Depression model leaves mice with molecular scar

In addition to triggering a depression-like social withdrawal syndrome, repeated defeat by dominant animals leaves a mouse with an enduring “molecular scar” in its brain that could help to explain why depression is so difficult to cure, suggest researchers funded by the National Institutes of Health’s (NIH) National Institute of Mental Health (NIMH).

In mice exposed to this animal model of depression, silencer molecules turned off a gene for a key protein in the brain’s hippocampus. By activating a compensatory mechanism, an antidepressant temporarily restored the animals’ sociability and the protein’s expression, but it failed to remove the silencers. A true cure for depression would likely have to target this persistent stress-induced scar, say the researchers, led by Eric Nestler, M.D., The University of Texas Southwestern Medical Center, who report on their findings online in Nature Neuroscience during the week of February 26, 2006.

“Our study provides insight into how chronic stress triggers changes in the brain that are much more long-lived than the effects of existing antidepressants,” explained Nestler.

Mice exposed to aggression by a different dominant mouse daily for 10 days became socially defeated; they vigorously avoided other mice, even weeks later. Expression of a representative gene in the hippocampus, a memory hub implicated in depression, plummeted three-fold and remained suppressed for weeks. However, chronic treatment with an antidepressant (the tricyclic imipramine) restored expression of the gene for brain derived neurotrophic factor (BDNF) to normal levels and reversed the social withdrawal behavior. BDNF in the hippocampus has been linked to memory, learning and depression, but Nestler said social defeat stress probably similarly affects other genes there as well.

The researchers pinpointed how social defeat changes the BDNF gene’s internal machinery. They traced the gene expression changes to long-lasting modifications in histones, proteins that regulate the turning on-and-off of genes via a process called methylation. Methyl groups, the silencer molecules, attach themselves to the histones, turning off the gene. Notably, imipramine was unable to remove these silencer molecules, suggesting that they remained a latent source of vulnerability to future depression-like responses to stress.

Imipramine reversed the suppressed BDNF gene expression by triggering a compensatory mechanism, acetylation, in which molecular activators attach themselves to the gene and overcome the silencer molecules. Imipramine turned off an enzyme (Hdac5) that degrades the activators, allowing them to accumulate.

“The molecular scar induced by chronic stress in the hippocampus, and perhaps elsewhere in the brain, can’t be easily reversed,” said Nestler. “To really cure depression, we probably need to find new treatments that can remove the silencer molecules.”

Media Contact

Jules Asher EurekAlert!

More Information:

http://www.nih.gov

All latest news from the category: Life Sciences and Chemistry

Articles and reports from the Life Sciences and chemistry area deal with applied and basic research into modern biology, chemistry and human medicine.

Valuable information can be found on a range of life sciences fields including bacteriology, biochemistry, bionics, bioinformatics, biophysics, biotechnology, genetics, geobotany, human biology, marine biology, microbiology, molecular biology, cellular biology, zoology, bioinorganic chemistry, microchemistry and environmental chemistry.

Back to home

Comments (0)

Write a comment

Newest articles

The Sound of the Perfect Coating

Fraunhofer IWS Transfers Laser-based Sound Analysis of Surfaces into Industrial Practice with “LAwave”. Sound waves can reveal surface properties. Parameters such as surface or coating quality of components can be…

Customized silicon chips

…from Saxony for material characterization of printed electronics. How efficient are new materials? Does changing the properties lead to better conductivity? The Fraunhofer Institute for Photonic Microsystems IPMS develops and…

Acetylation: a Time-Keeper of glucocorticoid Sensitivity

Understanding the regulatory mechanism paves the way to enhance the effectiveness of anti-inflammatory therapies and to develop strategies to counteract the negative effects of stress- and age-related cortisol excess. The…

Partners & Sponsors