# PACAP and the Response to Stressors: Neural Mechanisms

> **NIH NIH R01** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2020 · $347,274

## Abstract

Project Summary
 Many affective disorders are caused or exacerbated by exposure to severe or repeated
stressors. Despite the important role of stressor exposure in modulating emotion, the
mechanisms by which central emotional circuits are altered by stress are still unknown.
Substantial evidence has suggested that the dorsal anterior bed nucleus of the stria terminalis
(BNST) mediates anxiety-like behavior in humans and animals, and it is likely that altered BNST
function underlies anxiety disorders. We have shown that pituitary adenylate cyclase activating
polypeptide (PACAP) activation and release in the BNST mediates many of the behavioral
effects of repeated stress in males and females, and that circulating PACAP levels and a unique
single nucleotide polymorphism in the PAC1 receptor predict PTSD symptoms and diagnosis in
women, suggesting that PACAP systems. In non-stressed organisms, BNST PACAP release
likely originates from the lateral parabrachial nucleus (LPBn); however, we argue that following
chronic stress, local BNST PACAP production and release is increased concurrent to an
increase in PAC1 receptor-mediated activation of locally-projecting corticotropin-releasing factor
(CRF)-expressing neurons in the BNST to produce pathological anxiety. Importantly, different
PAC1 receptor isoforms can signal via multiple mechanisms to produce short-duration and
sustained effects on neuronal excitability. Hence, the activation of cAMP subsequent to
membrane-bound PAC1 receptor activation of adenylyl cyclase (AC) likely leads to the
immediate changes in BNSTov excitability observed following PACAP. However, the
phosphorylation and activation of extracellular signal-regulated kinase 1/2 (pERK) via
endosomal signaling likely leads to a sustained anxiogenic response, and pERK signaling may
also support trophic actions to enhance anxiety-like behavioral responding for even longer
periods. The experiments in this application use a combination of molecular, physiological and
behavioral approaches to investigate whether PACAP targets different populations of BNSTov
neurons in stress- and unstressed males and females, and whether different PAC1 receptor
signaling pathways mediate anxiogenic behavior with different temporal characteristics.
Understanding the signaling cascades and cellular targets that mediate the effects of BNST
PACAP could help to better target the maladaptive consequences of stressor exposure.

## Key facts

- **NIH application ID:** 9841448
- **Project number:** 5R01MH097988-07
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** SAYAMWONG E. HAMMACK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $347,274
- **Award type:** 5
- **Project period:** 2012-05-29 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841448

## Citation

> US National Institutes of Health, RePORTER application 9841448, PACAP and the Response to Stressors: Neural Mechanisms (5R01MH097988-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9841448. Licensed CC0.

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