CRCNS: State dependent neural mechanisms for respiratory pattern generation

描述（由申请人提供）：呼吸运动模式的生成在下脑干中进行，涉及细胞、网络和系统级机制的复杂跨级交互。由于这些复杂的相互作用，系统可以在不同的功能状态下运行，并在每个状态下采用不同的节律机制。我们假设呼吸网络中运行的节律机制（即基于网络、起搏器驱动或混合）是由前 Botzinger 复合体的状态定义的，而前 Botzinger 复合体又在其他髓质和脑桥回路的控制下运行。我们还认为，脑桥直接和/或通过其他髓质回路（例如 Botzinger 复合体）控制前 Botzinger 复合体的状态（从而控制节律发生机制）。这个多学科合作项目的总体目标是通过实验研究与计算模型相结合来调查和理解这些复杂的相互作用以及呼吸节律生成的状态依赖性。实验研究将由 Smith 博士（NINDS、NIH）和 Paton 博士（布里斯托大学）进行。应用的实验方法将包括（1）通过应用于脑桥和延髓的连续和高精度横断来减少运行的呼吸网络，以及（2）使用内在神经元特性的特定阻滞剂（例如持久性钠和其他离子通道）和网络相互作用（例如抑制性突触传递）应用于完整和减少的制剂。 Rybak 博士（德雷克塞尔大学）小组将与 Drs. Rybak 博士密切互动合作，进一步开发脑桥延髓呼吸网络的计算模型。史密斯和佩顿使用他们实验室积累的数据。反过来，这些实验室的补充实验研究将由建模预测驱动。将开发、测试和详细阐述由此产生的综合计算模型，以重现不同实验条件下实验观察到的呼吸神经元放电模式和输出运动神经（膈神经、舌下神经、中央迷走神经和腹部神经）放电模式的状态依赖性变化。拟议的合作研究将为控制呼吸的复杂神经机制提供重要见解。最终，该项目中开发的模型可用于模拟多种呼吸系统疾病（例如睡眠呼吸暂停、脑干/脊髓损伤、CCHS），并用于开发和研究治疗这些疾病的新方法。

DESCRIPTION (provided by applicant): Generation of the respiratory motor pattern is performed in the lower brainstem and involves complex cross-level interactions of cellular, network, and systems-level mechanisms. Because of these complex interactions, the system can operate in different functional states and engage different rhythmogenic mechanisms in each state. We hypothesize that the rhythmogenic mechanism operating in the respiratory network (i.e., network-based, pacemaker-driven or hybrid) is defined by the state of the pre-Botzinger complex, which in turn operates under control of other medullary and pontine circuits. We also suggest that the pons controls the state of the pre-Botzinger complex (and hence the rhythmogenic mechanism) directly and/or through other medullary circuits, such as the Botzinger complex. The overall goal of this multidisciplinary collaborative project is to investigate and understand these complex interactions and the state-dependency of respiratory rhythm generation by using experimental studies combined with computational modeling. The experimental studies will be performed by Dr. Smith (NINDS, NIH) and Dr. Paton (University of Bristol). The applied experimental methods will include (1) reduction of the operating respiratory network by sequential and highly precise transections applied to the pons and medulla and (2) using specific blockers of intrinsic neuronal properties (e.g., persistent sodium and other ionic channels) and network interactions (e.g., inhibitory synaptic transmission) applied to intact and reduced preparations. The computational model of the ponto-medullary respiratory network will be further developed by the group of Dr. Rybak (Drexel University) in close interactive collaboration with Drs. Smith and Paton using data accumulated in their laboratories. In turn, complementary experimental studies in these laboratories will be driven by modeling predictions. The resultant comprehensive computational model will be developed, tested and elaborated to reproduce the experimentally observed state-dependent changes in the firing patterns of respiratory neurons and in the discharge patterns of output motor nerves (phrenic, hypoglossal, central vagal and abdominal) under different experimental conditions. The proposed collaborative study will provide important insights into the complex neural mechanisms for control of breathing Ultimately, the model that will be developed in this project may be used for simulation of multiple respiratory disorders and diseases (e.g., sleep apnea, brainstem/spinal cord injury, CCHS), and for developing and investigations new methods for their treatment.