# Coupling neuroimaging with CLARITY and single cell genomics to dissect sex differences in the developing brain

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $474,813

## Abstract

Abstract
 Many neurobehavioral diseases affect females and males differently, and emerge at different
stages of life, leading to the conclusion that one sex is protected from diseases by inherent sex factors,
such as gonadal hormones and sex chromosomes. The sites and timing of these effects on brain
development are unknown. The method of high-throughput high-precision whole-brain MRI imaging has
the power to detect such changes with great sensitivity, in both animal models and humans. This
project will exploit these powerful methods to separate gonadal hormonal and sex chromosome effects
in the mouse model “Sex Chromosome Trisomy” (SCT), at 9 different ages of development, to discover
where and when these factors cause sex differences in brain development (Aim 1). The SCT model
compares mice with different numbers and types of sex chromosomes (XX, XY, XXY, XYY), each genotype
present in gonadal males or females. Then, a novel pipeline of analysis will compare mouse and human
brain development at many stages and in informative groups (differing by age, sex, hormonal status, and
sex chromosome complement) to determine which changes in mouse brain are also found in humans, in
specific brain regions related to different diseases (Aim 2). The analysis will point to changes in mouse
brain that model human brain development. These studies will also pinpoint new sex-biasing effects of
hormones and sex chromosomes at localized brain regions at specific developmental stages in mice,
leading to further investigation of cellular and molecular changes caused by sex at those sites (Aim 3).
Cellular effects (cell size, number, density of defined cell populations) of sex-biasing factors will be
measured using CLARITY (Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging-compatible Tissue-
hYdrogel). Gene pathways responding to hormonal and sex chromosome effects in individual cell types
in specific brain regions will be measured using single cell RNA-seq. These studies, combining high-
resolution neuroimaging, CLARITY, and single cell sequencing, will provide a foundation of concepts
about where in the brain, and when during development, specific cell populations respond to sex
factors, as a prelude for hypothesizing which sex differences underlie the protective effects of sex-
biased factors in cells.

## Key facts

- **NIH application ID:** 9997724
- **Project number:** 1R01HD100298-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Arthur P Arnold
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $474,813
- **Award type:** 1
- **Project period:** 2020-04-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997724

## Citation

> US National Institutes of Health, RePORTER application 9997724, Coupling neuroimaging with CLARITY and single cell genomics to dissect sex differences in the developing brain (1R01HD100298-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9997724. Licensed CC0.

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