A notable portion of the adult US population (2-4%, possibly more) suffers from sleep-disordered breathing, a condition characterized by frequent interruptions of breathing (apneas) and poor sleep. Apneas, whatever their cause, reduce the body's oxygen level (hypoxia) and increase carbon dioxide (CO2, hypercapnia). These changes in blood gases in turn disrupt sleep, affect memory and have adverse health consequences such as increased blood pressure and heart rate, chronic hypertension and exacerbation of diabetes. The main objective of the research is to understand the mechanisms that sustain breathing automaticity, especially during sleep and how failure of this homeostatic mechanism, in turn, disrupts sleep. That involuntary breathing is driven to a large extent by the level of oxygen and carbon dioxide in the blood has been common knowledge for a long time but the mechanisms are still far from clear. We have recently identified a small group of brain neurons, called retrotrapezoid nucleus (RTN), that encode the blood concentration of carbon dioxide. There are multiple reasons to hypothesize that these neurons play a critical role in sustaining breathing during sleep. One especially convincing argument is that RTN neurons fail to develop in a mouse model of a human genetic disease characterized both by the inability to breathe at night and by an insensitivity to carbon dioxide (congenital central hypoventilation syndrome). We have therefore designed experiments to test the function of RTN neurons in fully conscious rodents so that the results might be as relevant as possible to humans. We will also be exploring how RTN neurons respond to hypoxia in an attempt to explain the respiratory insufficiency caused by altitude, which we believe to be caused by a reduced activity of RTN neurons. Finally, neuroanatomical experiments will be conducted to find out the brain circuitry through which RTN neurons stimulate breathing. This project will be carried out using advanced optogenetic and intersectional genetic method and viral vectors designed to propagate in the anterograde or retrograde direction across synapses. This research is expected to clarify how breathing automaticity is maintained during sleep and how respiratory insufficiency or failure in turn disrupts sleep. Novel therapeutic interventions benefiting sleep disordered breathing could result from this research if RTN neurons prove to be as important as we postulate and a way can be found to activate them pharmacologically.

Public Health Relevance

The mechanisms that maintain breathing automaticity are essential to life and are dysfunctional in a significant proportion of the population. Examples include congestive heart failure, central or obstructive sleep apnea, sudden infant death syndrome (SIDS), apnea-bradycardia of premature infants, congenital central hypoventilation syndrome, breathing at altitude and when pain is treated with opiates. All these pathologies involve some problem with the neural control of breathing and its regulation by oxygen and carbon dioxide. The goal of our research is to figure out how breathing is regulated by changes in blood gases during sleep and, conversely, how blood gas abnormalities disrupt sleep. We will identify the brain circuits responsible for the effects of these gases on breathing and sleep and will explore novel ways by which breathing could be stimulated to maintain adequate tissue oxygenation in humans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074011-14
Application #
8986810
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Laposky, Aaron D
Project Start
2003-07-01
Project End
2018-12-31
Budget Start
2016-01-01
Budget End
2016-12-31
Support Year
14
Fiscal Year
2016
Total Cost
$430,991
Indirect Cost
$158,211
Name
University of Virginia
Department
Pharmacology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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Guyenet, Patrice G; Bayliss, Douglas A; Stornetta, Ruth L et al. (2016) Proton detection and breathing regulation by the retrotrapezoid nucleus. J Physiol 594:1529-51

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