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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, 2005.

"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 mo
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Source:NIH/National Institute of Mental Health


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