Neuronal Determinants of Respiratory Rhythmogenesis

描述（由申请人提供）：神经科学中的一个主要问题是神经元网络如何产生负责持续健康和福祉的复杂行为;呼吸的神经控制系统就是这样一个网络。过去十年的证据表明，前Botzinger复合体（PBC）是延髓腹外侧的双侧分布亚区，包含对呼吸节律产生重要的脑干区域。本申请的目的是开发计算模型，以阐明在横向切片中的PBC水平上的节律生成机制。这个特定项目的基本原理是，需要最终了解内在和突触细胞特性如何有助于呼吸节律的产生和控制，以了解在生理和病理生理状态下体内呼吸的神经控制。计算方法对于这项研究特别有用，因为单细胞和网络动力学是复杂的，难以单独通过实验方法进行机械分析。我们特别准备好进行这项拟议的研究，因为我们以前制定了最小的计算模型的pBC节律生成，已经开发并正在继续开发更复杂的离子通道为基础的模型的神经元在横向切片，并有一个积极的合作关系与领先的实验室在这一领域。该提议的目的是1）研究依赖于内在离子通道以及突触性质的基于兴奋性耦合的节律产生的多种机制。2)开发横切片中主要神经元相关神经元类型的综合离子通道模型，包括pBC神经元、运动前神经元、舌下神经元以及为pBC神经元提供关键基线调节输入的raphi和强直神经元的最小模型。3)将Aim 2中的模型类型整合到一个全面的横向切片模型中，该模型包括从raphi到pBC到运动前区到运动神经元的完整通路。我们的方法是创新的，因为我们的一贯理念是从下往上，即从横向开始，有条不紊地采用这种方法。除了呼吸生理学的相关性，我们的研究结果也将有助于在一般的知识越来越多的一般机制，稳定的节奏产生神经种群。

DESCRIPTION (provided by applicant): A major issue in neuroscience is how networks of neurons generate complex behaviors responsible for sustained health and well being; the neural control system for breathing is one such network. Evidence over the past decade suggests that the pre- Botzinger Complex (pBC), a bilaterally distributed subregion of the ventrolateral medulla, contains a region of the brainstem important for respiratory rhythm generation. The objective of this application is to develop computational models to elucidate mechanisms for rhythm generation at the level of the pBC in the transverse slice. The rationale for this particular project is that an ultimate understanding of how intrinsic and synaptic cellular properties contribute to the generation and control of respiratory rhythmogenesis is required to understand the neural control of breathing in vivo, in both physiological and pathophysiological states. Computational approaches are particularly useful for this investigation because the single cell and network dynamics are complex and difficult to analyze mechanistically by experimental approaches alone. We are particularly well prepared to undertake this proposed research, since we previously formulated minimal computational models of pBC rhythm generation, have developed and are continuing to develop more complex ion-channel based models of neurons in the transverse slice, and have an active collaborative relationship with a leading experimental laboratory in this field. The aims of this proposal are 1) Investigate multiple mechanisms for excitatory- coupling based rhythm generation that depend on both intrinsic ion channel as well as synaptic properties. 2) Development of comprehensive ion channel models of the major respiratory-related neuron types in the transverse slice, including the pBC neurons, pre- motor neurons, hypoglossal neurons, and minimal models of raphi and tonic neurons providing critical baseline modulatory input to the pBC neurons. 3) Integrate the model types from Aim 2 into a comprehensive transverse slice model that includes a complete pathway from raphi to pBC to premotor to motoneuron. Our approach is innovative in that our continuing philosophy is to pursue this approach methodically, from the bottom up, i.e. starting with the transverse. Besides the relevance to respiratory physiology, our results will also contribute in general to a growing body of knowledge on general mechanisms of stable rhythm generation from neural populations.