# Postmortem studies of CRF-PACAP in human PTSD (Berretta)

> **NIH NIH P50** · MCLEAN HOSPITAL · 2021 · $334,704

## Abstract

SUMMARY: PROJECT 5 (POSTMORTEM STUDIES OF PACAP-CRF IN HUMAN PTSD/BERRETTA)
Compelling evidence indicates that corticotropic releasing factor (CRF) and pituitary adenylyl cyclase-activating
polypeptide (PACAP), as well as their interactions together, make critical contributions to stress responses,
anxiety, circadian rhythm regulation, and the pathophysiological mechanisms of post-traumatic stress disorder
(PTSD). The underlying neural circuitry involved is poorly understood, but important clues point to the bed
nucleus of the stria terminalis (BNST), amygdala (AMG), dorsal anterior cingulate gyrus (dACG), and the
hypothalamus (HPTh) as critical regulators of these functions. Current evidence indicates that CRF and PACAP
mechanisms that contribute to PTSD may be sex-specific, raising the possibility that the underlying brain
changes and potential therapeutic targets may differ in males and females. Current and preliminary data suggest
that PACAP signaling may directly affect CRF expressing cells and that circadian expression of PACAP and its
cognate receptor PAC1R, and their subsequent regulation of CRF systems, may vary during the course of the
day. Such variations may potentially contribute to disruptions of sleep/wake cycles associated with DSM-defined
illnesses including PTSD, major depression, and anxiety disorders. Surprisingly, virtually no information is
available on cell-level expression of CRF and PACAP signaling pathways in the human AMG, BNST, dACG and
HPTh, their relationships to circadian rhythms, and the involvement of CRF/PACAP interactions in the
neuropathology of PTSD. Our overarching hypothesis is that abnormalities affecting CRF/PACAP pathways in
the BNST, AMG and dACG and HPTh contribute to the pathology of PTSD. In Aim 1, we address a critical gap
of knowledge on the region-, sex- and circadian- specific expression and distribution of CRF, PACAP, and their
receptors in healthy human brain. Our hypothesis is that protein and mRNA expression of CRF, PACAP, and
their receptors are region- and sex-specific; in particular, we predict that PACAP receptors will show cell- and
sex- specificity and expression in CRF-positive neurons, supporting the hypothesis that PACAP regulates these
neurons in a sex dependent manner. In Aims 2 and 3, we examine whether—at the protein, gene expression,
and cellular level—signaling pathways in the dACG, AMG, BNST and HPTh are altered in PTSD. Our hypothesis
is that CRF and PACAP signaling pathways will be altered in subjects with PTSD, relative to healthy controls,
with increased PACAP expression correlated with CRF signaling pathway changes, in a region-, sex-, and
circadian rhythm-specific manner. We predict that increases of PACAP-positive cells and axons, reflecting
increased PACAP expression locally and from hypothalamic inputs, will be accompanied by altered expression
of PACAP receptors and down-stream signaling pathways in CRF-positive cells. Project 5 may identify CRF and
PACAP systems and ...

## Key facts

- **NIH application ID:** 10116486
- **Project number:** 5P50MH115874-03
- **Recipient organization:** MCLEAN HOSPITAL
- **Principal Investigator:** Sabina Berretta
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $334,704
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10116486

## Citation

> US National Institutes of Health, RePORTER application 10116486, Postmortem studies of CRF-PACAP in human PTSD (Berretta) (5P50MH115874-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10116486. Licensed CC0.

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