The objective of Project 4 is to translate the groundbreaking advances in our understanding of epigenetic mechanisms of depression from animal models in the preclinical Projects of this Center to depressed humans, using a postmortem collection of the highest quality and most extensive clinical characterization. Indeed, many of the epigenetic alterations observed to date in the PFC (prefrontal cortex) and NAc (nucleus accumbens) of rodent depression models, derived from Projects 1-3, show similar abnormalities in homologous regions of depressed humans. Conversely, we expect that genome-wide epigenetic analyses of human brain tissue will reveal novel modes of regulation in depressed humans and thereby generate new hypotheses to be tested and characterized functionally in Projects 1-3. The proposed investigations will include genome-wide ChlP-Seq studies of both standard histone modifications and the more advanced chromatin endpoints of interest to our preclinical Projects, as well as RNA-Seq to characterize depression- associated changes in gene expression. Such analyses will be performed on whole extracts of brain regions as well as on isolated neuronal nuclei, using expertise that is uniquely available in our Center. The translation of animal outcomes to human brain disease is even more critical now than ever before, as the field strives to refine the clinical disease itself and to develop novel targets for rational treatments. We will promote the target validation goal of our human studies: 1) by examining how validated chromatin mechanisms cluster with distinct clinical phenotypes of human depression as a way to help generate markers of disease subgroups, and 2) by evaluating the markers more completely throughout the brain circuitry implicated in human depression. In the future, the novel molecular mechanisms of human depression derived from the Center's research on chromatin biology will also help drive efforts in the field to identify biomarkers of depression in living humans. Together, work of Project 4 promises fundamentally new knowledge of the basic molecular and neurobiological mechanisms of depression and of antidepressant treatments that will define new approaches in the field for years to come.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZMH1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Icahn School of Medicine at Mount Sinai
New York
United States
Zip Code
Labonté, Benoit; Engmann, Olivia; Purushothaman, Immanuel et al. (2017) Sex-specific transcriptional signatures in human depression. Nat Med 23:1102-1111
Zhao, Jian-Yuan; Liang, Lingli; Gu, Xiyao et al. (2017) DNA methyltransferase DNMT3a contributes to neuropathic pain by repressing Kcna2 in primary afferent neurons. Nat Commun 8:14712
Nätt, Daniel; Barchiesi, Riccardo; Murad, Josef et al. (2017) Perinatal Malnutrition Leads to Sexually Dimorphic Behavioral Responses with Associated Epigenetic Changes in the Mouse Brain. Sci Rep 7:11082
Loh, Yong-Hwee Eddie; Feng, Jian; Nestler, Eric et al. (2017) Bioinformatic Analysis for Profiling Drug-induced Chromatin Modification Landscapes in Mouse Brain Using ChlP-seq Data. Bio Protoc 7:
Peña, Catherine J; Kronman, Hope G; Walker, Deena M et al. (2017) Early life stress confers lifelong stress susceptibility in mice via ventral tegmental area OTX2. Science 356:1185-1188
Lopez, Juan Pablo; Fiori, Laura M; Cruceanu, Cristiana et al. (2017) MicroRNAs 146a/b-5 and 425-3p and 24-3p are markers of antidepressant response and regulate MAPK/Wnt-system genes. Nat Commun 8:15497
Jiang, C; Lin, W-J; Sadahiro, M et al. (2017) VGF function in depression and antidepressant efficacy. Mol Psychiatry :
Ménard, Caroline; Pfau, Madeline L; Hodes, Georgia E et al. (2017) Immune and Neuroendocrine Mechanisms of Stress Vulnerability and Resilience. Neuropsychopharmacology 42:62-80
Brancato, Anna; Bregman, Dana; Ahn, H Francisica et al. (2017) Sub-chronic variable stress induces sex-specific effects on glutamatergic synapses in the nucleus accumbens. Neuroscience 350:180-189
Feng, Jian; Pena, Catherine J; Purushothaman, Immanuel et al. (2017) Tet1 in Nucleus Accumbens Opposes Depression- and Anxiety-Like Behaviors. Neuropsychopharmacology 42:1657-1669

Showing the most recent 10 out of 192 publications