In obstructive sleep apnea (OSA), patients repeatedly lose ainway motor tone during sleep, resulting in collapse of the airway and apnea. This results in hypoxia, hypercarbia, and increased respiratory effort, until there is an arousal in which the ainway patency is restored. The EEG arousal causes sleep fragmentation and the autonomic arousal causes increased sympathetic tone, which may have deleterious long term cognitive and cardiovascular consequences, but the mechanisms for these arousals are not know. In Project 1, we hypothesize that glutamatergic neurons in the parabrachial nucleus (PB) and adjacent precoeruleus region (PC) play a key role in causing EEG and autonomic arousals during obstructive sleep apnea OSA.
In Specific Aim 1, we will test whether the glutamatergic neurons in the PB/PC that show Fos-activation during repeated brief episodes of hypercarbia during sleep project to key forebrain targets for producing EEG arousal (hypothalamus, thalamus, basal forebrain, amygdala, prefrontal cortex) and key brainstem targets for producing autonomic arousal, by combining retrograde tracing with Fos immunohistochemistry and vesicular glutamate transporter 2 (VGLUT2) in situ hybridization.
In Specific Aims 2 and 3, we determine the effects of deleting glutamatergic transmission in subsets of these VGLUT2+ PB/PC neurons, respectively on EEG and autonomic (HR, ECG power spectrum) arousal. We will do this by using VGLUT2 conditional knockout mice and adeno-associated viral vectors (/VAV) containing the genes for Cre recombinase and Green Fluorescent Protein (GFP). We will inject the AAV-Cre/GFP into the PB/PC, deleting VGLUT2 expression and glutamate transmission from subsets of PB/PC neurons, and correlate this with the EEG (duration of arousal, high frequency/low frequency EEG power) and the ECG (HR, low frequency/high frequency ECG power) consequences on arousals during repeated brief C02 exposures. We will then trace the projections from the affected PB/PC neurons with GFP, and determine which targets are critical for the alterations that are seen. These studies will help in deciphering the brain circuitry causing EEG and autonomic arousals during OSA, and in designing interventions to minimize its cognitive and cardiovascular consequences.

Public Health Relevance

OSA is a common disorder in which repeated ainway collapse during sleep produces arousals, which result in sleep fragmentation and elevation of blood pressure and heart rate, producing long terni cognitive impairment and cardiovascular disease. We will study the brain circuitry that underiies the arousals in OSA. These results will be necessary to design inten/entions that minimize the cognitive and cardiovascular consequences of repeated arousals in OSA.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Beth Israel Deaconess Medical Center
United States
Zip Code
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) K├Âlliker-Fuse GABAergic and glutamatergic neurons project to distinct targets. J Comp Neurol 525:1844-1860

Showing the most recent 10 out of 173 publications