CRCNS: State dependent neural mechanisms for respiratory pattern generation

描述(申请人提供)：呼吸运动模式的产生是在较低的脑干进行的，涉及细胞、网络和系统水平机制的复杂的跨水平相互作用。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，并在每种状态下进行不同的节律机制。我们假设，在呼吸网络中工作的节律机制(即，基于网络的、起搏器驱动的或混合的)是由前Botzinger复合体的状态定义的，该复合体在其他延髓和桥脑回路的控制下工作。我们还认为，脑桥直接和/或通过其他延髓回路，如Botzinger复合体，控制前Botzinger复合体的状态(从而控制节律机制)。这个多学科合作项目的总体目标是通过实验研究和计算建模相结合的方法来调查和理解这些复杂的相互作用和呼吸节律产生的状态依赖。实验研究将由史密斯博士(NINDS，NIH)和佩顿博士(布里斯托尔大学)进行。应用的实验方法将包括(1)通过对脑桥和延髓进行连续和高精度的横切来减少操作呼吸网络，以及(2)使用固有神经元特性(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)的特定阻滞剂，应用于完整和减少的准备。Rybak博士(德雷克塞尔大学)的团队将利用他们实验室中积累的数据，与Smith博士和Paton博士密切互动，进一步开发桥-髓质呼吸网络的计算模型。反过来，这些实验室的互补性实验研究将受到建模预测的推动。合成的综合计算模型将被开发、测试和详细说明，以再现在不同实验条件下呼吸神经元的放电模式和输出运动神经(膈、舌下、迷走神经和腹部)的放电模式的实验观察到的状态依赖变化。这项拟议的合作研究最终将为控制呼吸的复杂神经机制提供重要的见解，该项目将开发的模型可能用于模拟多种呼吸系统疾病和疾病(例如睡眠呼吸暂停、脑干/脊髓损伤)，并为其开发和研究新的治疗方法。

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.