Arousal from obstructive sleep apnea (OSA) plays a life-saving role, and we hypothesize that it is supported by the same circuitry that produces arousal during normal wakefulness. The orexin neurons in the lateral hypothalamus play a critical role in producing arousal, and lack of orexin neurotransmission produces a chronic state of hypoarousal. These studies will provide key insights into an important aspect of this Program Project: Defining the mechanisms through which the orexin neurons ultimately activate the cortex. We present a testable model in which the orexin neurons promote arousal by exciting basal forebrain neurons that activate the cortex. In addition to the orexin peptides, the orexin neurons probably co-release the inhibitory neuropeptide dynorphin, and we hypothesize that dynorphin and orexin act synergistically in the basal forebrain to promote full arousal. We will use powerful genetic, anatomic, and physiologic techniques to identify the neural circuits through which the orexin neurons promote arousal. To define the brain regions through which orexin promotes arousal, we will study sleep/wake behavior in mice that express orexin receptors only in the basal forebrain, thalamus, or cortex. Using slice recordings, we will determine the pre- and postsynaptic effects of orexin and dynorphin on neurochemically-defined basal forebrain neurons, including those projecting to prefrontal cortex. We will also map the basal forebrain pathways through which orexin and dynorphin promote wakefulness. Collectively, these multidisciplinary experiments will define the pathways through which orexin, in combination with dynorphin, promotes cortical activation, thus providing an anatomic and physiologic framework to better understand the neurobiology of arousal and the clinical problem of sleepiness.

Public Health Relevance

Disrupted sleep and daytime sleepiness affect many people with obstructive sleep apnea and other sleep disorders. These studies will improve our understanding of how the orexin neurons promote cortical activation and arousals from sleep triggered by high levels of C02. Ultimately, these insights should lead to better treatments for the sleepiness and disrupted sleep of people with sleep apnea and other disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL095491-04
Application #
8435428
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2013
Total Cost
$348,576
Indirect Cost
$92,951
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
Taranto-Montemurro, Luigi; Sands, Scott A; Edwards, Bradley A et al. (2017) Effects of Tiagabine on Slow Wave Sleep and Arousal Threshold in Patients With Obstructive Sleep Apnea. Sleep 40:

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