# Mechanisms of sleep and sleep apnea

> **NIH NIH P01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $2,693,865

## Abstract

Summary - Overall
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 sleep 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
have found that the EEG arousal depends on two circuits, the CGRP-expressing neurons in the parabrachial
nucleus (PBCGRP cells), and the dorsal raphe serotonin neurons that provide input to them. The increase in
airway dilator tone, in part through genioglossus muscle (GG) tone, allows breathing to restart in OSA, and
relies on two different circuits: FoxP2 neurons in the PB (PBFoxP2 neurons) and medullary serotonin neurons
that innervate the medulllary respiratory control system. Project 1 will examine the effects on ventilation and
GG-EMG of activating or inhibiting the PBFoxp2 neurons optogenetically and the firing of PBFoxP2 neurons in real
time with calcium imaging,.at baseline and during CO2 exposure. It will then use chemogenetics to enhance
the firing of the PBFoxP2 neurons and ventilator (tidal volume, respiratory rate) and GG-EMG response, while
inhibiting the PBCGRP neurons and EEG arousal during CO2 exposure. Project 2 and 3 will run in parallel to
identify the forebrain inputs to the PBCGRP and PBFoxP2 neurons that activate them during EEG arousal. Their
shared strategy is to identify druggable receptors on the PB cells that respond to CO2, to suggest therapies
that can be used to augment firing of PBFoxP2 neurons and suppress PBCGRP neurons during CO2 exposure.
They will use single cell RNA-Seq to identify the receptors on these neurons, and rabies virus tracing
combined with channelrhodopsin-assisted circuit mapping to determine their inputs, and then GCaMP6 fiber
photometry to determine which of these inputs is activated during the EEG arousal that accompanies CO2
exposure. Project 4 examines the inputs to the respiratory control system from the medullary serotonin
neurons that are required to produce the ventilatory and GG-EMG response to CO2. It takes advantage of
identifying genetically distinct subsets of medullary serotonin neurons that innervate the sensory and motor
components of the respiratory control system. It will then identify the forebrain inputs to these different
serotonin neurons, to determine which ones activate them, and with what receptor types, during CO2
exposure. Finally, Project 5 will use information from Projects 1-4 that identifies druggable receptors that
increase airway dilator tone, while suppressing EEG arousals during sleep apnea. We expect with refinement
of th...

## Key facts

- **NIH application ID:** 9854428
- **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:** $2,693,865
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9854428

## Citation

> US National Institutes of Health, RePORTER application 9854428, Mechanisms of sleep and sleep apnea (1P01HL149630-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9854428. Licensed CC0.

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