# The Role of Vitronectin in Neuron-Microglia Interactions in the Context of Social Stress

> **NIH NIH F99** · UNIVERSITY OF MARYLAND BALTIMORE · 2024 · $39,674

## Abstract

Project Summary
Exposure to chronic stress is a known risk factor for neuropsychiatric disease and yields structural and molecular
changes to the brain and immune system. The nucleus accumbens (NAc), a hub for integrating reward and
motivation, exhibits molecular and cellular alterations that are found in postmortem tissue of patients with stress-
related disorders, such as major depressive disorder, and drive motivational deficits in rodents. Specifically,
dendritic atrophy of dopamine receptor type 1 (D1), but not type 2 (D2) expressing medium spiny neurons
(MSNs) is necessary and sufficient for stress-induced negative behavioral outcomes. Emerging evidence
implicates microglia as potential mediators of neuronal atrophy and motivational deficits after social stress. Since
microglia can interact with neurons and facilitate neuronal dysfunction and cell death, they are prime candidates
for investigating the relationship between chronic stress and D1-MSN atrophy. Recent work from the lab shows
that chronic social defeat stress (CSDS) reduced overall D1-MSN and microglia contact, but not D2 MSNs, and
analyses of individual microglia within the D1-MSN microenvironment revealed reductions in microglia
complexity in animals that exhibited negative affective behavior after CSDS. Thus, while it is evident that CSDS
alters D1-MSN-microglia contact and morphology, the molecular mechanisms driving these cell-subtype specific,
stress-induced changes in the NAc microenvironment remain unclear. Preliminary RNA-seq analysis from the
lab points to vitronectin, an extracellular matrix substrate, as a promising molecular messenger mediating D1-
MSN and microglia interactions because it plays a driving role in a network of genes altered by chronic stress
and is specifically differentially expressed in D1-MSNs. In this proposal, I will virally knock down vitronectin
expression in D1-MSNs using a Cre-dependent CRISPR/Cas9 construct in mice before subjecting them to either
CSDS or Chronic Witness Defeat Stress (CWDS) to interrogate the role of vitronectin expression in D1-MSN-
microglia interactions, D1-MSN and microglia morphology, and stress-induced behavioral outcomes. It is
hypothesized that knocking down vitronectin expression in D1-MSNs will rescue D1-MSN stress-induced
dendritic atrophy, restore D1-MSN-microglia contact, and prevent negative affective behavior. Understanding
the molecular mechanisms driving altered stress-induced behavioral states can shed light on novel therapeutics
designed to protect and/or treat the deleterious effects of chronic stress. The proposed training at the University
of Maryland Baltimore, School of Medicine will facilitate my transition to a postdoctoral fellowship and allow me
to continue to research stress-related neuropsychiatric disease by characterizing neuron, microglia, and
extracellular matrix relationships in the context of stress exposure. With the support of my excellent scientific
community comprising of my mentor, t...

## Key facts

- **NIH application ID:** 10932436
- **Project number:** 5F99NS135696-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Daniela Franco Hernandez
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $39,674
- **Award type:** 5
- **Project period:** 2023-09-20 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932436

## Citation

> US National Institutes of Health, RePORTER application 10932436, The Role of Vitronectin in Neuron-Microglia Interactions in the Context of Social Stress (5F99NS135696-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10932436. Licensed CC0.

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