# Immune basis for hippocampal cholinergic deficits in pyridostigmine-treated rats

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2022 · —

## Abstract

Following return from the Gulf War (GW), veterans have experienced of a constellation of symptoms,
designated Gulf War Illness (GWI), that cannot be associated with a single disease. In this regard, GW
veterans exhibit structural and functional deficits in the central nervous system (CNS), along with
cardiovascular complications. One of the more insidious aspects of GWI is that it is a chronic and
progressive disorder; indeed, the number of veterans diagnosed with GWI continues to rise in the post-
deployment period. Although the mechanisms underlying the myriad of symptoms associated with GWI
remain to be elucidated, some studies have determined that GWI veterans exhibit exaggerated immune
responses to physiological stressors, which when combined with other studies support the concept that
neuroinflammation is a key component in the etiology and progression of GWI.
During the previous funding period we developed a rodent model of GWI in which rats were administered
the acetylcholinesterase (AChE) inhibitor pyridostigmine bromide (PB) alone and in combination with
repeated restraint stress (RRS). Our ongoing studies have revealed that PB and RRS elicit alterations in
cardiovascular, neuroendocrine, neuroimmune and behavioral measures. Perhaps more importantly, our
preliminary studies indicate that these PB+RRS-induced alterations are exacerbated by lipopolysaccharide
(LPS) or acute exposure to heterogeneous social stressors. Such observations suggest that in addition to
baseline differences, a prior history of PB and stress may predispose GWI veterans to exaggerated
responses to immune challenges or stressful life experiences after deployment in the GW. Surprisingly,
relatively few studies have directly tested this hypothesis to determine the underlying mechanisms
responsible for exacerbated responses to stress or immune challenges after exposure to PB. Accordingly,
the goal of this project is to directly test our overarching hypothesis that immune challenges and stressful
stimuli lead to exacerbated neuroimmune, neurochemical, cardiovascular and behavioral deficits after
exposure to cholinesterase inhibition in an animal model of Gulf War Illness. This hypothesis will be tested
in the following Aims:
• Aim 1 will examine whether immune or stress challenges lead to potentiated neuroimmune responses in
 PB+RRS rats
• Aim 2 will determine whether LPS or to exposure social stress enhances cardiovascular complications in
 enhanced in PB+RRS rats.
• Aim 3 will determined whether the performance of hippocampal and prefrontal cortex-dependent
 behaviors are adversely affected by LPS administration or acute social stress.
Successful completion of these studies will demonstrate that PB treatment in combination with stress elicits
fundamental alterations in brain and body responses that may be much more evident following immune and
social stress challenges, which would be highly consistent with the progress nature of GWI
pathophysiology. Most importantly, ...

## Key facts

- **NIH application ID:** 10412922
- **Project number:** 5I01BX002664-07
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** LAWRENCE P REAGAN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2015-07-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10412922

## Citation

> US National Institutes of Health, RePORTER application 10412922, Immune basis for hippocampal cholinergic deficits in pyridostigmine-treated rats (5I01BX002664-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10412922. Licensed CC0.

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