# Neuropeptide Mechanisms and Stress Pathologies

> **NIH VA I01** · CINCINNATI VA MEDICAL CENTER RESEARCH · 2020 · —

## Abstract

Incidence of post-traumatic stress disorder is a major problem for the VA, affecting roughly 20% 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
(e.g., SSRIs) 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. This proposal is
designed to examine the role of pituitary adenylate cyclase activating peptide, or PACAP, in mediating the
development of aberrant physiological and behavioral fear responses following exposure to a chronic stress
regimen. Recent studies indicate that polymorphisms in the primary PACAP receptor, PAC1, are linked to
PTSD susceptibility in women. Preclinical data link deficits in PACAP to impaired emotional memory and
blunted corticosterone stress responses, both of which accompany PTSD. Moreover, our preliminary studies
suggest that chronic stress produces a profound and long-lasting deficit in PACAP expression in the prefrontal
cortex, a region known to be dysfunctional in PTSD patients. These studies will use behavioral, physiological
and genetic approaches to test the hypothesis that prefrontal cortex PACAP inhibits the development of
PTSD-related physiological and behavioral deficits caused by chronic stress, identifying it as a potential
therapeutic target. Aim 1 will test whether prefrontal PACAP signaling is necessary and sufficient to block the
negative impact of chronic stress on behavioral and physiological indices of post-traumatic stress in rats.
Endpoints tested include fear conditioning, extinction and extinction recall; fear generalization; anxiety-related
behaviors; and hypothalamo-pituitary responses, all of which are disrupted following chronic stress (and in
PTSD). Aim 2 will use prefrontal cortex-directed RNA interference and PACAP supplementation to test
whether supplementation of PACAP during chronic stress can prevent the development of post-traumatic
endpoints, or if loss of PACAP signaling is sufficient to induce aberrant emotional responses in otherwise
unstressed animals. Aim 3 will test use electrophysiology and state-of-the-art imaging approaches to test the
role of PACAP in mitigating potentially deleterious neuroplastic responses to chronic stress at the cellular level.
In all cases, experiments will be performed in male and female subjects, to evaluate the possibility that females
may be more sensitive to perturbations in PACAP signaling. These studies will provide important information
regarding the prospect of using PACAP supplementation as a PTSD treatment, and determine whether
females may be more likely to benefit from PACAP therapy.

## Key facts

- **NIH application ID:** 9932294
- **Project number:** 5I01BX003858-04
- **Recipient organization:** CINCINNATI VA MEDICAL CENTER RESEARCH
- **Principal Investigator:** James P Herman
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-07-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932294

## Citation

> US National Institutes of Health, RePORTER application 9932294, Neuropeptide Mechanisms and Stress Pathologies (5I01BX003858-04). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9932294. Licensed CC0.

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