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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hypertension and Microcirculation Study Section (HM)
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Charette, Marc F
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University of Missouri-Columbia
Veterinary Sciences
Schools of Veterinary Medicine
United States
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