# Glucocorticoid Receptor Mechanisms of Traumatic Stress Pathology

> **NIH VA I01** · CINCINNATI VA MEDICAL CENTER RESEARCH · 2022 · —

## Abstract

Incidence of post-traumatic stress disorder is a major problem for the VA, affecting roughly 13% of individuals
serving in OIF or OEF. Women appear to be more susceptible to development of PTSD than men, often
occurring in the context of sexual assault (which can occur during military service). Frontline treatment options
can improve symptoms but do not currently offer a cure. To develop further strategies to this end, it is critical
to understand the foundations of the disease process as it develops. The proposal is designed to test the
hypothesis that hormonal responsiveness to stress and trauma are critical for driving susceptibility to
development of behavior pathologies relevant to PTSD. In humans, PTSD is linked to heightened sensitivity to
glucocorticoid signals, due to enhanced glucocorticoid receptor (GR) signaling (due to increased glucocorticoid
receptor expression and/or decreased expression of its inhibitory binding partner FKBP5). Both GR and
FKBP5 gene variants are linked to PTSD incidence or severity, indicating of a role as trait variable influencing
disease development or progression. PTSD-related GR and HPA axis dysfunction are emulated in rodent
models, suggesting that they contribute to pathological behaviors associated with trauma. Pathological
mechanisms are thought to be driven by disruption of prefrontal cortex-amygdala connections controlling
expression of fear, anxiety and emotional memory, processes that are in turn subject to regulation by stress
hormones. This proposal tests the hypothesis that post-trauma glucocorticoid signaling disrupts prefrontal
(infralimbic) cortex and amygdala circuitry responsible for fear regulation, causing lasting decrements in
neurocircuit function and behavior. Here we employ pharmacological, genetic and physiological approaches to
understand glucocorticoid control of neurocircuit mechanisms driving posttraumatic pathologies, using a well-
characterized and reproducible rodent single prolonged stress (SPS) model to emulate core symptoms of
PTSD. Aim 1 uses pharmacological approach to either block or amplify infralimbic cortex glucocorticoid signals
in the aftermath of SPS, testing the impact of altered glucocorticoid receptor binding on generation of
enhanced anxiety related behaviors, social withdrawal, impaired extinction of fear memories and impaired
decision making. Novel machine learning approaches are used to model the constellation of behavioral deficits
following SPS and determine how blocking or amplifying infralimbic GR signaling modifies the pathology
model. Aim 2 uses a recently-developed conditional rat GR deletion model to test the specific role of the
infralimbic GR signaling in mediating stress pathologies, including direct query of GR action across the
infralimbic-basolateral amygdala connection. Aim 3 addresses possible mechanisms of post-SPS GR signaling
in disruption of infralimbic-amygdala circuit function, employing electrophysiological approaches to test the role
o...

## Key facts

- **NIH application ID:** 10480199
- **Project number:** 1I01BX005923-01
- **Recipient organization:** CINCINNATI VA MEDICAL CENTER RESEARCH
- **Principal Investigator:** James P Herman
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10480199

## Citation

> US National Institutes of Health, RePORTER application 10480199, Glucocorticoid Receptor Mechanisms of Traumatic Stress Pathology (1I01BX005923-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10480199. Licensed CC0.

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