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 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."
Tsankova NM, Berton O, Renthal W, Kumar A, Neve R, Nestler EJ. Sustained
hippocampal chromatin regulation in a mouse model of depression and
antidepressant action. Nature Neuroscience. Online, 2/26/2006.
