Multiscale Model of the Vagal Outflow to the Heart

项目总结 迷走神经控制心脏重新引起了人们的兴趣，这是因为现在公认的操纵心脏的潜力 心脏迷走神经活动为治疗心脏病提供新的治疗机会。最近的解剖和 生理证据表明，迷走神经的心脏控制在节前和节后都是多模式的。 神经元水平。多种控制模式之间的协调(例如，心率，心室收缩能力， 等)对心脏健康是必不可少的。这种协调能力的中断是心力衰竭和心律失常的标志， 例如。到目前为止，研究主要集中在迷走神经对心率的生理影响上。 不深入研究底层神经网络，其中的洞察力可能会产生细粒度的目标 操纵迷走神经活动来治疗心脏病。我们的项目旨在通过以下方式解决这一未得到满足的需求 重点放在中枢神经元和心脏神经节回路驱动计时器、液态器和离子- 向心性。我们将采用集成的多尺度建模策略，将细粒度的解剖学 控制电路的追踪和高通量的单个神经元转录分析 电路连通性，具有多尺度迷走神经闭环心脏控制的计算模型。这些 涉及血流动力学、脑干神经元网络和心脏神经节环路 协调的变力性和变时性心脏控制。我们将开发详细的电生理学 疑核和背侧运动核神经元兴奋性的模型 靶向心脏神经节，并结合冠脉结扎所识别的转录变化 在这些模型中进行实验。我们假设利率和利率控制的协调和整合 在NA/DMV水平和心脏神经节水平上发生的收缩能力是 保护心脏的迷走神经心脏流出。我们将在三个目标上检验这一假设：(1)发展多尺度 集成控制SA节点和左心室的关键模块的网络模型框架。(2)确定 影响协调性参与心脏功能调控的分子机制 将基因调控网络和神经网络行为联系起来。(3)选择中的测试模型预测 机能实验的操控。我们的多尺度计算建模框架将使我们能够 结合并解释实验的解剖学、转录和生理学结果。我们的 调查小组此前曾合作对压力反射进行建模，并包括 在提案的所有方面都有专门知识。我们的方法有望确定以下各项的相对贡献 脑干环路和心神经节环路对多模式迷走神经的协调控制。我们期望的是 结果，通过揭示潜在的分子和生理机制的来源和维持 协调迷走神经流出，对确定早期诊断、预防、 甚至还有治疗心脏病的新的姑息疗法。

PROJECT SUMMARY Vagal control of the heart has seen renewed interest due to the now well-recognized potential of manipulating cardiac vagal activity for novel therapeutic opportunities in treating heart disease. Recent anatomical and physiological evidence shows that vagal cardiac control is multimodal at both pre- and post-ganglionic neuronal levels. Coordination between multiple modes of control (e.g., of heart rate, ventricular contractility, etc) is essential for heart health. Disruption of such coordination is a hallmark of heart failure and arrhythmias, for example. Studies thus far have largely focused on the physiological effects of the vagus on heart rate without delving into the underlying neural networks, where insights are likely to yield targets for fine-grained manipulation of vagal activity to treat heart disease. Our project is aimed at addressing this unmet need by focusing on the central neuronal as well as cardiac ganglionic circuits driving chrono-, dromo- and iono- tropism. We will pursue an integrated multiscale modeling strategy that combines fine-grained anatomical tracing of control circuits and high-throughput transcriptional analysis of single neurons identified based on circuit connectivity, with computational modeling of the multiscale closed loop vagal cardiac control. These involve hemodynamics, brainstem neuronal networks, and cardiac ganglionic circuits involved in the coordinated inotropic and chronotropic control of the heart. We will develop detailed electrophysiological models of neuronal excitability in nucleus ambiguus (NA) and dorsal motor nucleus (DMV), as well as the targeted cardiac ganglia, and incorporate the transcriptional changes identified from coronary artery ligation experiments in these models. We hypothesize that coordination and integration of the control of rate and contractility occurring at the level of the NA/DMV and the level of the cardiac ganglia are the basis for cardioprotective vagal cardiac outflows. We will test this hypothesis in three Aims: (1) Develop a multiscale network model framework integrating the key modules controlling SA node and left ventricle. (2) Determine the molecular mechanisms affecting the coordination involved in cardiac functional control in heart disease by linking gene regulatory networks and neural network behavior. (3) Test model predictions in selective manipulation of function experiments. Our multiscale computational modeling framework will enable us to combine and interpret the anatomical, transcriptional, and physiological results from experiments. Our investigative team has previously collaborated in modeling the baroreflexes and comprises complementary expertise in all aspects of the proposal. Our approach is expected to identify the relative contribution of brainstem circuits and cardiac ganglionic circuits to the coordination of multimodal vagal control. Our expected results, by uncovering the molecular and physiological mechanisms underlying the source and maintenance of coordinated vagal outflows, have significant implications for identifying targets for early diagnosis, prevention, and even novel palliative therapy in treating heart disease.