Multi-Scale Models of Neural Mechanisms Controlling Breathing in Mammals

本研究涉及进一步开发和测试新的神经动力学模型，包括在啮齿动物脑干中平行实验研究的呼吸神经控制系统的神经元和网络。不断发展的基于数据的模型包括：(1)脑干呼吸神经元的生物物理逼真的细胞水平计算模型，特别是在吸气振荡器（preBotzinger复合物）中，结合细胞结构和生物物理特性的当前信息，如神经元活动背后的离子电导机制；(2)结合现有网络功能和结构结构信息的脑干呼吸神经网络多尺度模型。这些建模研究的总体目标是获得对细胞和电路级特性集成到微电路以及哺乳动物呼吸神经控制系统动态操作的大规模呼吸网络的方式的机制见解。目前，一种新的啮齿类动物脑干呼吸中枢模式发生器（CPG）网络模型正在进一步发展，该模型由相互作用的兴奋和抑制子网络组成，这些子网络分布在顺序排列的脑干结构室中，每个子网络在正常的吸气和呼气呼吸周期中进化的呼吸神经活动模式的产生和控制中具有不同的功能作用。该CPG模型中使用的基本网络结构和细胞特性来源于大鼠和小鼠脑干-脊髓原位电生理和神经解剖学重建研究，以及在体外活性回路的活脑干切片制备中分离的子网络。这些模型还纳入了通过建模传入输入信号对不同电路组件的调节，包括来自关键神经调节控制系统的节律性和张力性活跃输入，这些系统已知参与呼吸活动模式产生的调节。对于CPG网络运行的分析，还应用了动力系统理论的方法来识别电路运行的关键动态变量和参数，这些变量和参数是呼吸节律产生的基础，并控制着吸气和呼气神经活动的不同功能阶段之间的有序转换。正在进行的微电路和大规模网络模型的计算机模拟能够模拟在不同体外和原位条件下实验发现的单细胞和神经元群体活动模式的许多特征，包括在电路活动的光遗传学操作期间。从实验研究中得出的一个主要的新假设，正在用这些模型进一步验证，即在细胞和网络组织的多个层面上，呼吸CPG中存在产生振荡活动的能力，形成了一个强大的振荡机制动力系统。因此，呼吸节律产生的不同机制可以以脑状态依赖的方式在功能上表达，并成为多种呼吸运动行为的基础，其中一些发生在各种正常生理条件下，另一些出现在病理生理条件下，如严重脑缺氧（异常低氧条件）和相关的呼吸回路突触抑制失败。不同层次的细胞和网络复杂性模型的模拟进一步证实了这一概念的合理性，并提供了对所涉及的基本细胞和网络机制的见解。我们还继续在大型分布式并行处理系统上实施涉及集群计算的仿真方法，包括NIH Biowulf高性能计算集群，允许大规模网络模型的实时仿真。在系统水平上，呼吸神经控制系统的模型之前已经开发出来，将基本神经回路动力学与外周呼吸泵力学、氧气和二氧化碳交换、血气运输以及通过血液/大脑氧气和二氧化碳水平等信号对中枢呼吸回路的生理反馈调节结合起来。这些模型在开环和闭环模型配置中评估了系统级的操作和控制。这些模型代表了第一代系统级控制模型，集成了神经系统结构功能特性的基本要素和呼吸气体交换和运输系统的现实特征。所有这些模型目前都被应用于进一步探索脑干呼吸回路的运作原理和呼吸活动的控制，包括在与大脑和身体氧/二氧化碳稳态紊乱相关的各种（病理）生理条件下。

This research involved the further development and testing of novel neurodynamical models of neurons and networks comprising the respiratory neural control system as studied experimentally in parallel in the rodent brainstem. Data-based models under continuous development included: (1) biophysically realistic cellular-level computational models of brainstem respiratory neurons especially in the inspiratory oscillator (the preBotzinger complex) incorporating current information on cellular architecture and biophysical properties such as ionic conductance mechanisms underlying neuronal activity; and (2) multi-scale models of brainstem respiratory neural networks incorporating available information on network functional and structural architecture. The overall objective of these modeling studies was to gain mechanistic insights into the manner in which cellular- and circuit-level properties are integrated into microcircuits as well as large-scale respiratory networks for the dynamical operation of the mammalian respiratory neural control system. A new model of respiratory central pattern generator (CPG) networks in the rodent brainstem is currently being further developed consisting of interacting excitatory and inhibitory subnetworks distributed in serially arranged brainstem structural compartments, each with distinct functional roles in the generation and control of the respiratory neural activity patterns that evolve during the normal breathing cycle of inspiration followed by expiration. The basic network architecture and cellular properties used in this CPG model are derived from electrophysiological and neuroanatomical reconstruction studies conducted in the rat and mouse brainstem-spinal cord in situ and on subnetworks isolated in living brainstem slice preparations with active circuits in vitro. These models also incorporate regulation of different circuit components by modeled afferent input signals, including rhythmically- and tonically-active inputs from critical neuromodulatory control systems that are known to be involved in the regulation of respiratory activity pattern generation. For analyses of CPG network operation, methods from dynamical systems theory are also applied to identify critical dynamical variables and parameters of circuit operation that underlie respiratory rhythm generation and control the orderly transitions between the functionally distinct phases of inspiratory and expiratory neural activity. In-progress computer simulations with the microcircuit and large-scale network models are able to mimic many features of the single-cell and neuron population activity patterns found experimentally under different in vitro and in situ conditions, including during optogenetic manipulations of circuit activity. A major new hypothesis derived from experimental studies and is being further tested with these models is that the capability to generate oscillatory activity exists within the respiratory CPG at multiple levels of cellular and network organization, forming a robust dynamical system of oscillatory mechanisms. Thus different mechanisms of respiratory rhythm generation can be functionally expressed in a brain state-dependent manner and underlie multiple respiratory motor behaviors, some of which occur under various normal physiological conditions and others of which emerge under pathophysiological conditions such as during severe brain hypoxia (conditions of abnormally low oxygen) and associated failure of synaptic inhibition in respiratory circuits. Simulations with models of different levels of cellular and network complexity are further confirming the plausibility of this concept and have provided insights into the essential cellular and network mechanisms involved. We have also continued implementation of simulation approaches involving cluster computing on large distributed parallel processing systems including the NIH Biowulf high-performance computing cluster that allow real-time simulation of large-scale network models. At the system level, models of the respiratory neural control system were previously developed that couple essential neural circuit dynamics with peripheral respiratory pump mechanics, oxygen and carbon dioxide exchange, blood gas transport, and physiological feedback regulation of central respiratory circuits by signals such as blood/brain levels of oxygen and carbon dioxide. These models have evaluated system-level operation and control in open- and closed-loop model configurations. These models represent the first generation of system-level control models that integrate essential elements of nervous system structural-functional properties and realistic features of the respiratory gas exchange and transport system. All of these models are currently being applied to further explore principles of operation of brainstem respiratory circuits and control of respiratory activity including under various (patho)physiological conditions associated with disturbances of brain and body oxygen/carbon dioxide homeostasis.