# Project 1

> **NIH NIH P01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $438,302

## Abstract

Summary/Abstract: Project 1
Patients with obstructive sleep apnea (OSA) may have hundreds of cycles over the night of loss of airway
dilator motor tone and airway obstruction, followed by apnea, which is ended by an arousal, in which there is
EEG desynchronization accompanied by return of airway dilator muscle tone, opening of the airway, and re-
established ventilation. The EEG arousals cause sleep fragmentation and loss, resulting in cognitive
impairment, and metabolic and cardiovascular consequences. We hypothesize that by augmenting brain
circuits that keep the airway open while suppressing the EEG arousals, we can prevent these outcomes. We
previously demonstrated that the EEG arousal to CO2 depends upon a population of CGRP neurons in the
parabrachial nucleus (PBCGRP neurons). We now have identified a population of neurons expressing the
transcription factor FoxP2 (PBFoxP2 neurons) which are just lateral to the PBCGRP neurons and which appear to
be responsible for much of the increase in ventilation and in EMG tone of the genioglossus muscle (GG-EMG),
an airway dilator, during CO2 exposure. In Specific Aim 1 we plan to use Channelrhodopsin2 to
optogenetically activate PBFoxP2 neurons at baseline and during CO2 arousal, and will measure changes in
respiratory rate, tidal volume, minute ventilation, and GG-EMG. We hypothesize that we can increase the
respiratory response to CO2 in this way. We will then activate specific terminal fields of the PBFoxP2 neurons in
the dorsal (nucleus of the solitary tract, hypoglossal nucleus) and ventral (preBötzinger complex, caudal
ventrolateral medulla) to determine which of these contribute to the overall respiratory response. In Specific
Aim 2 we will use ArchaerhodopsinT to inhibit the PBFoxP2 neurons or their terminal fields in the medulla, at
baseline and during CO2 exposure, to see which are required for the respiratory response to CO2. Specific
Aim 3 will use GCaMP6 calcium imaging to examine the responses of PBFoxP2 and PBCGRP neurons to CO2
arousal. We will examine this initially with fiber photometry, but then will record the responses of individual
FoxP2 or CGRP neurons in the PB during CO2 arousal and other stimuli, to determine whether there are
subsets within these groups that respond to specific classes of stimuli. Finally, in Specific Aim 4, we will use
chemogenetics to enhance the firing of the PBFoxP2 neurons with the hM3Dq excitatory receptor and to
suppress the firing of the PBCGRP neurons with the hGlyR inhibitory receptor. We plan then to combine these
approaches in single animals to provide a proof of principle that selective and simultaneous activation of
PBFoxP2 neurons and inhibition of PBCGRP neurons can allow a vigorous respiratory response, including
increased GG-EMG in response to CO2 during sleep, without resulting in EEG arousal.

## Key facts

- **NIH application ID:** 9854432
- **Project number:** 1P01HL149630-01
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** CLIFFORD B SAPER
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $438,302
- **Award type:** 1
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9854432

## Citation

> US National Institutes of Health, RePORTER application 9854432, Project 1 (1P01HL149630-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9854432. Licensed CC0.

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