CRCNS: Modeling the respiratory-sympathetic coupling in neurogenic hypertension

CRCNS：神经源性高血压中呼吸交感神经耦合的建模

• 批准号: 8837111
• 负责人: Yaroslav Molkov
• 金额: $ 29.91万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2016-01-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8837111
• 关键词: Abdomen; Adult; Affect; Animals; Antihypertensive Agents; Autonomic Dysfunction; Blood Pressure; Brain Stem; Breathing; Calculi; Cardiovascular system; Cell Nucleus; Cephalic; Chronic; Clinical; Collaborations; Complex; Computer Simulation; Computer Systems; Coupled; Coupling; Data; Development; Disease; Education; Exposure to; Extramural Activities; Female; Functional disorder; Funding; Goals; Government; Health; Heating; Hypercapnia; Hypertension; Hypoxia; Individual; Institution; Investigation; Lead; Link; Lung; Maintenance; Metabolic; Modeling; Motor; Motor Activity; Motor output; Movement; Nerve; Nervous system structure; Neurons; Norepinephrine; Obstructive Sleep Apnea; Patients; Pattern; Phase; Physiological; Plasma; Plastics; Play; Pontine structure; Population; Process; Property; Public Health; Rattus; Recurrence; Refractory; Reporting; Research; Research Personnel; Resistance; Resistant Hypertension; Resolution; Respiration; Rest; Rodent Model; Role; Shapes; Sleep; Spinal; Students; Sympathetic Nervous System; Synapses; System; Testing; Training; United States National Institutes of Health; Vasomotor; base; central pattern generator; design; expiration; hypertension treatment; mathematical model; multi-scale modeling; neural model; neurogenic hypertension; neuromechanism; novel; novel therapeutics; parallel computer; relating to nervous system; research study; respiratory; response; training project; treatment strategy

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.

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发挥着相关作用。在高血压患者中，特别是在顽固性高血压患者中，经常观察到这种情况。阻塞性睡眠呼吸暂停 (OSA) 患者中发生的慢性暴露于间歇性缺氧 (CIH) 的比例被认为是导致交感神经过度活跃和高血压的主要因素。 CIH 引起的神经系统变化仍在研究中，这些变化支撑着交感神经活动增强的发展，我们之前证明，接受 CIH 治疗的大鼠基线交感神经活动水平较高，与常氧/正常二氧化碳条件下主动呼气模式的出现相关。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在 CIH 条件下交感神经过度活跃中发挥着重要作用，从而产生呼气运动输出以应对环境挑战。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器，以揭示 CIH/OSA 条件下交感神经过度活跃的神经机制。第一个振荡器是位于脑干的呼吸中枢模式发生器（CPG），该 CPG 的核心由前 B¿ tzinger（B¿tC 之前）和 B¿t tzinger 复合体 (B¿tC) 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 的喙部。梯形后核 (RTN) 中的 tC 在某些条件下出现的 pFRG 振荡与 B¿ tC/pre-B¿ tC 振荡并驱动表达的呼气运动活动。有人提出，这些呼吸回路与交感神经系统相互作用，以在交感神经驱动中产生状态依赖性呼吸相关振荡。 CIH 暴露会导致这些中枢呼吸交感神经机制发生塑性变化，从而有助于增强基线交感神经活动。然而，对于 CIH 的确切生理作用仍存在激烈争论。 pFRG 振荡、其出现的具体条件以及它们在健康和疾病状态下与交感神经系统的耦合在本研究中，我们的目标是建立神经心肺网络的多尺度计算模型，这将有助于揭示交感神经过度活跃的中心机制。我们将通过结合计算和数学模型以及电生理学和免疫组织化学实验来研究：(i) B¿ 之间相互作用的神经机制。 tC/pre-B¿ tC 和 pFRG 振荡器，(ii) 在不同代谢条件下（静息、缺氧和高碳酸血症）这些相互作用在塑造协调呼吸和交感运动输出方面的作用；以及 (iii) CIH 诱导的 pFRG 相关成分出现的神经机制；交感活动。 智力优点：智力优点在于，这将是中枢交感呼吸网络的第一个综合计算模型，它将提供健康和疾病中心肺耦合的细胞水平分辨率。这项研究将带来更好的理解。神经源性高血压等自主神经功能障碍的研究，并将有助于新治疗策略的设计。 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，它将公开。 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，所有开发的模型都将集成到 NIH Biowulf 分布式并行计算系统中，并通过该项目代表了三位年轻研究人员最近形成的独特合作，他们都没有担任过任何政府或外部资助的 PI 或 Co-PI，其中一位 Co-PI 博士 Ana Abdala 是一位非常出色的人。多产女性神经科学家。