Unraveling the Link Between Genes and Environment

MONDAY May 5, 2008 -- New studies in the field of epigenetics -- which looks at how environmental factors can change gene function without altering DNA sequence -- are identifying new molecular targets that may lead to improved drug treatment of depression, scientists report.

Epigenetics plays a major role in depression and the actions of antidepressants.

"The mechanisms that precipitate depression, such as stress, are incompletely understood," Dr. Eric Nestler, of the University of Texas Southwestern Medical School in Dallas, said in a prepared statement. "One mystery of the disease is its long-lasting nature and delayed response to antidepressant treatment. This persistence is thought to be influenced by slowly developing but stable adaptations, which might include epigenetic regulation."

Nestler held a symposium Monday on epigenetics at the American Psychiatric Association annual meeting, in Washington, D.C. A number of scientists outlined their research on epigenetics and depression. The symposium was sponsored by the U.S. National Institute of Mental Health.

Epigenetic changes aren't the same as genetic mutations, which are variations in the sequences of building blocks that make up the DNA in a gene. In epigenetic changes, genes remain stable, but environmental factors such as diet, stress and a mother's care act on the supporting structures of DNA, such as chromatin, molecules that package genes into chromosomes, according to background information in a news release about the symposium.

Certain chemical reactions can unravel the chromatin, which can affect a gene's DNA code and turn a gene on or off. As a result, a gene may produce more or less protein than normal which, in turn, can affect physical and behavioral traits. This change in protein production can be passed on from one cell to another as they multiply and can also be passed from parents to children.

Research conducted by Nestler and colleagues found that chronic social stress can cause chromatin changes in genes in the brain's nucleus accumbens and hippocampus.

"In both brain regions, we have been able to directly relate these chromatin changes to some of the behavioral abnormalities observed," Nestler said.

In animal models of chronic stress, he and his colleagues were able to manipulate these two brain areas in ways that produced antidepressant-like effects.

In other research, a team at the University of Massachusetts Medical School in Worcester are examining changes in methylation, a type of chemical modification of the DNA and of histones, the protein "backbone" of chromatin.

"We found that these chemical modifications in brain chromatin are dynamically regulated from the perinatal period to old age and could be involved in epigenetic control of gene expression, including genes for brain-derived neurotrophic factor and others implicated in mood and anxiety spectrum disorders," Dr. Schahram Akbarian said in a prepared statement.

He said the findings could help in the design of new antidepressant treatments. Preliminary findings from research in mice suggest that chemical modification of epigenetic-related factors could enhance response to widely used antidepressants.

Researchers at McGill University in Montreal found that separating rats from their mothers at an early age altered the methylation state of specific genes in the hippocampus, resulting in long-term behavioral changes.

They found that differences in a mother's care, such as licking and grooming, can change the development of rat pups' hormonal and behavioral response to stress, resulting in lifelong changes in the pups' response to stress and how they process information about stressors.

"This may reveal experience-dependent adaptability in the chemistry of the DNA and chromatin structure," researcher Michael Meaney said in a prepared statement.

Posted: May 2008


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