# Mechanisms of stress-induced neurovascular damage promoting immune infiltration and depression-like behaviors

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $666,089

## Abstract

Multiple clinical studies suggest that heightened peripheral inflammation contributes to major
depressive disorder (MDD) pathogenesis. Co-morbidity of inflammatory disease with MDD is highly prevalent,
and MDD patients have a higher risk of developing those diseases. It has been hypothesized that circulating
inflammatory molecules are released following chronic stress, penetrate the blood brain barrier (BBB), and
affect neural circuits, mediating stress vulnerability and depression. However, despite years of intensive
research into the role of cytokines in depression, we have very little direct evidence of how cytokines enter the
brain and in which circuits they act. Recently, we have begun to investigate the effect of chronic social defeat
stress (CSDS), a mouse model of stress that induces depression-like behavior, on BBB permeability.
Endothelial cells and astrocytes play critical roles in maintaining vascular impermeability. Endothelial cells, via
expression of tight junction proteins, establish the paracellular barrier between the perivascular space and
brain parenchyma. Breakdown of the endothelial barrier can lead to infiltration of peripheral immune signals—
such as IL-6—that we have shown previously to increase stress susceptibility. Our new data shows that 10
days of CSDS downregulates expression of the tight junction protein Cldn5 in the NAc of stress-susceptible
mice leading to loss of integrity of the endothelial barrier, immune infiltration and expression of depression-like
behaviors. Expanding upon these preliminary observations, we will probe the detailed molecular and cellular
mechanisms by which peripheral immune signals interface with mood-related brain circuitry to control
depression-like behaviors following social stress. By understanding how chronic stress affects the BBB we may
be able to augment current antidepressant treatment or design new therapeutic strategies promoting vascular
health by preventing BBB degeneration.

## Key facts

- **NIH application ID:** 9840932
- **Project number:** 5R01MH104559-07
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** SCOTT JAMES RUSSO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $666,089
- **Award type:** 5
- **Project period:** 2014-07-24 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840932

## Citation

> US National Institutes of Health, RePORTER application 9840932, Mechanisms of stress-induced neurovascular damage promoting immune infiltration and depression-like behaviors (5R01MH104559-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9840932. Licensed CC0.

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