# Project 4

> **NIH NIH P01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $467,688

## Abstract

Project Summary
Obstructive sleep apnea (OSA) is a debilitating condition leaving 14%-49% of middle-aged adults with
excessive daytime sleepiness and impaired cognitive, metabolic, and cardiovascular functioning. Treatments
beyond the often poorly tolerated CPAP remain limited, despite this unmet medical need. This Program Project
seeks to identify new intervention points in neural brain circuits to combat OSA. In OSA, the activity of muscles
that keep the airway open drops leading to airway collapse and impeded ventilation. Tissue and blood oxygen
levels fall and carbon dioxide (CO2) levels rise (hypercapnia). This leads to an intensification of breathing
movements, meant to improve ventilation, but which only worsen the airway collapse by generating negative
pressure. Once a threshold of hypercapnia is reached, the brain arouses, rapidly leading to robust airway
opening, resumption of ventilation, and return to sleep. This OSA cycle occurs many times per night,
fragmenting sleep and inflicting autonomic surges underlying vasoconstriction and tachycardia that drive much
of the comorbidity. Our Program seeks to identify neural brain circuits to optimize the activity of muscles that
keep the airway open and to augment breathing (Respiratory Augmentation) without arousing the brain. In
Project 4, we focus on the serotonergic neuronal system in the lower brainstem in mice, leveraging our team’s
recent discovery of two genetically distinct subtypes of serotonergic neurons each critical for a robust
ventilatory response to hypercapnia, yet each acting on largely distinct components of the neural respiratory
arousal circuit. The subtype denoted Egr2-Pet1 increases respiratory drive by connections to centers that
measure pCO2 and that mediate arousal, whereas the second subtype, denoted Tac1-Pet1, sends connections
to motor centers that control airway dilation and inspiration. By modulating these subtypes separately it may be
possible to a) optimize airway dilator tone to avoid airway closure, b) optimize ventilation to avoid exacerbation
of airway closure, c) optimize EEG arousal threshold to reduce sleep fragmentation, and d) avoid
cardiovascular stress. In Aim 1, we will study how Egr2-Pet1 and Tac1-Pet1 populations modulate each of
these different functions during wake, sleep, and arousal, enabled via intersectional chemogenetic tools in
combination with a Repeated-CO2-Arousal model for OSA, while measuring diaphragm and airway dilator
muscle activity, brain activity, heart rate, and respiratory rate and depth. In Aim 2, we will use in vivo and in
vitro optogenetic and calcium imaging tools to determine circuit nodes to which Egr2-Pet1 and Tac1-Pet1
neurons functionally connect, relevant for airway dilation, ventilation, and arousal. In Aim 3, we will visualize
the circuit nodes from which Tac1-Pet1 and Egr2-Pet1 neurons receive input. Throughout, we will query
response dependence on serotonin receptors, relevant for pharmacological strategies in OS...

## Key facts

- **NIH application ID:** 9854435
- **Project number:** 1P01HL149630-01
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Veronique VanderHorst
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $467,688
- **Award type:** 1
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9854435

## Citation

> US National Institutes of Health, RePORTER application 9854435, Project 4 (1P01HL149630-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9854435. Licensed CC0.

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