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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL095491-05
Application #
8634586
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Twery, Michael
Project Start
2010-03-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2014
Total Cost
$2,297,146
Indirect Cost
$757,993
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Geerling, Joel C; Kim, Minjee; Mahoney, Carrie E et al. (2016) Genetic identity of thermosensory relay neurons in the lateral parabrachial nucleus. Am J Physiol Regul Integr Comp Physiol 310:R41-54
Abbott, Stephen B G; Machado, Natalia L S; Geerling, Joel C et al. (2016) Reciprocal Control of Drinking Behavior by Median Preoptic Neurons in Mice. J Neurosci 36:8228-37
Zant, Janneke C; Kim, Tae; Prokai, Laszlo et al. (2016) Cholinergic Neurons in the Basal Forebrain Promote Wakefulness by Actions on Neighboring Non-Cholinergic Neurons: An Opto-Dialysis Study. J Neurosci 36:2057-67
Taranto-Montemurro, Luigi; Edwards, Bradley A; Sands, Scott A et al. (2016) Desipramine Increases Genioglossus Activity and Reduces Upper Airway Collapsibility during Non-REM Sleep in Healthy Subjects. Am J Respir Crit Care Med 194:878-885
Genta, Pedro R; Edwards, Bradley A; Sands, Scott A et al. (2016) Tube Law of the Pharyngeal Airway in Sleeping Patients with Obstructive Sleep Apnea. Sleep 39:337-43
Arrigoni, Elda; Chen, Michael C; Fuller, Patrick M (2016) The anatomical, cellular and synaptic basis of motor atonia during rapid eye movement sleep. J Physiol 594:5391-414
Ferrari, L L; Agostinelli, L J; Krashes, M J et al. (2016) Dynorphin inhibits basal forebrain cholinergic neurons by pre- and postsynaptic mechanisms. J Physiol 594:1069-85
Vetrivelan, Ramalingam; Kong, Dong; Ferrari, Loris L et al. (2016) Melanin-concentrating hormone neurons specifically promote rapid eye movement sleep in mice. Neuroscience 336:102-113
Brown, Ritchie E; McKenna, James T (2015) Turning a Negative into a Positive: Ascending GABAergic Control of Cortical Activation and Arousal. Front Neurol 6:135
Sherman, David; Fuller, Patrick M; Marcus, Jacob et al. (2015) Anatomical Location of the Mesencephalic Locomotor Region and Its Possible Role in Locomotion, Posture, Cataplexy, and Parkinsonism. Front Neurol 6:140

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