The objective of the Animal Models Core is to provide a broad range of the most sophisticated mouse behavioral models of depression and antidepressant action to support the Center's goals to establish epigenetic mechanisms of depression. Such models include several chronic stress paradigms in adult mice as well as paradigms of early life stress, and include comparisons of stress responses in male and female animals across the life cycle. The imperative to employ this broad behavioral battery is that it is difficult to infer something about such a complex behavioral syndrome as depression, about which there is still limited etiologic and pathophysiological information, from a single model or even a limited number of models. The Core then utilizes these models in two main ways. First, the Core provides microdissections of limbic brain regions from carefully defined mouse models for molecular characterization in each Project and in the Chromatin and Gene Analysis Core. Second, the Core provides extensive behavioral characterization after manipulation of specific genes of interest to the Projects and is, consequently, instrumental in providing causal, mechanistic data on how specific epigenetic mechanisms influence depression-related behaviors as well as providing insight into the underlying neurobiology. The Core accomplishes this by analyzing a range of genetic mutant mice as well as by utilizing intra-cerebral injection of viral vectors or of small molecule activators/inhibitors of target proteins. Additionally, the Core is responsible for generating all of the viral vectors used by Project investigators. The vectors are often generated initially to meet the specific needs of an individual Project, but then are provided to other Projects to broaden their application and thereby promote Center integration. The Animal Models Core services Project 1, 2, and 3, but not Project 4, which by definition is focused on translation to human brain tissue. By consolidating this behavioral and viral vector work within a centralized Core, we ensure rigorous control over the data and facilitate comparisons and contrasts of experimental results across the individual Projects. This consolidation also makes financial sense, since we concentrate and maximize efficient use of our behavioral expertise.
Depression has a lifetime risk of-15% for the U.S. general population, yet available antidepressant therapies are based on serendipitous discoveries over 6 decades ago, and fully treat <50% of all affected individuals. An improved understanding of the molecular basis of depression will lead to improved treatments and diagnostic tests-a high priority for the National Institutes of Health.
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