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.
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.
|Scammell, Thomas E; Arrigoni, Elda; Lipton, Jonathan O (2017) Neural Circuitry of Wakefulness and Sleep. Neuron 93:747-765|
|Yang, Chun; McKenna, James T; Brown, Ritchie E (2017) Intrinsic membrane properties and cholinergic modulation of mouse basal forebrain glutamatergic neurons in vitro. Neuroscience 352:249-261|
|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|
|Marques, Melania; Genta, Pedro R; Sands, Scott A et al. (2017) Effect of Sleeping Position on Upper Airway Patency in Obstructive Sleep Apnea Is Determined by the Pharyngeal Structure Causing Collapse. Sleep 40:|
|Azarbarzin, Ali; Sands, Scott A; Taranto-Montemurro, Luigi et al. (2017) Estimation of Pharyngeal Collapsibility During Sleep by Peak Inspiratory Airflow. Sleep 40:|
|Kroeger, Daniel; Ferrari, Loris L; Petit, Gaetan et al. (2017) Cholinergic, Glutamatergic, and GABAergic Neurons of the Pedunculopontine Tegmental Nucleus Have Distinct Effects on Sleep/Wake Behavior in Mice. J Neurosci 37:1352-1366|
|Rukhadze, Irma; Carballo, Nancy J; Bandaru, Sathyajit S et al. (2017) Catecholaminergic A1/C1 neurons contribute to the maintenance of upper airway muscle tone but may not participate in NREM sleep-related depression of these muscles. Respir Physiol Neurobiol 244:41-50|
|Kim, Bowon; Kocsis, Bernat; Hwang, Eunjin et al. (2017) Differential modulation of global and local neural oscillations in REM sleep by homeostatic sleep regulation. Proc Natl Acad Sci U S A 114:E1727-E1736|
|Kaur, Satvinder; Wang, Joshua L; Ferrari, Loris et al. (2017) A Genetically Defined Circuit for Arousal from Sleep during Hypercapnia. Neuron 96:1153-1167.e5|
|Geerling, Joel C; Yokota, Shigefumi; Rukhadze, Irma et al. (2017) Kölliker-Fuse GABAergic and glutamatergic neurons project to distinct targets. J Comp Neurol 525:1844-1860|
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