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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL095491-05
Application #
8634587
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2014
Total Cost
$443,354
Indirect Cost
$188,553
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

Showing the most recent 10 out of 145 publications