CRCNS: Modeling the respiratory-sympathetic coupling in neurogenic hypertension

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Excessive sympathetic activity plays a crucial role in the development and maintenance of hypertension. Such autonomic dysfunction is observed in hypertensive patients with obstructive sleep apnea (OSA). Chronic exposure to intermittent hypoxia (CIH) that occurs in OSA is the main factor leading to sympathetic overactivity and hypertension. A CIH-driven increase in sympathetic output is largely dependent on the emergence of active expiratory pattern. The respiratory central pattern generator (rCPG) is composed of two interacting oscillators. The first occupies B6tzinger/pre-B6tzinger complexes and generates self-sustained respiratory rhythm controlling the diaphragm to provide inspiration. The second oscillator, the parafacial respiratory group (pFRG), resides in the retrotrapezoid nucleus (RTN). The RTN/pFRG oscillations emerge in hypoxic and hypercapnic conditions, and drive motor output to abdominal muscles for active (forced) expiration. Interactions of these respiratory circuits with the sympathetic neurons ofthe rostral and caudal ventrolateral medulla evoke respiratory-related oscillations in sympathetic efferent drive. Exposure to CIH leads to alterations in excitability of RTN/pFRG neuronal population and/or modiflcations in synaptic connections between respiratory oscillators and sympathetic neurons which ultimately results in the elevated baseline sympathetic activity and arterial pressure. This interdisciplinary project aims to reveal the mechanisms that couple breathing and control of blood pressure in the brain in health and disease, and for the first time translate them into a realistic computational model. Such a model will have the unprecedented potential for generating effective non-pharmacological means of controlling blood pressure and breathing via implantable biofeedback devices (e.g. vagus nerve stimulation) and non-invasive devices for guided control of autonomic function (e.g. device-guided paced respiration). Furthermore, it will provide a robust scientific substrate for evaluating the usefulness and safety of alternative and complementary medicine interventions, such as controlled breathing practices (e.g. through meditation and yoga), for lowering blood pressure and improving heart rate variability.