# Neuroinflammation, Epigenetics and Male Vulnerability

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $386,250

## Abstract

Summary
Developing males are broadly vulnerable, making them more susceptible to early onset neuropsychiatric and
neurological disorders and more severely affected by neonatal brain injury. Clues to the origins of heightened
male vulnerability can be found in the mechanisms of masculinization of brain and behavior. Working with the
laboratory rat we have discovered surprising origins of sex differences in the brain that begin with non-neuronal
immune cells and inflammatory signaling molecules. In particular we find that microglia, the brains innate
immune system, are more numerous and more activated in regions of male brain than female and that these
cells are a dominant source of the prostaglandin, PGE2, which is also elevated in males compared to females.
Mast cells, another non-neuronal immune cell, are also found in greater numbers and in a more activated state
in males. Histamine released from mast cells stimulates PGE2 production by neighboring microglia and
promotes the formation and stabilization of dendritic spine synapses. The result is sexually differentiated
synaptic patterning that regulates adult sex-typic behavior. We further determined that immune response
genes are epigenetically repressed in female brains compared to males, due to greater DNA methylation. Pilot
data connects neuroinflammation and epigenetics with the observation that either PGE2 or mast cell
degranulation can inhibit DNA methylating enzymes. Specific Aim 1 will measure the impact of
neuroinflammation on the epigenome in developing brain while Specific Aim 2 takes the opposite tact
and will test the effect of epigenome regulation on neuroinflammation in developing brain. Ultimately
the question is why normal healthy males have higher neuroinflammation during development and here we
propose the novel PREMISE: Maternal immune response directed at male fetuses increases their
vulnerability. In Specific Aim 3 we will utilize a female dam with a male immune system via bone marrow
transplantation to test the impact of the sex of the maternal immune system on the sexual
differentiation of her offspring. Chimeric females will be generated using GFP-expressing stem cells to allow
for tracking of maternal immune cells into the placenta and fetal compartment, including the fetal brain.
Maternal Immune Activation (MIA) will be employed to assess for pathology. For each aim we will conduct
experiments that measure inflammatory molecules, microglia and mast cell activation, DNMT activity and DNA
methylation, the transcriptome using nanoString quantification of mRNA and juvenile and adult behaviors
influenced by sex.

## Key facts

- **NIH application ID:** 9903454
- **Project number:** 5R01MH052716-24
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** MARGARET M. MCCARTHY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $386,250
- **Award type:** 5
- **Project period:** 1995-04-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9903454

## Citation

> US National Institutes of Health, RePORTER application 9903454, Neuroinflammation, Epigenetics and Male Vulnerability (5R01MH052716-24). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9903454. Licensed CC0.

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