# Regulation of PACAP expression and its role in protecting early neonatal respiration.

> **NIH NIH F31** · UNIVERSITY OF VIRGINIA · 2024 · $38,198

## Abstract

Project Summary
The first breath of air for an infant is a crucial and complex event that requires coordination of many
physiological systems; however, the neural circuitry and molecular signals that help mediate the initiation of
respiration in this critical time remains unclear. In adults, regulation of breathing occurs through careful
coordination of multiple brainstem nuclei which make up the respiratory central pattern generator. Among these
brainstem nuclei is the retrotrapezoid nucleus (RTN), a group of central respiratory chemoreceptors located
along the ventral lateral medulla. These glutamatergic neurons increase their firing rate in response to elevated
levels of arterial CO2 (PCO2), which in turn can drive respiratory output to re-establish and maintain PCO2
homeostasis via input to other brainstem nuclei within the respiratory network. All RTN neurons express the
transcription factor Phox2b, and neuropeptides Neuromedin B (Nmb), and pituitary-adenylate cyclase
activating peptide (PACAP). These neurons intrinsically respond to changes in CO2/H+ through two proton
sensors: TASK-2, and GPR4. GWAS analysis has revealed PACAP variants have been associated with higher
incidence of sudden infant death syndrome (SIDS), and PACAP-KO mice have been observed to have a SIDS-
like phenotype. Recent work from our laboratory demonstrated a striking upregulation of PACAP expression in
the RTN at the time of birth. Further we have shown that neonatal mice (p2-p12) lacking PACAP have
significantly more apneas when exposed to thermal stress, and a blunted respiratory response to hypercapnia
compared to their control littermates. These findings unveil a novel role for this peptidergic circuit in protecting
respiratory rhythm in neonates. It is currently unknown if PACAP is necessary for the initial establishment or
protection of a stable respiratory rhythm in the critical period immediately following birth, and further how this
dynamic expression of PACAP is regulated in the first moments of life. I hypothesize that PACAP expression
in the RTN is mediated through changes in blood gas homeostasis immediately following birth and is
necessary for establishing and protecting respiratory stability in neonates. In Specific Aim 1, I use
conditional PACAP knockout mice and whole-body plethysmography to test whether PACAP is necessary for
protection of stable respiratory rhythmogenesis in the face of thermal stress, and/or for establishment of normal
CO2 stimulated breathing over the course of the first hours of life. In Specific Aim 2, I investigate the
mechanism by which PACAP expression is stimulated at the time of birth by manipulating the principal RTN
chemosensitive feedback in opposing ways, or by genetically eliminating the putative CO2 sensors of the RTN,
while assessing PACAP expression through multiplex in situ hybridization or single cell-qPCR. The proposed
studies will provide novel information regarding molecular mechanisms which regulate the gene ...

## Key facts

- **NIH application ID:** 10997466
- **Project number:** 1F31HL176159-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Rachel Clements
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $38,198
- **Award type:** 1
- **Project period:** 2024-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10997466

## Citation

> US National Institutes of Health, RePORTER application 10997466, Regulation of PACAP expression and its role in protecting early neonatal respiration. (1F31HL176159-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10997466. Licensed CC0.

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