Overview of the Conte Center on

Epigenetic Mechanisms of Depression

Epigenetic Mechanisms of Depression | Conte Center | Mount SinaiThe objective of this translational research Center is to utilize recent advances in chromatin biology, so-called epigenetics, to gain fundamentally increased understanding of the long-lasting abnormalities in the brain that cause depression and that mediate antidepressant responses. Our work focuses on key limbic brain regions, in particular, nucleus accumbens (NAc), several areas of prefrontal cortex (PFC), hippocampus, amygdala, and ventral tegmental area (VTA), which have been implicated directly in the control of mood in health and disease. Our goal and expectation is that this highly collaborative effort, among scientists at the Icahn School of Medicine at Mount Sinai in NYC, The Rockefeller University, UT Southwestern Medical Center at Dallas, and Massachusetts Institute of Technology, will provide an improved understanding of the molecular basis of these phenomena and lead to dramatically better treatments and diagnostic tests for depression and other stress-related illnesses.

Our Center takes advantage of state-of-the-art methods of chromatin biology to decipher the epigenetic mechanisms by which chronic stress controls an individual's life-long vulnerability for depression or other stress-related illnesses as well as responses to antidepressant treatment. Epigenetic mechanisms, by their very nature, are ideal candidates to mediate life-long vulnerabilities to stress and treatment responses. The Center utilizes a wide range of chronic stress paradigms in mice that potently regulate an animal's susceptibility or resilience to subsequent stress exposures over a lifetime, as well as an extensive collection of postmortem brains from depressed humans and carefully matched controls. Dramatic differences in stress responses seen in females vs. males—in both animal models and depressed humans—are a major focus of the Center's research.

The Center's vast datasets of genome-wide gene expression and chromatin regulation findings are used to identify previously unknown mechanisms of depression and antidepressant action, which are directly interrogated in animal models by use of advanced tools in neuroscience, including viral-mediated gene transfer, inducible mutations in mice, neurophysiological recordings, as well as optogenetic and fiber photometry approaches. Together, this work is contributing importantly to the evolving understanding of depression and its treatment at the molecular, cellular, circuit, and behavioral levels.

Translation means that the Center uses basic findings from laboratory animals to guide and direct studies of human brains. In parallel, original findings in humans feed back and inform ongoing animal investigations to understand the detailed molecular and cellular mechanisms involved. Translational is thus bidirectional, with both approaches crucial for successful bridging of basic and clinical research.

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