CRCNS: State dependent neural mechanisms for respiratory pattern generation

CRCNS：呼吸模式生成的状态依赖神经机制

基本信息

批准号：
7476380
负责人：
Ilya A Rybak
金额：
$ 28.4万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-02 至 2011-07-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：在较低的脑干中进行呼吸运动模式的产生，并涉及细胞，网络和系统级机制的复杂跨层次相互作用。由于这些复杂的相互作用，该系统可以在不同的功能状态下运行，并在每个状态下参与不同的节律机制。我们假设在呼吸网络（即基于网络的，起搏器驱动或杂种）中运行的节奏机制是由前杂种综合体的状态定义的，而前动物疗法的状态反过来又在其他髓样和蓬托米电路的控制下运作。我们还建议PON直接控制肉毒前复合物（以及节律机理）的状态和/或通过其他髓质回路，例如botzinger复合物。这个多学科协作项目的总体目标是通过使用实验研究与计算建模相结合，调查和理解这些复杂的相互作用以及呼吸节奏生成的状态依赖性。实验研究将由Smith（Ninds，NIH）和Paton博士（布里斯托尔大学）进行。应用的实验方法将包括（1）通过应用于Pons和Medulla的顺序和高度精确的过渡降低工作呼吸网络，以及（2）使用固有神经元特性的特定阻滞剂（例如，持久性钠和其他离子钠和其他离子通道）和其他离子通道和其他网络相互作用（例如，抑制性的抑制性传输和良好的启动）。 Rybak博士（Drexel University）小组与DRS的互动合作将进一步开发Ponto-Mudullary呼吸网络的计算模型。 Smith和Paton使用其实验室中积累的数据。反过来，这些实验室中的互补实验研究将由建模预测来驱动。在不同的实验条件下，将开发，测试和详细开发，测试和详细研究综合计算模型，以重现呼吸神经元的发射模式以及输出运动神经的放电模式中的实验观察到的状态依赖性变化。拟议的协作研究将为控制呼吸的复杂神经机制提供重要的见解，最终将使用该项目开发的模型来模拟多种呼吸道疾病和疾病（例如，睡眠呼吸暂停，脑干/脊髓索损伤，CCH，CCH，CCH，CCH），以及开发和研究新方法的新方法。