Obstructive sleep apnea (OSA) is a common sleep disorder that is characterized by frequent arousals from sleep caused by the collapse of the upper ainway and resulting hypercarbia/hypoxemia. Frequent arousals from sleep interfere with the architecture of normal sleep, reduce deep sleep, and impair the restorative/ cognitive benefits of sleep. Despite the importance of preventing arousals from sleep in order to improve sleep quality for millions of Americans with OSA, very little is known about the neural control mechanisms that mediate arousals during OSA. Recent work using anatomical methods suggests that the brainstem glutamatergic neurons of the parabrachial complex (PB/PC), which receive visceral and respiratory input, are important for arousal during OSA via their projections to the basal forebrain (BF), a region containing cortically projecting &wakefulness promoting neurons. However, these findings have not yet been complemented by an essential element, the recording of neurons in this circuit. This project addresses this need by using tetrode/multiple single unit recordings of PB/PC and BF neurons during natural sleep cycles and during arousals from both slow wave sleep (non-REM sleep) and REM sleep provoked by hypercarbia, thus mimicking the stimuli from OSA. To model the arousals of sleep apnea, rats will be exposed to 10% carbon dioxide to awaken them from sleep. We hypothesize that the cortical activation seen in the arousals of sleep apnea is mediated by the projection from PB/PC to BF. Since PB neurons receive input about levels of carbon dioxide and respiratory effort, we predict that PB/PC neurons will exhibit an increase in discharge activity that precedes cortical activation when the arousals from sleep are produced by carbon dioxide, but not when the arousals are spontaneous, or induced by acoustic stimulation. Reversible muscimol inactivation of PB/PC will further test the role of PB/PC in arousals. We predict that all types of arousals from sleep &the accompanying cortical activation will correlate with the elevated discharge of BF wakefulness promoting neurons. This project's precise information on the timing of neuronal activation relative to hypercarbia will complement and enhance the other projects of this program project grant.

Public Health Relevance

Sleep, an essential part of human life, is needed for optimal health &performance. Millions of (Americans suffer from disorders, such as sleep apnea, in which frequent arousals from sleep lead to excessive daytime sleepiness &cognitive impairments. This proposal investigates brain mechanisms underiying arousals from sleep in order to provide a rational basis for the development of therapies to reduce arousals from sleep.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL095491-03
Application #
8377820
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
3
Fiscal Year
2012
Total Cost
$336,507
Indirect Cost
$29,983
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Taranto-Montemurro, Luigi; Sands, Scott A; Grace, Kevin P et al. (2018) Neural memory of the genioglossus muscle during sleep is stage-dependent in healthy subjects and obstructive sleep apnoea patients. J Physiol 596:5163-5173
Ferrari, Loris L; Park, Daniel; Zhu, Lin et al. (2018) Regulation of Lateral Hypothalamic Orexin Activity by Local GABAergic Neurons. J Neurosci 38:1588-1599
Sands, Scott A; Terrill, Philip I; Edwards, Bradley A et al. (2018) Quantifying the Arousal Threshold Using Polysomnography in Obstructive Sleep Apnea. Sleep 41:
Sands, Scott A; Edwards, Bradley A; Terrill, Philip I et al. (2018) Phenotyping Pharyngeal Pathophysiology using Polysomnography in Patients with Obstructive Sleep Apnea. Am J Respir Crit Care Med 197:1187-1197
Sands, Scott A; Edwards, Bradley A; Terrill, Philip I et al. (2018) Identifying obstructive sleep apnoea patients responsive to supplemental oxygen therapy. Eur Respir J 52:
Todd, William D; Fenselau, Henning; Wang, Joshua L et al. (2018) A hypothalamic circuit for the circadian control of aggression. Nat Neurosci 21:717-724
Kroeger, Daniel; Absi, Gianna; Gagliardi, Celia et al. (2018) Galanin neurons in the ventrolateral preoptic area promote sleep and heat loss in mice. Nat Commun 9:4129
Boes, Aaron D; Fischer, David; Geerling, Joel C et al. (2018) Connectivity of sleep- and wake-promoting regions of the human hypothalamus observed during resting wakefulness. Sleep 41:
Yang, Chun; Larin, Andrei; McKenna, James T et al. (2018) Activation of basal forebrain purinergic P2 receptors promotes wakefulness in mice. Sci Rep 8:10730
Pedersen, Nigel P; Ferrari, Loris; Venner, Anne et al. (2017) Supramammillary glutamate neurons are a key node of the arousal system. Nat Commun 8:1405

Showing the most recent 10 out of 186 publications