|Depression Model Leaves Mice with Molecular Scar
In addition to triggering a depression (http://www.nimh.nih.gov/healthinformation/depressionmenu.cfm)-like
social withdrawal syndrome, repeated defeat (http://www.nimh.nih.gov/press/bdnfknockdown.cfm)
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 National Institutes of Health’s (NIH) National Institute of Mental
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
In the study, 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 (http://www.nimh.nih.gov/press/prbdnf.cfm),
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
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