# Epigenetic Regulation of Sex Differences in the Brain

> **NIH NIH R01** · COLD SPRING HARBOR LABORATORY · 2024 · $632,824

## Abstract

PROJECT SUMMARY/ABSTRACT
There are pronounced sex differences in the incidence and etiology of mental health conditions. However, the
developmental mechanisms that give rise to sex differences in disease susceptibility or resilience remain
largely unknown. In this application we will explore the developmental origins of brain sex differences. 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, neural circuitry, and gene expression. To understand the actions of estrogen on the brain, we
recently identified the genomic targets of estrogen receptor alpha (ERα) and revealed that these genes are
differentially invoked in the developing and adult brain of both sexes. The goal of this proposal is to determine
the molecular and circuit consequences of early life ERα actions, with the long-term intent of connecting
individual ERα target genes to discrete sex-variable phenotypes. The posterior division of the bed nucleus of
the stria terminalis (BNSTp) is a key node in neural circuits that mediate social behaviors and is larger in males
compared to females. We hypothesize that BNSTp sexual dimorphism is specified by parallel epigenetic
events during a perinatal critical period: initiation of a persistent male-biased gene expression signature and
establishment of sex-specific neuronal connectivity. In Aim 1 we will determine the transcriptional mechanisms
that define sex differential gene regulation strategies: persistent early life gene expression in males, and
fluctuations in response to estrous hormones in adult females. In Aim 2 we will map the connectivity of the two
male-biased cell types we previously identified in the BNSTp, in both adults and across postnatal development.
In Aim 3 we will test the causality of perinatal ERα target genes and loci in specifying BNSTp sex differences.
Taken together, our findings will reveal how gonadal hormone signaling during early life permanently
influences adult gene expression, neuronal connectivity, and ultimately, sex-variable 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:** 10789940
- **Project number:** 5R01MH113628-07
- **Recipient organization:** COLD SPRING HARBOR LABORATORY
- **Principal Investigator:** Jessica Tollkuhn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $632,824
- **Award type:** 5
- **Project period:** 2018-03-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10789940

## Citation

> US National Institutes of Health, RePORTER application 10789940, Epigenetic Regulation of Sex Differences in the Brain (5R01MH113628-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10789940. Licensed CC0.

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