. Koenen, Sandro Galea, Chiou-Miin Wang, Marianne L. Seney, Etienne Sibille, Douglas E. Williamson and Ahmad R. Hariri. Nature Neuroscience, August 3, 2014. DOI: 10.1038/nn.3778

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russell_russell
not rated yet Aug 03, 2014
Exciting bold research.

The fact that serotonin transporter methylation patterns were similar in saliva, blood and brain also suggests that these patterns may be passed down through generations rather than acquired by individuals based on their own experiences.


Yes.
The best way to conserve acquired experience (memory) is to pass this on to offspring.
So what if newborns soon-to-be signal processing of pending similar experience is ' methylation-rigged' - inherited from the carriers (parents) already in possession of experience-based methylation patterns?

The title is misleading. Modification of DNA expression predicts brain's threat respond.

JVK
1 / 5 (1) Aug 04, 2014
Ecological variation in sunlight and nutrient-dependent methylation link the vitamin D hormone to biophysically-constrained cell type differentiation via amino acid substitutions associated with epigenetic effects of food odors on the de novo creation of olfactory receptor genes. Thus, conserved molecular mechanisms across all genera appear to link the epigenetic landscape to the physical landscape of DNA in the organized genomes of species from microbes to man via cell type differentiation in plants and animals.

Other works co-authored by Etienne Sibillie make the link from vitamin D to serotonin regulation and behavior clearer via what is known about nutrient-dependent pheromone-controlled hormone-organized and hormone-activated behaviors. See: http://www.bsd-jo...t/4/1/20 and also learn more about how "Vitamin D hormone regulates serotonin synthesis" http://medicalxpr...nin.html in the context of learning and memory.
JVK
1 / 5 (1) Aug 04, 2014
See also Nobel Laureate Eric Kandel's: The Molecular and Systems Biology of Memory http://www.cell.c...00290-6.

"...even a single amino acid mutation that prevented the autophosphorylation, and thus the persistent activation of the kinase, was also sufficient to disrupt both LTP and memory (Giese et al., 1998)."

Unfortunately, the links between nutrient-uptake and the epigenetic effects of vitamins, such as the vitamin D hormone are not typically placed into the context of nutrient-dependent learning and memory that enables the pheromone-controlled physiology of reproduction to control cell type differentiation in species from microbes to man.

Focus has been on mutation-initiated natural selection and the evolution of biodiversity instead of on biological facts incorporated into a model of ecological variation and adaptations:
http://figshare.c...s/994281
animah
not rated yet Aug 06, 2014
Says JVK - James V Kohl, purveyor of sex paraphernalia, thus great peddler of Sin and the destruction of Christian morality.

In any case your product, "scent of Eros" is snake oil and cannot possibly work. As Rob van den Hurk (a pheromone specialist) noted, pheromones work "in concentrations of nanograms to picograms. When administered in higher concentrations, pheromones often result in no or a repulsive behavioral effect. "

This kind of concentration is not consistently achievable in a consumer product. A user is also likely to over-apply. So At best your "Scent of Eros" scam has no effect, and there is a good chance it is actually repulsive to women.

So for you to pretend science supports your self-serving commercial aims is beyond the pale.
JVK
not rated yet Aug 06, 2014
The anonymous "animah" has posted this same comment on several different discussion threads. The intent is to limit discussion to the invented theories about evolution. No attempt is made to address the facts included in my published works with details about cell type differentiation.

Obviously, there are many people too afraid that the facts will eliminate evolutionary theory from any further consideration whatsoever. But that's what happens when people begin to look at what they accepted because they were taught to believe in, and accepted it as if it ever was anything more than pseudoscientific nonsense.

It never was, and evolutionary theory never will be more than the invention of population geneticists and their idiot minions.

See: Replace the Modern Synthesis (Neo-Darwinism): An Interview With Denis Noble
http://www.huffin...211.html

"[W]hat Haldane, Fisher, Sewell Wright, Hardy, Weinberg et al. did was invent...."