CRCNS: Modeling the respiratory-sympathetic coupling in neurogenic hypertension

描述（由申请人提供）：控制交感神经活动的机制功能障碍在动脉性高血压的发生中起相关作用。过度交感神经活动常见于高血压患者，尤其是顽固性高血压患者。这种情况也见于很大比例的阻塞性睡眠呼吸暂停（OSA）患者。慢性暴露于间歇性缺氧（CIH）发生在OSA被认为是导致交感神经过度活跃和高血压的主要因素。然而，cih引起的神经系统变化是增强交感神经活动发展的基础，目前仍在研究中。我们之前已经证明，高水平的基线交感神经活动与常压/常压条件下活跃呼气模式的出现密切相关。这些发现表明，提供呼气运动活动的中枢机制及其与交感神经系统的相互作用的变化在CIH条件下交感神经过度活动中起重要作用。在环境挑战下产生呼气运动输出所需的神经基质及其与交感神经活动的相互作用仍不清楚。因此，本项目重点研究可能参与呼吸和交感神经活动动态控制的两种神经振荡，以揭示CIH/OSA条件下交感神经过度活动的神经机制。第一个振荡器是位于脑干的呼吸中枢模式发生器（CPG）。该CPG的核心是由pre-B¿tzinger （pre-B¿tC）和B¿tzinger复合物（B¿tC）组成，它们共同产生控制肺运动的呼吸振荡。第二个振荡器称为面旁呼吸群（pFRG），主要位于后梯形核（RTN）的B¿tC。在某些条件下出现的pFRG振荡与B¿tC/ B¿tC前振荡同步，并驱动表达的呼气运动活动。这两种振荡器都需要脑桥强直驱动来协调颅和脊髓运动流出。这些呼吸回路与交感神经系统相互作用，在交感驱动中产生状态依赖的呼吸相关振荡。有研究认为，暴露于高氧联苯会导致这些中枢呼吸-交感神经机制发生可塑性变化，从而增强交感神经活动基线。然而，关于pFRG振荡的确切生理作用、其产生的具体条件以及在健康和疾病状态下与交感神经系统的耦合，目前仍存在激烈的争论。在本研究中，我们旨在建立一个神经心肺网络的多尺度计算模型，这将有助于揭示与OSA相关的交感神经过度活动的中枢机制。我们将通过结合计算和数学建模以及电生理和免疫组织化学实验来做到这一点。总体目标是研究：(i) B¿tC/前B¿tC和pFRG振荡之间相互作用的神经机制，（ii）这些相互作用在不同代谢条件下形成协调的呼吸和交感运动输出中的作用：静息、缺氧和高碳血症；（iii） cih诱导交感神经传出活动中pfr相关成分出现的神经机制。

DESCRIPTION (provided by applicant): 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-B¿tzinger (pre-B¿tC) and B¿tzinger complexes (B¿tC) which together generate respiratory oscillations controlling lung movements. The second oscillator, termed the parafacial respiratory group (pFRG), resides rostally to B¿tC in the retrotrapezoid nucleus (RTN). The pFRG oscillations, emerging in certain conditions, are synchronized with the B¿tC/pre-B¿tC 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 B¿tC/pre-B¿tC 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.