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Eric J. Nestler, MD, PhD

Nash Family Professor of Neuroscience Chairman of the Department of Neuroscience Director of the Friedman Brain Institute
Icahn School of Medicine at Mount Sinai
Keynote address: "Transcriptional and Epigenetic Mechanisms of Depression."
Presentation Abstract :

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 disease 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 several chronic stress procedures in mice, such as chronic social defeat stress and chronic variable stress, as models of depression that mimic key symptoms seen in humans. An important feature of this work is to examine not only those mice that succumb to the stress (susceptibility), but also those that avoid deleterious outcomes (resilience). We are exploring the molecular basis of stress-induced behavioral pathology, antidepressant action, and resilience by analyzing genome-wide changes in gene expression and chromatin modifications in several limbic brain structures. Parallel work has focused on homologous regions in the brains of depressed humans examined postmortem. We are using these datasets to understand prominent sex differences in stress responses in mice and depression in humans as well as to identify the mechanisms by which early life experience controls stress vulnerability for a lifetime.

Together, this work is providing novel insight into the molecular mechanisms underlying depression and other stress-related disorders. 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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