Sleep apnea poses a significant health risk and has rapidly gained recognition as a common co-morbid factor in patients diagnosed with metabolic syndrome. Epidemiological studies have revealed a strong association between sleep apnea and increased blood pressure and exaggerated sympathetic nerve discharge, even during the daytime when apneic episodes are not occurring. Chronic exposure to intermittent hypoxia (CIH) during the nocturnal period in animals mimics the repetitive bouts of arterial hypoxemia that occur during sleep apnea. Rats exposed to CIH develop a persistently increased blood pressure as observed in humans with sleep apnea. There is a surprising paucity of information concerning how sleep apnea and CIH alter synaptic processing among sympathetic regulatory neurons and how these alterations lead to a persistent rise in sympathetic nerve discharge and a sustained increase in blood pressure. The Program objectives are to address mechanisms within the central nervous system that mediate CIH-induced hypertension and elevated sympathetic nervous system activity and to provide insights into potential therapeutic targets and strategies. Our work has demonstrated that the persistent increase in blood pressure during the first 7 days of exposure to CIH is dependent upon arterial chemoreceptors and angiotensin (ANG II) acting within the forebrain. Three projects are proposed which will utilize state-of-the-art neuroanatomical, in vivo and in vitro electrophysiological and molecular approaches to provide a comprehensive analysis of the central circuitry mediating the persistent increase in blood pressure induced by CIH. Project 1, led by S. Mifflin, will test the hypothesis that repetitive activation of the arterial chemoreceptors by CIH induces activity-dependent changes in neurons in the nucleus of the solitary tract (NTS) that regulate sympathetic and HPA axis function. Project 2, led by T. Cunningham, will test the hypothesis that increased activity of the renin-angiotensin system during CIH induces activity-dependent changes in neurons in the lamina terminalis that project to the PVN and increase sympathetic outflow. Project 3, led by G. Toney, will test the hypothesis that chemoreceptor- and ANG ll-sensitive inputs induce activity-dependent changes in sympatho-excitatory PVN neurons that increase their discharge and excitability. Achieving the goals of these projects will be facilitated by 4 Core facilities (Administrative, Animal, Neuroanatomy, Biochemical/Molecular). The studies will determine mechanisms that mediate neuronal plasticity and are important in the development of CIH-hypertension. The proposed studies will identify sites and mechanisms that could be beneficial therapeutic targets in sleep apnea patients. The results will also have relevance to our understanding of other conditions associated with central nervous system hypoxia (heart failure, stroke) and other sodium-dependent and ANG ll-dependent models of hypertension (obesity).

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Thrasher, Terry N
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University of North Texas
Other Domestic Higher Education
Fort Worth
United States
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Faulk, Katelynn; Shell, Brent; Nedungadi, T Prashant et al. (2017) Role of angiotensin-converting enzyme 1 within the median preoptic nucleus following chronic intermittent hypoxia. Am J Physiol Regul Integr Comp Physiol 312:R245-R252
Snyder, Brina; Shell, Brent; Cunningham, J Thomas et al. (2017) Chronic intermittent hypoxia induces oxidative stress and inflammation in brain regions associated with early-stage neurodegeneration. Physiol Rep 5:
Shell, Brent; Faulk, Katelynn; Cunningham, J Thomas (2016) Neural Control of Blood Pressure in Chronic Intermittent Hypoxia. Curr Hypertens Rep 18:19
Carmichael, C Y; Carmichael, A C T; Kuwabara, J T et al. (2016) Impaired sodium-evoked paraventricular nucleus neuronal activation and blood pressure regulation in conscious Sprague-Dawley rats lacking central G?i2 proteins. Acta Physiol (Oxf) 216:314-29
Mifflin, Steve; Cunningham, J Thomas; Toney, Glenn M (2015) Neurogenic mechanisms underlying the rapid onset of sympathetic responses to intermittent hypoxia. J Appl Physiol (1985) 119:1441-8
Holbein, Walter W; Toney, Glenn M (2015) Activation of the hypothalamic paraventricular nucleus by forebrain hypertonicity selectively increases tonic vasomotor sympathetic nerve activity. Am J Physiol Regul Integr Comp Physiol 308:R351-9
Yamamoto, Kenta; Lalley, Peter; Mifflin, Steve (2015) Acute intermittent optogenetic stimulation of nucleus tractus solitarius neurons induces sympathetic long-term facilitation. Am J Physiol Regul Integr Comp Physiol 308:R266-75
Saxena, Ashwini; Little, Joel T; Nedungadi, T Prashant et al. (2015) Angiotensin II type 1a receptors in subfornical organ contribute towards chronic intermittent hypoxia-associated sustained increase in mean arterial pressure. Am J Physiol Heart Circ Physiol 308:H435-46
Saxena, Ashwini; Bachelor, Martha; Park, Yong H et al. (2014) Angiotensin II induces membrane trafficking of natively expressed transient receptor potential vanilloid type 4 channels in hypothalamic 4B cells. Am J Physiol Regul Integr Comp Physiol 307:R945-55
Holbein, Walter W; Bardgett, Megan E; Toney, Glenn M (2014) Blood pressure is maintained during dehydration by hypothalamic paraventricular nucleus-driven tonic sympathetic nerve activity. J Physiol 592:3783-99

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