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高血压的发生中起相关作用。高血压患者，特别是顽固性高血压患者，经常报告交感神经活动过度。这种情况也在大部分患有阻塞性睡眠呼吸暂停（OSA）的患者中观察到。慢性间歇性缺氧（CIH）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引起的神经系统的变化，加强交感神经活动的发展仍在调查中。我们以前证明，CIH治疗大鼠的基线交感神经活动水平较高，与在含氧量正常/碳酸量正常条件下出现的主动呼气模式密切相关。这些研究结果表明，提供呼气运动活动及其与交感神经系统的相互作用的中枢机制的变化在CIH条件下的交感神经过度活跃中起着至关重要的作用。产生呼气运动输出所需的神经基质，以响应环境的挑战和它们与交感神经活动的相互作用仍然是未知的。因此，本项目的重点是研究两个神经振荡器可能参与呼吸和交感神经活动的动态控制，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中的呼吸中枢模式发生器（CPG）。该CPG的核心由前B tzinger（pre-B tzinger）复合物（pre-B tC）和B tzinger复合物（B tzinger）组成，它们一起产生控制肺运动的呼吸振荡。第二个振子称为面旁呼吸群（parasfacial respiratory group，pFRG），位于斜方后核（retrotrapezoidal nucleus，RTN）内，位于B tC的吻侧.在某些条件下出现的pFRG振荡与B tC/前B tC振荡同步，并驱动表达的呼气运动活动。这两个振荡器都需要脑桥紧张性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，以在交感驱动中产生状态依赖的呼吸相关振荡。有人提出CIH暴露在这些中枢交感神经机制中引入了可塑性变化，这些机制有助于增强基线交感神经活动。然而，关于pFRG振荡的确切生理作用、其出现的具体条件以及其在健康和疾病状态下与交感神经系统的耦合仍然存在激烈的争论。在本研究中，我们的目标是建立一个多尺度的计算模型的神经心肺网络，这将有助于揭示中枢机制的交感神经过度活跃与OSA。我们将通过结合计算和数学建模以及电生理学和免疫组织化学实验来实现这一目标。总体目标是研究：（i）参与B β tC/pre-B β tC和pFRG振荡器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的作用：休息，缺氧和高碳酸血症;和（iii）CIH诱导的交感传出活动中pFRG相关成分出现的神经机制。 智力优势：智力上的优点在于，这将是第一个全面的计算模型的中央交感神经-呼吸网络，将提供细胞水平的分辨率的心脏呼吸耦合在健康和疾病。这项研究将导致更好地了解自主神经功能障碍，如神经源性高血压，并将有助于设计新的治疗策略。 更广泛的影响：拟议的研究将产生更广泛的影响，因为它将作为神经振荡回路建模的基石。模型将公开提供。它将 还通过培训研究生和医学博士生，促进参与该项目的所有三个机构的研究和教育一体化。到项目结束时，所有开发的模型将被集成到NIH Biowulf分布式并行计算系统中，并通过NIH提供给神经科学家。该项目代表了三位年轻研究人员之间最近形成的独特合作，其中没有一位曾在任何政府或校外资助中担任PI或Co-PI。其中一位合作PI，Ana Abdala博士是一位非常富有成效的女性神经科学家。

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.