# Developmental "Chromatin Scars" in Mouse Depression Models

> **NIH NIH P50** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $270,411

## Abstract

PROJECT SUMMARY – PROJECT 1
Project 1 focuses on transcriptional and epigenetic mechanisms in the nucleus accumbens (NAc) and ventral
tegmental area (VTA), key brain reward regions implicated in depression and other stress-related disorders.
Over the past four years, we made significant progress in demonstrating the direct relevance of several modes
of chromatin regulation to depression-related phenomena in VTA and NAc both in animal models and, with
Project 4, in postmortem human brain. One of the primary rationales for focusing on chromatin mechanisms is
their heuristic importance in mediating lifelong consequences of prior behavioral experience. Accordingly, with
the Animal Models Core, we optimized a protocol where maternal separation (MS) during postnatal days P11-
20, but not other time windows, increases the susceptibility of male and female mice to subsequent stress in
adulthood. This increase in stress susceptibility is latent: without subsequent stress the animals appear normal.
This establishes an ideal system in which to study the chromatin mechanisms that mediate a lifelong increase
in stress susceptibility, which we refer to colloquially as “chromatin scars.” RNA-seq, with the Chromatin and
Gene Analysis Core, revealed lasting gene expression abnormalities in VTA and NAc in MS-exposed mice
before adult stress exposure. We focus here on two of the inferred top upstream regulators of these gene
expression abnormalities, two transcription factors, OTX2 in dopamine neurons (DA) of VTA and ESR1 in D2-
type medium spiny neurons (MSNs) of NAc. Indeed, we have found that both genes, upon their manipulation in
the respective brain area and cell type, drive stress susceptibility. We are now characterizing the underlying
mechanisms involved by defining chromatin changes that are induced at specific target genes in concert with
alterations in OTX2 or ESR1 to control their lifelong expression in response to early life stress. We are also
analyzing a small number of these target genes to understand how their lasting regulation controls the
functioning of VTA DA neurons and D2 NAc MSNs to regulate stress susceptibility for a lifetime. Together,
these studies are providing new insight into how early life stress controls stress susceptibility in males and
females over the life cycle.

## Key facts

- **NIH application ID:** 9878920
- **Project number:** 5P50MH096890-09
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** ERIC J. NESTLER
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $270,411
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878920

## Citation

> US National Institutes of Health, RePORTER application 9878920, Developmental "Chromatin Scars" in Mouse Depression Models (5P50MH096890-09). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9878920. Licensed CC0.

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