The neural mechanisms that automatically regulate breathing and the circulation during sleep reside primarily within the lower brainstem. These mechanisms are implicated in many human diseases or conditions such as obstructive sleep apnea (OSA), the treatment of pain with opiates, central sleep apnea, sudden infant death syndrome (SIDS), and rare diseases such as congenital central hypoventilation syndrome (CCHS). Under the auspices of this grant, we have extensively studied the brainstem network that mediates the cardio respiratory adjustments to changes in blood gases. An important component of this network consists of modified catecholaminergic neurons called the C1 neurons that innervate the spinal cord and regulate sympathetic tone to the heart and blood vessels. The contribution of the C1 neurons to blood pressure stabilization, including during hypoxia, is well established, thanks in part to our work. However, the commonly held view that these neurons merely regulate the activity of the sympathetic system is outdated because these cells also obviously play a major role in the activation of the hypothalamo-pituitary axis during stresses such as infection, hypotension, pain and hypoxia and they also contribute to the regulation of glucose metabolism. Collectively, these data suggest that the C1 cells mediate neuroendocrine responses (sympathoadrenal activation, CRF/ACTH/corticosteroid release) to acute stresses. We think that this view is closer to reality but still falls short of fully describing the role of the C1 neurons, especially during asphyxia and sleep. The present project is designed to test three novel hypotheses. First, activation of the C1 neurons contributes to the arousal effect of acute asphyxia/hypoxia. Second, the breathing stimulation caused by acute hypoxia/asphyxia is partly due to an excitatory input from the C1 neurons to the retrotrapezoid nucleus, a nearby collection of lower brainstem neurons that play a major role in the involuntary regulation of breathing. Third, the C1 neurons also regulate the circulation via the control that they exert over lower brainstem noradrenergic neurons (A5 and locus coeruleus). These hypotheses are supported by neuroanatomical evidence and by preliminary physiological evidence that stimulation of the C1 neurons increases breathing, causes EEG desynchronization and activates wake-promoting neurons such as the locus coeruleus. Our experimental approach is unique as it brings to bear the power of optogenetics to the study of cardiorespiratory integration. This approach, recently developed under the auspices of this grant, allows us to study the effects produced by selective activation of the C1 neurons in conscious rats in a time-controlled and artifact-free manner. The forthcoming results will have a significant impact on current knowledge of cardiorespiratory integration and of the mechanisms by which acute asphyxia produces arousal. These issues are paramount to understanding the effects of hypoxia on the cardiovascular system and the pathology of OSA, particularly the hypertension associated with this disease.

Public Health Relevance

A brief period of asphyxia activates breathing, blood pressure and the cardiac output. Asphyxia also produces arousal from sleep which enables corrective behavior for example in case of airway obstruction. These reflexes are essential for survival because they quickly restore tissue oxygenation. Unfortunately, they are also a common source of human pathology. In obstructive sleep apnea (OSA), a condition that affects roughly one person in 15 in the US, periodic asphyxia due to airway collapse disrupts sleep and causes a cohort of adverse health consequences including acute and chronic cardiovascular morbidity. Failure to arouse in response to asphyxia is equally problematic. It is characteristic of a rare genetic disease called congenital central hypoventilation syndrome and is a probable mechanism of sudden infant death syndrome (SIDS), the main cause of infant mortality in industrialized countries (5 per thousand live births). Our basic research seeks to understand the central nervous system mechanisms implicated in the effects of asphyxia on the cardiovascular and respiratory systems during sleep. This research focuses on specific neuronal networks located in the lower part of the brain called the medulla oblongata and its ultimate goal is to uncover novel treatments for OSA and other sleep-related respiratory disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL028785-32
Application #
8588947
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Maric-Bilkan, Christine
Project Start
1989-04-01
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
32
Fiscal Year
2014
Total Cost
$438,751
Indirect Cost
$153,848
Name
University of Virginia
Department
Pharmacology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Bochorishvili, Genrieta; Nguyen, Thanh; Coates, Melissa B et al. (2014) The orexinergic neurons receive synaptic input from C1 cells in rats. J Comp Neurol 522:3834-46
Abbott, Stephen B G; Holloway, Benjamin B; Viar, Kenneth E et al. (2014) Vesicular glutamate transporter 2 is required for the respiratory and parasympathetic activation produced by optogenetic stimulation of catecholaminergic neurons in the rostral ventrolateral medulla of mice in vivo. Eur J Neurosci 39:98-106
Abbott, Stephen B G; DePuy, Seth D; Nguyen, Thanh et al. (2013) Selective optogenetic activation of rostral ventrolateral medullary catecholaminergic neurons produces cardiorespiratory stimulation in conscious mice. J Neurosci 33:3164-77
DePuy, Seth D; Stornetta, Ruth L; Bochorishvili, Genrieta et al. (2013) Glutamatergic neurotransmission between the C1 neurons and the parasympathetic preganglionic neurons of the dorsal motor nucleus of the vagus. J Neurosci 33:1486-97
Stornetta, Ruth L; Macon, Conrad J; Nguyen, Thanh M et al. (2013) Cholinergic neurons in the mouse rostral ventrolateral medulla target sensory afferent areas. Brain Struct Funct 218:455-75
Abbott, Stephen B G; Coates, Melissa B; Stornetta, Ruth L et al. (2013) Optogenetic stimulation of c1 and retrotrapezoid nucleus neurons causes sleep state-dependent cardiorespiratory stimulation and arousal in rats. Hypertension 61:835-41
Guyenet, Patrice G; Abbott, Stephen B G (2013) Chemoreception and asphyxia-induced arousal. Respir Physiol Neurobiol 188:333-43
Guyenet, Patrice G; Stornetta, Ruth L; Bochorishvili, Genrieta et al. (2013) C1 neurons: the body's EMTs. Am J Physiol Regul Integr Comp Physiol 305:R187-204
Bochorishvili, Genrieta; Stornetta, Ruth L; Coates, Melissa B et al. (2012) Pre-Botzinger complex receives glutamatergic innervation from galaninergic and other retrotrapezoid nucleus neurons. J Comp Neurol 520:1047-61
Kanbar, Roy; Depuy, Seth D; West, Gavin H et al. (2011) Regulation of visceral sympathetic tone by A5 noradrenergic neurons in rodents. J Physiol 589:903-17

Showing the most recent 10 out of 120 publications