Depression is a common, chronic, and debilitating disease. Although many patients benefit from antidepressant medications or other therapies, only about half show complete remission. Factors that precipitate depression, such as stress, are incompletely understood.
We have used chronic social defeat stress as an animal model of depression. Prolonged exposure to an aggressor induces lasting changes in behavior such as social avoidance and anhedonia-like symptoms, which are reversed by chronic (but not acute) treatment with available antidepressants. 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 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.
About the Speaker
Dr. Nestler is the Nash Family Professor of Neuroscience at the Mount Sinai School of Medicine in New York, where he serves as Chair of the Department of Neuroscience and Director of the Friedman Brain Institute. He received his B.A., Ph.D., and M.D. degrees, and psychiatry residency training, from Yale University. He served on the Yale faculty from 1987-2000, where he was the Elizabeth Mears and House Jameson Professor of Psychiatry and Neurobiology, and Director of the Division of Molecular Psychiatry. He moved to Dallas in 2000 where he served as the Lou and Ellen McGinley Distinguished Professor and Chair of the Department of Psychiatry at The University of Texas Southwestern Medical Center until moving to New York in 2008. Dr. Nestler is a member of the Institute of Medicine and a Fellow of the American Academy of Arts and Sciences. The goal of Dr. Nestler’s research is to better understand the molecular mechanisms of addiction and depression based on work in animal models, and to use this information to develop improved treatments of these disorders.
“Transcriptional and Epigenetic Mechanisms of Depression” lecture slides (pdf)
“Hidden Switches in the Mind” (pdf)