Patients with obstructive sleep apnea (OSA) suffer from repetitive collapse of the airway, resulting in apnea, hypercarbia, and hypoxia, resulting in increased respiratory drive and arousal, with BEG activation and a surge in sympathetic activity and tone in the airway dilator muscles. This cycle re-establishes airway patency, but also causes sleep fragmentation and cardiovascular disease. Despite the critical nature of these events, the brain circuitry that underlies respiratory, EEG, and autonomic arousals during OSA remains unknown. In this PPG, we hypothesize that the parabrachial nucleus (PB) plays a key role in arousals in OSA, as a nodal point in receiving sensory input during apnea, and activating arousal responses. Projects 1 and 5 will examine the circuitry underlying EEG and autonomic (Project 1) and respiratory (Project 5) arousals directly, by tracing the inputs and outputs from PB neurons that respond to hypercarbia. These projects will also use a conditional knockout strategy to test whether the PB neurons that cause arousal use glutamate as their main neurotransmitter. Project 4 will test the role of the PB neurons in arousal, and examine their relationship with the basal forebrain neurons that play a major role in relaying the PB arousal influence to the cerebral cortex. It will test antidromic and orthodromic activation of PB and basal forebrain neurons recorded across wake-sleep states in unrestrained rats, and determine how their firing rate changes during both hypercarbic and auditory arousals. Project 3 will focus on the role of the orexin neurons in the lateral hypothalamus in relaying the arousal influence from the PB. By using mice with conditional knockouts for the orexin type 1 and 2 receptors, the role of the different orexin receptors at specific forebrain targets in producing arousal will be tested. Project 2 is a translational study that tests whether some patients with OSA have a high threshold for arousal, permitting greater hypoxia during airway collapse. It will test whether this threshold is altered by CPAP treatment and whether a novel treatment with a non-myorelaxant hypnotic drug can stabilize breathing in a subset of OSA patients with lower arousal thresholds. This work will help to design interventions for improving the health of patients with OSA.

Public Health Relevance

OSA is a common disorder that causes cognitive impairment and long term cardiovascular disease. The arousals that terminate each apnea cycle are a two-edged sword, re-establishing the airway, but causing sleep fragmentation and sympathetic activation. By understanding the brain circuitry that causes the autonomic, respiratory, and EEG components of arousal, we aim to design interventions that can stabilize breathing while minimizing the cognitive and cardiovascular consequences of OSA.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Twery, Michael
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Beth Israel Deaconess Medical Center
United States
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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
Landry, Shane A; Joosten, Simon A; Sands, Scott A et al. (2017) Response to a combination of oxygen and a hypnotic as treatment for obstructive sleep apnoea is predicted by a patient's therapeutic CPAP requirement. Respirology 22:1219-1224

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