# Epigenetic regulation of sex differences in the brain

> **NIH NIH R01** · COLD SPRING HARBOR LABORATORY · 2020 · $480,000

## Abstract

Our grant application tests the hypothesis that sex differences in the brain are regulated by epigenetic events
during a perinatal critical period. In many vertebrates, including mice, sex-specific neural circuitry develops
under the control of estrogen signaling during the first few days of life. Treating neonatal females with estrogen
irreversibly masculinizes adult social behavior and gene expression. However, the molecular strategies used
by estrogen to exert lasting effects on the brain are poorly understood. The goal of this proposal is to identify
sex differences in gene expression and chromatin in two sexually dimorphic brain regions. The posterior
division of the bed nucleus of the stria terminalis (BNST), and the medial amygdala (MeA) are highly
interconnected brain regions that develop under the control of neonatal estrogen and regulate innate sex-
specific social behaviors such as mating and aggression. We hypothesize that neonatal estrogen generates
male-specific chromatin states that fundamentally alter the cellular identity of neurons and thus their function in
behavioral circuitry. We will test this hypothesis through genome-wide analysis of gene expression and
chromatin specifically in ERα-expressing neurons in both pups and adults. In Specific Aim 1 we will determine
the sex-specific gene programs in the BNST/MeA and explore how these programs are acutely modulated by
distinct adult hormonal profiles in males and females. In Specific Aim 2 we will identify cis-regulatory elements,
such as enhancers, in ERα neurons from BNST/MeA, and investigate sex differences in transcription factor
occupancy of these elements. In Specific Aim 3 we will test the requirement for a novel sexually dimorphic
transcription factor in generating sex differences in gene expression and behavior. Taken together, our findings
will reveal how estrogen signaling during early life permanently influences adult gene expression and
ultimately, sex-specific behaviors. This work will provide insight into how a transient event during a critical
developmental period can have significant impact on the brain and behavior in adulthood. This critical period
permanently affects brain structures and function, suggesting that sex differences in psychiatric disorders, such
as autism and depression, may originate during sexual differentiation of the brain.

## Key facts

- **NIH application ID:** 9842296
- **Project number:** 5R01MH113628-03
- **Recipient organization:** COLD SPRING HARBOR LABORATORY
- **Principal Investigator:** Jessica Tollkuhn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $480,000
- **Award type:** 5
- **Project period:** 2018-03-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9842296

## Citation

> US National Institutes of Health, RePORTER application 9842296, Epigenetic regulation of sex differences in the brain (5R01MH113628-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9842296. Licensed CC0.

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