# Targeting the inflammatory response to treat post-traumatic anxiety and depression.

> **NIH VA I01** · BALTIMORE VA MEDICAL CENTER · 2020 · —

## Abstract

The stress of deployment and exposure to traumatic events puts soldiers at a greater risk than the
general public for the development of psychological disorders, including anxiety and depression, as well as
post-traumatic stress disorder. These mental disorders occur with high comorbidity, and the prevalence of
these conditions in Veterans of the recent Iraq and Afghanistan wars (OEF/OIF) is a concern of high
significance for the VA. While a number of therapeutic options are available for the treatment of these
conditions, they are marginally responsive to classical anxiolytic and antidepressant treatment when they
develop as a consequence of traumatic stress exposure. Extensive research in the field of
psychoneuroimmunology has indicated that these conditions are associated with dysregulated immune
function, manifested as increased systemic inflammation and altered cellular and humoral immunity; which is
believed to be a mechanism underlying the pathophysiology of these disorders. Our previous studies and
others in the literature have shown that T cells are responsive to traumatic stress exposure and can influence
behavioral responses of mice, conferring either resilience or susceptibility to stress depending upon the type of
T cell and the cytokine milieu. Our preliminary results strongly indicate that CD8+ cytotoxic T cells are a major
source of systemic and brain inflammation and promote susceptibility to develop maladaptive behavioral
responses to stress. On the other side, our recently published study indicates that CD4+ T cells improve
behavioral responses to stress, perhaps by reducing inflammation, in line with the work of others in the field.
Thus, the overall objective of this application is to test, in a pre-clinical mouse model, the therapeutic efficacy
of treating anxiety and depression by reducing inflammatory processes triggered by traumatic stress exposure.
We propose to specifically manipulate CD4+ and CD8+ T cell mediated immunity to reduce systemic and brain
inflammation, and improve behavioral outcomes. We propose 3 specific aims:
 Specific Aim 1 will identify mechanisms by which traumatic stress alters T cell functions by examining
homing properties of CD4+ and CD8+ T cells in response to stress, and whether they develop alterations in
glucocorticoid receptor sensitivity. To accomplish this we will reconstitute T cell deficient Rag2-/- mice with T
cell subsets derived from green fluorescent protein (GFP) expressing mice, allowing for the tracking and
identification of T cells in multiple tissues- including the brain. Additionally, we will conduct transcriptome
analysis of T cells of stressed vs non-stressed wild type mice using RNA-sequencing (RNAseq) to identify
pathways of T cell activation induced by traumatic stress. Specific Aim 2 is designed to determine the effects
on behavior of manipulating CD4+ and CD8+ T cells in stressed mice. The approach will involve a)
reconstitution in Rag2-/- mice with CD4+ or CD8+ T cells f...

## Key facts

- **NIH application ID:** 9932270
- **Project number:** 5I01BX003631-04
- **Recipient organization:** BALTIMORE VA MEDICAL CENTER
- **Principal Investigator:** Todd D Gould
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932270

## Citation

> US National Institutes of Health, RePORTER application 9932270, Targeting the inflammatory response to treat post-traumatic anxiety and depression. (5I01BX003631-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9932270. Licensed CC0.

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