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 #
5P01HL095491-03
Application #
8377818
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
$455,747
Indirect Cost
$193,823
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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