# The role of the brain endothelium in neuroinflammatory responses to social stress

> **NIH NIH F30** · OHIO STATE UNIVERSITY · 2022 · $51,752

## Abstract

PROJECT SUMMARY / ABSTRACT
Inflammatory signaling after psychosocial stress may mediate maladaptive physiologic and behavioral
responses to stress. For example, patients with anxiety or depression often have increased pro-inflammatory
cytokines in circulation and altered leukocyte function, which correlates with disease severity and resistance to
treatment. Repeated social defeat (RSD) is a murine model of psychosocial stress that recapitulates key
components of the human response to chronic social stress, including increased circulating cytokines, production
of pro-inflammatory monocytes, and development of anxiety-like behaviors. We have previously shown that RSD
alters bidirectional signaling between the brain and immune system specifically in regions of the brain associated
with threat appraisal and behavioral responses to stress, such as the amygdala and prelimbic cortex. Within
these regions, microglia become activated, and recruit circulating pro-inflammatory monocytes to neurovascular
endothelial cells. Monocyte signaling to endothelial cells through the interleukin(IL)-1β receptor (IL-1R1) is critical
for the development of anxiety-like behavior after stress. Currently, the endothelial response to monocyte-derived
IL-1β is unknown. Here, I show preliminary data that IL-1β may decrease endothelial tight junction protein
expression and induce cyclooxegenase-2, an enzyme involved in prostaglandin production. This proposal will
investigate how neurovascular endothelial function changes after stress by addressing whether inflammatory
signaling impacts the permeability of the blood-brain barrier and revealing whether endothelial-derived
prostaglandins impact other cells of the central nervous system (CNS). I propose three aims to test the
hypothesis that IL-1β signaling through endothelial IL-1R1 disrupts tight junction integrity in regions involved in
fear and threat appraisal, and stimulates endothelial production of prostaglandins which signal to CNS cells to
impact behavioral responses to stress. First, I will determine whether RSD decreases tight junction protein
expression in IL-1R1+ endothelial cells and if RSD increases blood-brain barrier permeability. Next, I will
characterize the transcriptional profile of neurovascular endothelial cells within fear-responsive regions of the
brain after RSD with and without the IL-1β signal from monocytes. Finally, I will inhibit prostaglandin production
using pharmacologic interventions and genetic knockouts to elucidate the effects of endothelial-derived
prostaglandins on neuronal and microglial activation and behavioral deficits after RSD. Overall, this will reveal a
novel mechanism by which stress can perturb immune signaling in the CNS which ultimately impacts behavior.
Understanding the biology of stress responses is vital to understanding mental health disorders, which are highly
prevalent in the population. Neurovascular endothelial cells are a potential target for therapeutic intervention t...

## Key facts

- **NIH application ID:** 10426142
- **Project number:** 5F30MH125524-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Wenyuan Yin
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,752
- **Award type:** 5
- **Project period:** 2021-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10426142

## Citation

> US National Institutes of Health, RePORTER application 10426142, The role of the brain endothelium in neuroinflammatory responses to social stress (5F30MH125524-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10426142. Licensed CC0.

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