# Decoding the X-chromosome Dynamics in the Adult Female Brain

> **NIH NIH R21** · FORDHAM UNIVERSITY · 2024 · $174,427

## Abstract

Project Summary/Abstract
Ovarian hormone fluctuations critically shape the brain and behavior and represent a major contributor to female
specific risks for neuropsychiatric disorders including depression and anxiety disorders. Another female-specific
factor is a double dose of the X chromosome, one of which is typically “inactivated” during development and
stays in a repressed form in somatic female cells including neurons. A subset of genes called “X escapees” are
able to escape this inactivation and contribute to sex-specific gene expression across tissues including the brain.
While some cell-, tissue-, and species-specific escapees have been described, “dynamic X escapees” are
unknown. However, in our recent study, we described putative “estrous cycle-dependent X escapees” associated
with substantial dynamism in 3D genome structure of the X chromosome across the mouse estrous cycle.
Intriguingly, we have a strong indication that the volume of the inactive X chromosome (Xi) changes in response
to fluctuating ovarian hormones. We hypothesize that Xi undergoes conformational changes in neurons across
the ovarian cycle, which can alter both X-linked and autosomal gene expression and contribute to behavioral
adaptation in response to reproductive hormone changes. In this project, we will perform two independent aims
to test our hypothesis, by studying the estrous cycle effects in two mouse genetic models. In Aim 1, we will use
the ΔXist mutant mice that will allow us to perform allele-specific genomics analyses and distinguish between
active (Xa) and inactive (Xi) X chromosomes and confirm hormone-induced Xi plasticity. In Aim 2, we will use
the 39,XO female mice that lack the inactive X chromosome and will allow us to assess the functional role of Xi
and its dynamics in gene regulation and behavior. In both aims, we will use cutting-edge, neuron-specific
genomics assays to characterize gene expression (RNA-seq) and 3D genome organization (Hi-C) in ventral
hippocampal neurons across the estrous cycle. We will also test anxiety-related behavior in XO mice and
compare it to XX and XY counterparts, to determine whether the inactive X chromosome interacts with the
estrous cycle to regulate behavior. Our findings can provide radically novel insights into sex-specific brain
regulation, opening new avenues for sex-and gender-informed treatments of brain disorders, with critical
implications for women’s mental health.

## Key facts

- **NIH application ID:** 10870942
- **Project number:** 1R21MH136483-01
- **Recipient organization:** FORDHAM UNIVERSITY
- **Principal Investigator:** Marija Kundakovic
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $174,427
- **Award type:** 1
- **Project period:** 2024-02-08 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10870942

## Citation

> US National Institutes of Health, RePORTER application 10870942, Decoding the X-chromosome Dynamics in the Adult Female Brain (1R21MH136483-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10870942. Licensed CC0.

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