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
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
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

Showing the most recent 10 out of 186 publications