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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH096890-02
Application #
8463052
Study Section
Special Emphasis Panel (ZMH1-ERB-S)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$152,639
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Jiang, C; Lin, W-J; Sadahiro, M et al. (2018) VGF function in depression and antidepressant efficacy. Mol Psychiatry 23:1632-1642
Monteggia, Lisa M; Heimer, Hakon; Nestler, Eric J (2018) Meeting Report: Can We Make Animal Models of Human Mental Illness? Biol Psychiatry 84:542-545
Muir, Jessie; Lorsch, Zachary S; Ramakrishnan, Charu et al. (2018) In Vivo Fiber Photometry Reveals Signature of Future Stress Susceptibility in Nucleus Accumbens. Neuropsychopharmacology 43:255-263
Hamilton, Peter J; Burek, Dominika J; Lombroso, Sonia I et al. (2018) Cell-Type-Specific Epigenetic Editing at the Fosb Gene Controls Susceptibility to Social Defeat Stress. Neuropsychopharmacology 43:272-284
Mao, Wenjie; Salzberg, Anna C; Uchigashima, Motokazu et al. (2018) Activity-Induced Regulation of Synaptic Strength through the Chromatin Reader L3mbtl1. Cell Rep 23:3209-3222
Aleyasin, Hossein; Flanigan, Meghan E; Golden, Sam A et al. (2018) Cell-Type-Specific Role of ?FosB in Nucleus Accumbens In Modulating Intermale Aggression. J Neurosci 38:5913-5924
Lorsch, Zachary S; Loh, Yong-Hwee Eddie; Purushothaman, Immanuel et al. (2018) Estrogen receptor ? drives pro-resilient transcription in mouse models of depression. Nat Commun 9:1116
Aleyasin, Hossein; Flanigan, Meghan E; Russo, Scott J (2018) Neurocircuitry of aggression and aggression seeking behavior: nose poking into brain circuitry controlling aggression. Curr Opin Neurobiol 49:184-191
Hultman, Rainbo; Ulrich, Kyle; Sachs, Benjamin D et al. (2018) Brain-wide Electrical Spatiotemporal Dynamics Encode Depression Vulnerability. Cell 173:166-180.e14
Zhang, Song; Zhang, Hongxing; Ku, Stacy M et al. (2018) Sex Differences in the Neuroadaptations of Reward-related Circuits in Response to Subchronic Variable Stress. Neuroscience 376:108-116

Showing the most recent 10 out of 215 publications