# The Role of Reactive Brain Endothelium in Modulating Stress-Induced Immunological and Behavioral Changes

> **NIH NIH F30** · OHIO STATE UNIVERSITY · 2020 · $33,665

## Abstract

Project Summary:
Immunological adaptations to psychosocial stress may promote the pathophysiology of chronic inflammatory
diseases. In humans, social stress activates neuronal and neuroendocrine pathways that result in significant
physiological, immunological, and behavioral consequences associated with the development and recurrence
of mental health complications, including anxiety. Repeated social defeat (RSD) is a murine stressor that
replicates many aspects of the human stress response, including increased circulating cytokines, monocyte
trafficking, and prolonged anxiety-like behavior. In both humans and rodents, the brain interprets physiological
stress within fear and threat appraisal circuitry. My lab has shown that RSD induces activation of microglia
within discrete stress-responsive brain regions, such as the prefrontal cortex. This is relevant because stress-
induced recruitment of circulating monocytes to these brain regions promotes the development of anxiety-like
behavior. Emerging evidence suggests that microglia propagate neuroinflammatory signaling that modulates
neuronal and endocrine responses to stress. For example, microglia are the primary source of pro-
inflammatory cytokines, including interleukin (IL)-1β. Unfortunately, the mechanisms that underlie stress-
induced monocyte recruitment and subsequent neurobehavioral deficits are not completely understood.
Monocyte recruitment to the brain after RSD likely involves dynamic interactions among cell types that
comprise the neurovascular unit, including endothelial cells and microglia. In support of this, RSD induces the
expression of key adhesion molecules on vascular endothelial cells within the same brain regions where
previous findings of microglial activation and monocyte trafficking occurred. Additionally, I show novel data that
inhibition of microglial activation with minocycline attenuates RSD-induced neuroinflammatory gene
expression, monocyte trafficking to the brain, and development of anxiety-like behavior. Therefore, it is
plausible that stress-induced microglial activation and brain cytokine signaling enhance neuroendocrine outflow
that may further reinforce stress-related behaviors. Here, I will use a murine model of stress to test the
hypothesis: microglia-derived IL-1β signaling activates vascular endothelial cells after RSD, which facilitate
region-specific monocyte recruitment to the brain via neurovascular adhesion molecule expression to promote
anxiety-like behavior. I propose three specific aims to address this hypothesis. The first aim defines the role of
microglia in activating brain region-specific vascular endothelium after RSD. The second aim characterizes the
degree of endothelial activation by microglia-derived IL-1β signaling after RSD. The third aim determines if
adhesion molecule blockade prevents RSD-induced neuroinflammation and anxiety. Overall, this proposal will
advance our knowledge on the role of reactive brain endothelium in modulating st...

## Key facts

- **NIH application ID:** 10075224
- **Project number:** 5F30DE026075-04
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Caroline Sawicki
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $33,665
- **Award type:** 5
- **Project period:** 2017-01-01 → 2020-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10075224

## Citation

> US National Institutes of Health, RePORTER application 10075224, The Role of Reactive Brain Endothelium in Modulating Stress-Induced Immunological and Behavioral Changes (5F30DE026075-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10075224. Licensed CC0.

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