Project 3: Circuitry mediating increased ventilation with EEG arousal

Beth Israel Deaconess Medical Center, Boston MA

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY Obstructive Sleep Apnea (OSA) is a prevalent breathing disorder marked by recurring episodes of partial and complete airway obstructions during sleep. It poses a considerable public health burden due to its association with adverse cardiovascular and neurological conditions. Importantly, the re-establishment of airway patency after an obstructive event often triggers arousal from sleep, causing sleep fragmentation, reduced sleep time, and excessive daytime sleepiness. The disruption of sleep continuity is thought to contribute dramatically to the pathological consequences of OSA. Despite numerous attempts to pharmacologically treat OSA by boosting the ventilatory drive, the increase in arousability (as unwanted effect) has limited success. Recent evidence suggests that the glutamatergic neurons expressing Forkhead box protein P2 (FoxP2) in the parabrachial and Kölliker fuse nucleus (PB-KFFoxP2 neurons) increase respiration, while calcitonin gene-related peptide (CGRP)-expressing neurons of the external lateral PB (PBCGRP), regulate hypercapnia-induced cortical arousals. Both of these neuronal groups may contribute to opioid-induced respiratory depression (OIRD), as opioids directly inhibit these neurons to decrease breathing and cause sedation. Interestingly, the same circuits triggering forebrain (FB) arousal and increased respiration in response to CO2, express the mu-opioid receptor and are thought to contribute to OIRD. However, we lack knowledge about the FB inputs targeting PB-KFFoxP2 neurons that may be crucial for keeping augmented ventilation without affecting arousal. The central hypothesis posits that the manipulation of specific FB inputs to the PB-KFFoxP2 neurons will enhance ventilatory responses to hypercapnia/hypoxia without driving cortical arousals. Our goal is to understand the brain pathways that enhance ventilatory responses to hypercapnia while preventing cortical arousals, aiming to preserve sleep while opening the airway in mouse models of OSA and OIRD. The study will focus on four specific aims: 1) Characterize the FB inputs to PB-KFFoxP2 neurons; 2) Which FB inputs to the PB-KF are activated in advance of the PB-KFFoxP2 neurons during EEG arousal caused by hypercapnia/hypoxia? 3) What role do these FB inputs to the PB-KFFoxP2 neurons play in increasing ventilatory responses? 4) Test the synaptic connectivity of FB inputs to PB-KFFoxP2 and Tac1-Pet1 medullary raphe neurons and local PB circuitry with ChR2-assisted circuit mapping (CRACM). This research is intellectually and technically innovative, emphasizing the FB inputs to PB-KFFoxP2 neurons in the context of increased respiratory effort and employing a combination of technical approaches such as single nucleus RNA-sequencing, in vivo fiber photometry, in vivo optogenetics and in vitro circuit mapping. The significance of this work lies in its contribution to a broader continuum of research, ultimately leading to the identification and development of a clinically practical drug that can reduce the arousability in OSA patients during hypercapnia and can restore ventilation, particularly, during OIRD.