In addition to triggering a depression-like social withdrawal syndrome, repeated social 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.
In the study, mice exposed to 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, for brain derived neurotrophic factor (BDNF), which has been linked to memory, learning and depression, plummeted three-fold and remained suppressed for weeks. However, chronic treatment with an antidepressant (the tricyclic imipramine) restored BDNF expression to normal levels and reversed the social withdrawal behavior.
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.
