# Epigenetic Mechanisms of Depression in Human Limbic Circuits

> **NIH NIH P50** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $243,224

## Abstract

PROJECT SUMMARY – PROJECT 4 (UT SOUTHWESTERN AND MOUNT SINAI)
Over the past four years, Project 4 has made robust progress in defining gene expression and associated
chromatin abnormalities that occur in specific limbic brain regions of depressed humans. Working with Projects
1 through 3, we validated numerous findings from mouse models in human depression, which ensures that the
other Projects remain focused on mechanisms relevant to the human syndrome. In parallel, we defined novel
transcriptional and epigenetic abnormalities in the depressed human brain. A major milestone is completing
RNA-seq of six brain regions from ~100 subjects—half depressed, half control; half male, half female. While
the data revealed many genes similarly affected in depressed men and depressed women, striking sex
differences were observed as well, suggesting that depression may be a fundamentally distinct syndrome in
the two sexes. This dataset helped define the current focus of the other Projects. It also provides the
foundation for our proposed experiments. We will extend RNA-seq analysis to an additional cohort of 100
subjects, which is necessary given the heterogeneity of the depression syndrome. We will complement this
work with ChIP-seq and, with Projects 2 and 3 by mapping the 3D genome and nucleosome turnover, to begin
to define genome-wide the epigenetic mechanisms controlling the aberrant gene expression seen in human
depression. We will focus on key target genes identified in these studies as being altered in a sex-specific
manner in either prefrontal cortex (PFC) or nucleus accumbens (NAc) in human depression, regulation since
replicated in mouse models. Among the regulated genes are those that encode several long-noncoding RNAs
for which homologues do not exist in rodents—emphasizing the importance of gene discovery in human brain.
As well, we will relate gene and chromatin changes to demographic features of the cases and controls,
examining the effect of early life stress and moving beyond syndromal depression to key domains of behavioral
abnormalities. We also will continue to build our bank of depressed and control human brains. The work of
Project 4 thus embodies the bidirectional translation that defines this Center and its promise of discovering new
mechanisms for the pathophysiology of depression and other stress-related illnesses.

## Key facts

- **NIH application ID:** 10118219
- **Project number:** 5P50MH096890-10
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Carol A Tamminga
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $243,224
- **Award type:** 5
- **Project period:** 2012-05-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10118219

## Citation

> US National Institutes of Health, RePORTER application 10118219, Epigenetic Mechanisms of Depression in Human Limbic Circuits (5P50MH096890-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10118219. Licensed CC0.

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