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展中起着相关的作用。交感神经活动过度常见于高血压患者，尤其是顽固性高血压患者。这种情况在很大一部分阻塞性睡眠呼吸暂停(OSA)患者中也可以观察到。OSA患者长期暴露于间歇性低氧(CIH)被认为是导致交感神经过度活动和高血压的主要因素。然而，CIH引起的神经系统变化仍在调查中，这些变化支撑着交感神经活动增强的发展。我们先前证明，CIH处理的大鼠的基础交感神经活动水平较高，与常氧/常二氧化碳条件下主动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的改变及其与交感神经系统的相互作用在CIH条件下交感神经过度活动中起着重要作用。产生呼气运动输出以响应环境挑战所需的神经底物及其与交感神经活动的相互作用仍未确定。因此，本项目重点研究两种神经振荡器，它们可能参与呼吸和交感神经活动的动态控制，以揭示在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)。这种CPG的核心是由Pre-B�tzinger(Pre-B�tC)和B�tzinger Complex(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)，位于B�tC的斜方后核内。在特定条件下出现的pFRG振荡与B�tC/Pre-B�tC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张力驱动，以协调头颅和脊髓的运动流出。这些呼吸回路与交感神经系统相互作用，在交感神经驱动下产生状态依赖的呼吸相关振荡。已经有人提出，接触CIH会导致这些中枢呼吸-交感机制发生可塑性变化，从而有助于增强基线交感活动。然而，关于pFRG振荡的确切生理作用、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，仍存在激烈的争论。在目前的研究中，我们的目标是建立一个神经心肺网络的多尺度计算模型，这将有助于揭示与阻塞性睡眠呼吸暂停相关的交感神经过度活动的中枢机制。我们将通过将计算和数学建模以及电生理和免疫组织化学实验相结合来实现这一点。我们的总体目标是研究：(I)B-�tC/Pre-B-�tC与pFRG振荡器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；以及(Iii)CIH诱导交感传出活动中pFRG相关成分出现的神经机制。 智力价值：智力的价值在于这样一个事实，即这将是第一个全面的中枢交感-呼吸网络计算模型，将提供健康和疾病中心肺耦合的细胞水平分辨率。这项研究将有助于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，因为它将成为神经振荡电路建模的基石。模型将公开提供。会的 还通过培训研究生和医学博士研究生，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，所有开发的模型都将集成到NIH Biowulf分布式并行计算系统中，并通过NIH提供给神经科学家。这个项目代表了三位年轻研究人员最近形成的一项独特的合作，他们中没有一人在任何政府或外部资金中担任过PI或Co-PI。合作伙伴之一Ana Abdala博士是一位工作效率极高的女性神经学家。

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.