Dysfunctions of the mechanisms controlling sympathetic activity play a relevant role in the development of arterial hypertension. Excessive sympathetic activity is often reported in patients with hypertension, especially those with resistant hypertension. Such scenario is also observed in a large proportion of patients with obstructive sleep apnea (OSA). Chronic exposure to intermittent hypoxia (CIH) that occurs in OSA is considered a major factor leading to sympathetic overactivity and hypertension. However, the CIH-elicited changes in the nervous system that underpin the development of augmented sympathetic activity are still under investigation. We previously demonstrated that the higher levels of baseline sympathetic activity of CIH-treated rats strongly correlate with the emergence of active expiratory pattern at normoxic/normocapnic conditions. These findings indicate that changes in the central mechanisms providing expiratory motor activity and its interaction with sympathetic nervous systems play an essential role in sympathetic overactivity in CIH conditions. The neural substrates required for generating expiratory motor outputs in response to environmental challenges and their interactions with sympathetic activity are still unidentified. Therefore, this project focuses on the investigation of two neural oscillators potentially involved in the dynamic control of breathing and sympathetic activity, in order to reveal the neural mechanisms underlying sympathetic overactivity in CIH/OSA conditions. The first oscillator is the respiratory central pattern generator (CPG) located in the brainstem. The core of this CPG is composed of pre-Btzinger (pre-BtC) and Btzinger complexes (BtC) which together generate respiratory oscillations controlling lung movements. The second oscillator, termed the parafacial respiratory group (pFRG), resides rostally to BtC in the retrotrapezoid nucleus (RTN). The pFRG oscillations, emerging in certain conditions, are synchronized with the BtC/pre-BtC oscillations and drive an expressed expiratory motor activity. Both oscillators require pontine tonic drive for coordinating cranial and spinal motor outflows. These respiratory circuits interact with the sympathetic nervous system to generate state-dependent respiratory related oscillations in sympathetic drive. It has been proposed that CIH exposure introduces plastic changes in these central respiratory-sympathetic mechanisms that contribute to enhance baseline sympathetic activity. However, there are still heated debates on the exact physiological role of pFRG oscillations, the specific conditions for their emergence and their coupling with sympathetic nervous system in health and disease states. In the present study we aim to build a multi-scale computational model of the neural cardiorespiratory network that will help reveal central mechanisms underlying sympathetic overactivity associated with OSA. We will do so by combining computational and mathematical modeling and electrophysiological and immunohistochemical experiments. The overall goals are to investigate: (i) the neural mechanisms involved in the interactions between BtC/pre-BtC and pFRG oscillators, (ii) the role of these interactions in shaping coordinated respiratory and sympathetic motor outputs under different metabolic conditions: resting, hypoxia and hypercapnia; and (iii) the neural mechanisms underlying the CIH-induced emergence of pFRGrelated component in the sympathetic efferent activity. Intellectual Merit: The intellectual merit lies on the fact that this will be the first comprehensie computational model of the central sympathetic-respiratory network that will provide cellular level resolution of cardio-respiratory coupling in health and disease. This study will lead to a better understanding of autonomic dysfunctions such as neurogenic hypertension, and will contribute to the design of new treatment strategies. Broader Impacts: The proposed studies will have broader impacts as it will serve as corner stone for the modeling neural oscillatory circuits. Models will be made available publicly. It will also promote integration of research and education at all three institutions involved in the projec by training graduate and MD students. By the end of the project, all developed models will be integrated into the NIH Biowulf distributed parallel computing system and made available to neuroscientists through the NIH. This project represents a unique, recently formed collaboration among three young researchers, none of which has ever served as a PI or a Co-PI in any government or extramural funding. One of Co-PIs, Dr Ana Abdala, is an extremely productive female neuroscientist.
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