| The studies presented show the role of long-term changes that occur in the brain during a stress paradigm that induces depression-like behavior in mice. The focus is the nucleus accumbens, a key brain reward region implicated in depression. Major depressive disorder (MDD) is an exceedingly common illness that has a lifetime prevalence of 1 in 6 individuals. Though there are commercially available antidepressant therapies (e.g. Prozac), it is unclear how such drugs are able to effectively treat depression. Moreover, it is unknown why antidepressants must be taken for 4-6 weeks to see an effect, even though the drug is present in the brain within hours to days. It is also unknown why many individuals are resistant to the effects of antidepressant treatment. Here we show that changes induced in a mouse model of depression (social defeat) cause changes to the chromatin structure (the complex of DNA and the histones that it winds around) in nucleus accumbens neurons, and that these changes can be long lasting. Utilizing chromatin immunoprecipitation followed by gene promoter chip arrays (a way to look at the widespread changes occurring across the entire genome), we also demonstrate that the use of imipramine (an antidepressant) reverses many of these changes. We show in our model that some mice, even though they experience the same stress, do not show the depression-like phenotype. We term these mice resilient, much as we might call an individual who goes through traumatic life experience none the worse-for-the-wear, resilient. One gene that was reduced in the nucleus accumbens of defeated animals and corrected with imipramine treatment or normal in resiliency was dishevelled (DVL). We tested the role of this gene in depression by overexpressing it in the nucleus accumbens and measuring the resulting behavior. We found that overexpression of an inhibitory form of the protein generated a mouse that behaved in the same manner as those that went through the defeat paradigm. We show further that downregulation of DVL causes depression-like behavior by activating a downstream protein called glycogen synthase kinase-3beta (GSK3beta). We overexpressed GSK3beta, as well, and measured the behavioral effects with overexpression also causing a depression-like phenotype. Taken together, these data implicate a new signaling pathway in the pathogenesis of depression and suggest novel approaches toward the development of improved treatments. |
