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Role of Oxytocin Neurons in Obstructive Sleep Apnea Mediated Cardiovascular Disease Open Access

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Recent work has shown oxytocin (OXT), a neuropeptide released from parvocellular neurons in the paraventricular nucleus of the hypothalamus (PVN), could be cardioprotective by exciting parasympathetic cardiac vagal neurons (CVNs) in the brainstem and reducing cardiovascular responses to stress. Obstructive sleep apnea (OSA) is a very common, yet poorly understood disease that increases the incidence of hypertension, tachycardia, stroke and other adverse cardiovascular events. For this study I test the hypotheses that the release of OXT from PVN neurons onto CVNs is diminished with exposure to chronic intermittent hypoxia-hypercapnia (CIH/H), an animal model of OSA, and furthermore, selective activation of PVN OXT neurons can reduce adverse cardiovascular consequences, particularly the elevation of blood pressure to hypertensive levels, that occur with CIH/H. In order to elucidate the conditions required for OXT release from PVN fibers, we engineered and dispersed within the brainstem sniffer Chinese Hamster Ovarian (CHO) cells highly sensitive to oxytocin. These sniffer CHO cells were stably transfected to express the human recombinant OXT receptor, and calcium changes within these cells were visualized as these cells were also made to express the red fluorescent calcium indicator, R-GECO1. Our data show optogenetic stimulation of channelrhodopsin-2 –expressing hypothalamic PVN fibers in the brainstem evoked large, reproducible, and transient increases in calcium within sniffer CHO cells that are in close proximity to OXT fibers. The photostimulation-elicited increase in calcium in the sniffer CHO cells upon PVN fiber activation was abolished by application of the oxytocin receptor antagonist, OTA. In animals exposed to 21 days of CIH/H the OXT dependent calcium increases in CHO cells upon photoactivation of PVN fibers were blunted. This finding indicates there is reduced oxytocin neuron activity following CIH/H, and that reduced oxytocin neuron activity and/or function could contribute to the adverse cardiovascular events associated with OSA. We next tested if restoration of OXT neuron activity could prevent the adverse cardiovascular effects of CIH/H in vivo. To test this hypothesis we selectively expressed excitatory designer receptors exclusively activated by designer drugs (DREADDs) in PVN OXT neurons, and implanted animals with telemetry devices to monitor blood pressure and EKG activity. Selective chronic activation of PVN OXT neurons decreased resting blood pressure and heart rate, blunted the responses to acute hypoxia/hypercapnia, and perhaps more importantly, chronic PVN OXT neuron activation prevented the elevations in blood pressure and heart rate that occur with CIH/H. These results indicate that excitation of parvocellular PVN fibers releases OXT at brainstem CVN targets, selective activation of OXT neurons in the PVN decreases resting blood pressure and heart rate, and chronic activation of oxytocin neurons in the PVN prevents the elevations in blood pressure and heart rate that occur after 21 days of CIH/H.

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