The arterial chemoreflex increases breathing, sympathetic activity and arterial pressure during hypoxia (Hx); its over-activity is associated wit heart failure, hypertension and obstructive sleep apnea (OSA). OSA patients and animals experiencing intermittent hypoxia (IH) exhibit augmented chemoreflexes, sympathoexcitation and hypertension which persist beyond Hx episodes and contribute to increased morbidity and mortality. Carotid body chemoreceptors sense Hx and augment chemoafferent discharge that terminates in the nucleus tractus solitarii (nTS). Afferents release glutamate which binds to ionotropic glutamate receptors (iGluRs). The primary pathway thought to produce chemoreflex responses is from nTS to rostral ventrolateral medulla (RVLM). However, the paraventricular nucleus (PVN) is critical in modulating chemoreflex responses. We have shown in nTS that RVLM-projecting and catecholaminergic (TH+) PVN-projecting neurons are activated by Hx; and TH+ PVN-projecting neurons are critical for full expression of Hx ventilatory responses. Hx activates PVN neurons. Activation of spinal- and RVLM-projecting PVN neurons is minimal, but a substantial portion of activated PVN neurons project to nTS and contain CRF. Thus, a reciprocal nTS to PVN pathway may be critical to the Hx chemoreflex, possibly by activating nTS projections to RVLM. Reactive oxygen species (ROS) are vital signaling molecules and increases in ROS enhance sympathetic activity. ROS are produced in response to Hx, but our data indicate this may be limited by compensatory increases in ROS-catabolizing enzymes. Yet, increased ROS are involved in augmented cardiorespiratory responses in OSA patients. We have shown ROS enhance nTS discharge, nTS ROS contribute to augmented cardiorespiratory function after acute IH (AIH), and ROS catabolic enzyme mRNA and activity decrease after chronic IH (CIH). Because nTS TH+ neurons may play a role in the actions of ROS and PVN-projecting TH+ nTS neurons are strongly activated by Hx, ROS may strengthen reciprocal nTS to PVN pathway signaling. Our central hypothesis is that nTS catecholaminergic projections to the PVN augment the hypoxic cardiorespiratory response (HxCRR) by activating a reciprocal connection between PVN and nTS. Recruitment of this pathway enhances chemoreceptor to RVLM synaptic transmission in nTS. Increased ROS by repeated Hx strengthens this reciprocal pathway primarily through PVN iGluR and adrenergic activation.
Specific Aims : 1) Determine the extent to which PVN-projecting nTS neurons, and ROS and iGluRs as mediators, contribute to HxCRR and are important to plasticity in AIH and CIH. 2) Determine the extent to which PVN neurons, especially PVN neurons with projections to or from nTS, contribute to the HxCRR, are modulated by ROS, and participate in plasticity during AIH and CIH. 3): Determine the extent to which nTS neurons with PVN inputs, particularly RVLM-projecting nTS neurons, contribute to HxCRR, are modulated by ROS and contribute to plasticity in AIH and CIH.

Public Health Relevance

Obstructive Sleep Apnea (OSA) and many other disease states manifest as unstable breathing and hypertension; the central nervous system has been implicated in these pathophysiological responses but the site and mechanisms are not known. The possible role of reactive oxygen species in brainstem and forebrain regions vital for control of blood pressure and breathing also is unknown. Our studies will determine the importance of reactive oxygen species in brainstem and forebrain neurons, and the communication among them, in rat models of OSA with the expectation of understanding potential therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL098602-07
Application #
9405905
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Maric-Bilkan, Christine
Project Start
2009-12-01
Project End
2019-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Missouri-Columbia
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Ostrowski, Tim D; Dantzler, Heather A; Polo-Parada, Luis et al. (2017) H2O2 augments cytosolic calcium in nucleus tractus solitarii neurons via multiple voltage-gated calcium channels. Am J Physiol Cell Physiol 312:C651-C662
Coldren, K Max; Li, De-Pei; Kline, David D et al. (2017) Acute hypoxia activates neuroendocrine, but not presympathetic, neurons in the paraventricular nucleus of the hypothalamus: differential role of nitric oxide. Am J Physiol Regul Integr Comp Physiol 312:R982-R995
Matott, Michael P; Kline, David D; Hasser, Eileen M (2017) Glial EAAT2 regulation of extracellular nTS glutamate critically controls neuronal activity and cardiorespiratory reflexes. J Physiol 595:6045-6063
Kline, David D (2017) Tuning excitability of the hypothalamus via glutamate and potassium channel coupling. J Physiol 595:4583-4584
Matott, Michael P; Ruyle, Brian C; Hasser, Eileen M et al. (2016) Excitatory amino acid transporters tonically restrain nTS synaptic and neuronal activity to modulate cardiorespiratory function. J Neurophysiol 115:1691-702
Matott, Michael P; Kline, David D (2016) Activation of 5-hyrdoxytryptamine 7 receptors within the rat nucleus tractus solitarii modulates synaptic properties. Brain Res 1635:12-26
King, T Luise; Ruyle, Brian C; Kline, David D et al. (2015) Catecholaminergic neurons projecting to the paraventricular nucleus of the hypothalamus are essential for cardiorespiratory adjustments to hypoxia. Am J Physiol Regul Integr Comp Physiol 309:R721-31
Ostrowski, T D; Hasser, E M; Heesch, C M et al. (2014) H?O? induces delayed hyperexcitability in nucleus tractus solitarii neurons. Neuroscience 262:53-69
Ostrowski, Tim D; Ostrowski, Daniela; Hasser, Eileen M et al. (2014) Depressed GABA and glutamate synaptic signaling by 5-HT1A receptors in the nucleus tractus solitarii and their role in cardiorespiratory function. J Neurophysiol 111:2493-504
King, T Luise; Kline, David D; Ruyle, Brian C et al. (2013) Acute systemic hypoxia activates hypothalamic paraventricular nucleus-projecting catecholaminergic neurons in the caudal ventrolateral medulla. Am J Physiol Regul Integr Comp Physiol 305:R1112-23

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