Neuronal Determinants of Respiratory Rhythmogenesis

描述(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复杂的行为，对持续的健康和福祉负责；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)是延髓腹外侧区的一个两侧分布的亚区，包含脑干中对呼吸节律产生重要的区域。这项应用的目的是开发计算模型，以阐明在横切面PBC水平上的节律产生机制。这个项目的基本原理是，需要最终了解内在和突触细胞属性如何有助于呼吸节律的产生和控制，以了解体内呼吸的神经控制，无论是生理状态还是病理生理状态。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，单靠实验方法很难进行机械分析。我们已经为开展这项拟议的研究做好了准备，因为我们以前制定了PBC节律产生的最小计算模型，已经开发并正在继续开发更复杂的基于离子通道的横切片神经元模型，并与该领域的领先实验实验室保持着积极的合作关系。这个建议的目的是1)研究基于兴奋性耦合的节律产生的多种机制，这些机制既取决于固有的离子通道，也取决于突触的属性。2)建立横切片上与呼吸相关的主要神经元类型的离子通道模型，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制输入的Raphi神经元和紧张性神经元的最小模型。3)将AIM 2的模型类型整合为一个完整的横切面模型，该模型包括从Raphi到PBC再到运动前到运动神经元的完整通路。我们的方法是创新的，因为我们的持续哲学是有条不紊地自下而上地追求这一方法，即从横向开始。除了与呼吸生理学的相关性外，我们的结果还将有助于从神经群体中获得越来越多的关于稳定节律产生的一般机制的知识。

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.