# Promoting Resilience to Early Life Stress through Epigenetic Editing

> **NIH NIH F31** · PRINCETON UNIVERSITY · 2022 · $30,752

## Abstract

PROJECT SUMMARY / ABSTRACT
 Early life stress (ELS) is one of the strongest predictors for development of mood and anxiety disorders.
ELS can include trauma (neglect, and/or physical, sexual, and/or emotional abuse) or other negative childhood
experiences. However, the increased risk for depression following ELS is not well understood. Previous work in
a mouse model of stress across the lifespan has shown unique gene expression patterns after ELS and adult
stress in the nucleus accumbens (NAc), a key region of the reward pathway implicated in stress response. The
three-dimensional structure of chromatin is a key factor in determining how genes are regulated and
expressed, with more open and accessible chromatin being permissive for gene expression and more closed
chromatin repressing expression. We hypothesize that ELS changes chromatin accessibility within
stress-responsive neuronal cells in the NAc such that the chromatin adopts a comparatively open
conformation, making transcription more reactive to future stimuli. In Aim 1, I will determine how chromatin
architecture is altered specifically within ELS-activated neurons using a double-transgenic mouse to label and
capture both activated and non-activated neurons, then perform ATAC-sequencing and computational analyses
to determine chromatin accessibility across the entire genome. I will examine how ELS alters chromatin
structure in activated and non-activated cells in juvenile and adult mice of both sexes. In Aim 2, I will test the
functional impact of chromatin state on transcriptional and behavioral susceptibility to adulthood stressors.
First, I will apply CRISPR-dCas9-based epigenome editing tools to close chromatin at target genomic
enhancer regions already identified in preliminary data to prevent hypersensitivity to activation in vitro. Then, I
will use this tool in vivo to test the hypothesis that closing aberrantly open chromatin can reverse the impact of
ELS and promote transcriptional and behavioral resilience. Together, this research will generate fundamental
insights into how stress during key periods of development increases sensitivity to future stress at a molecular
level in the brain.This project contributes to our understanding of the epigenetic mechanisms driving
heightened risk of mood disorders following ELS.

## Key facts

- **NIH application ID:** 10536990
- **Project number:** 1F31MH131351-01
- **Recipient organization:** PRINCETON UNIVERSITY
- **Principal Investigator:** Rebekah Rashford
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $30,752
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10536990

## Citation

> US National Institutes of Health, RePORTER application 10536990, Promoting Resilience to Early Life Stress through Epigenetic Editing (1F31MH131351-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10536990. Licensed CC0.

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