# Dynamic Cellular Interactions Associated with Inflammatory Monocyte Accumulation in the Neurovasculature with Social Stress

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $542,782

## Abstract

Program Director/Principal Investigator (Sheridan, JF & Godbout JP):
PROJECT SUMMARY/ABSTRACT:
Dynamic inflammatory signaling in the brain may have a causative role in anxiety. We report that repeated
social defeat (RSD) in mice induces sympathetic-mediated release of primed monocytes from the bone marrow
that are actively recruited to the brain. Collectively, we show that RSD promotes prolonged anxiety-like
behavior that depends on activation of microglia and recruitment of inflammatory monocytes to threat appraisal
regions of the brain. This application demonstrates that microglial recruitment of IL-1β producing monocytes to
neurovascular endothelium is necessary for the potentiation of anxiety-like behavior in response to social
stress. Despite this knowledge, three key mechanistic questions remain to be answered, which will allow for
the development of novel interventions for treatment of neuropsychiatric complications associated with stress:
1) How does RSD activate microglia in threat appraisal regions? 2) How are inflammatory monocytes
selectivity recruited to neurovascular endothelium in threat appraisal regions? 3) What are the key factors
produced by neurovascular endothelia cells that potentiate neuroinflammation and anxiety? We show that
microglial activation in response to RSD depends on neuronal activation within threat appraisal regions.
Moreover, preliminary evidence suggests that this is mediated by activation of the purinergic receptor, P2RX7,
on microglia. Novel data presented here show that monocyte recruitment and the development of anxiety-like
behavior after RSD requires microglial activation. Furthermore, cell-specific transcriptional profiling indicates
that microglia recruit monocytes to the brain via chemokine ligand (CCL2) secretion. These recruited
monocytes produce IL-1and promote anxiety-like behavior by endothelial IL-1 Receptor-1 activation. Notably,
this IL-1R1 activation is associated with increased neurovascular expression of COX2, the enzyme that
synthesizes neuroactive prostaglandins. Thus, the goal of this project is to test the hypothesis that recruitment
and subsequent interaction of inflammatory monocytes with neurovascular endothelial cells is critical for the
augmentation of neuroinflammation and potentiation of anxiety-like behavior following RSD. To address this
hypothesis, three specific aims are proposed. In Aim-1, we will ascertain the extent to which RSD-induced
microglial activation is dependent on stimulation of the P2RX7 purinergic receptor. In Aim-2, we will determine
the degree to which microglial production of CCL2 is required for monocyte recruitment to threat appraisal
regions and the induction of anxiety-like behavior after RSD. In Aim-3, we will assess the role of endothelial
COX2 following RSD and determine other key factors produced by IL-1R1-stimulated endothelial cells that
facilitate anxiety-like behavior after RSD. Understanding how microglial recruitment of IL-1β producing
monoc...

## Key facts

- **NIH application ID:** 9879766
- **Project number:** 5R01MH119670-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Jonathan P Godbout
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $542,782
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9879766

## Citation

> US National Institutes of Health, RePORTER application 9879766, Dynamic Cellular Interactions Associated with Inflammatory Monocyte Accumulation in the Neurovasculature with Social Stress (5R01MH119670-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9879766. Licensed CC0.

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