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2013学年秋季学期系列学术讲座之六
题目：Transcriptional and Epigenetic Mechanisms of Depression
报告人：Eric J. Nestler, M.D., Ph.D.
Nash Family Professor and Chairman, Department of Neuroscience,
Director, Friedman Brain Institute,
Mount Sinai School of Medicine, New York, NY USA
时间：2013年11月1日（周五），下午13:00-14:30 PM
地点：beat365官方网站一楼邓祐才报告厅
Depression is a common, chronic, and debilitating disease. Although many patients benefit from antidepressant medications or other therapies, only about half of depressed patients show a complete remission, which underscores the need for more effective agents. The mechanisms that precipitate depression, such as stress, are incompletely understood. One mystery of the syndrome is its long-lasting nature and delayed response to antidepressant treatment. This persistence is thought to be mediated by slowly developing but stable adaptations in the brain, which might include regulation of gene expression and chromatin structure.
We have used chronic social defeat stress as an animal model of depression that mimics certain symptoms of human depression. Prolonged exposure to an aggressor induces lasting changes in mouse behavior such as social avoidance and anhedonia-like symptoms, which are reversed by chronic (but not acute) treatment with available antidepressants. Importantly, roughly one-third of mice subjected to social defeat stress do not exhibit these deleterious behaviors and appear “resilient.” We are exploring the molecular basis of defeat-induced behavioral pathology, antidepressant action, and resilience by analyzing genome-wide changes in gene expression and chromatin modifications in several limbic brain regions. One area of focus is the nucleus accumbens, a key brain reward region implicated in aspects of depression.
We have identified sets of genes that remain altered at least one month after defeat stress. Many of these changes are reversed by chronic antidepressant treatment. Interestingly, a large subset of these genes, whose abnormalities are corrected by antidepressants, appear normal in resilient mice. These findings suggest that antidepressants work in part by inducing changes in gene and chromatin regulation in nucleus accumbens that occur naturally in more resilient individuals. Current studies are underway to investigate the genes and molecular pathways involved in these various responses. Specific genes that control susceptibility, resilience, and antidepressant responses will be discussed.
Together, this work provides novel insight into the molecular mechanisms by which chronic stress produces lasting changes in specific brain areas, and associated changes in the functioning of neural circuits, to cause depression-like symptoms. The findings also suggest novel leads for the development of new antidepressant treatments. For example, our findings on resilience suggest the novel approach of developing medications that promote resilience and not just those that oppose the deleterious effects of stress.
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