# Epigenetic regulation of brain and behavior by the estrous cycle

> **NIH NIH R01** · FORDHAM UNIVERSITY · 2024 · $386,478

## Abstract

Project Summary/Abstract
Sex-hormone fluctuations across the ovarian cycle exert powerful effects on female brain and behavior, and are
likely contributors to female-specific risks for neuropsychiatric conditions. This is exemplified by anxiety and
depression, disorders twice as prevalent in women of reproductive age compared to their male counterparts.
However, the mechanisms underlying the dynamic nature of the female brain remain poorly understood, limiting
our ability to design sex-specific treatments for female-biased disorders. The goal of our research is to address
this critical need, and to reveal the molecular mechanisms through which sex hormones dynamically impact
female brain structure and behavior. To this end, we recently made the important discovery that chromatin
organization, a major epigenetic mechanism controlling gene expression, is highly dynamic in the female ventral
hippocampus (vHIP) of mouse, as a function of the estrous cycle stage. We linked these chromatin dynamics to
changes in neuronal gene expression and to variation in vHIP-dependent, anxiety-related behaviors in mice.
Based on these findings, we hypothesize that rhythmic sex-hormone changes induce extensive chromatin re-
organization in vHIP neurons across the ovarian cycle, resulting in cyclic changes in gene activity and
contributing to increased female vulnerability to anxiety-related phenotypes associated with the varying estrogen
state. To address this hypothesis, we designed the current study with three independent aims to reveal estrous
cycle- and sex-specific epigenetic gene regulation in vHIP neurons in mice, and to provide a mechanistic link
between vHIP chromatin dynamics and anxiety-related behavior. In Aim 1, we will use cutting-edge epigenomics
methods to identify estrous cycle- and sex-specific cis-regulatory elements and chromatin mechanisms driving
transcriptional programs in vHIP neurons. In Aim 2, we will use a single-cell transcriptomic analysis and RNA in
situ hybridization to reveal vHIP neuronal clusters that are transcriptionally responsive to cycling hormones and
possible drivers of cyclic changes in chromatin and behavior. In Aim 3, we will genetically manipulate a candidate
epigenetic regulator identified by bioinformatics approaches, to identify a functional role of these sex-specific
chromatin dynamics in gene regulation and anxiety-related behavior. Overall, these studies will reveal chromatin-
dependent molecular mechanisms controlling neuronal gene expression and anxiety-related behavior across the
estrous cycle. These findings will provide a necessary first step to identify candidate, sex-specific targets for the
treatment of female-biased disorders such as anxiety and depression.

## Key facts

- **NIH application ID:** 10755657
- **Project number:** 5R01MH123523-04
- **Recipient organization:** FORDHAM UNIVERSITY
- **Principal Investigator:** Marija Kundakovic
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $386,478
- **Award type:** 5
- **Project period:** 2021-03-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10755657

## Citation

> US National Institutes of Health, RePORTER application 10755657, Epigenetic regulation of brain and behavior by the estrous cycle (5R01MH123523-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10755657. Licensed CC0.

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