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），双侧分布的腹外侧延髓的子区域，包含一个区域的脑干呼吸节律的产生至关重要。这种节律在减少的标本中持续存在，例如含有pBC的横髓切片。这个特定应用的目的是开发计算模型，以阐明在PBC水平的节律生成机制，以及它如何与另一个更吻侧呼吸神经元群体相互作用。该建议的目的是1）开发可以解释pBC中神经元的电生理反应的不同库的离子通道模型，并研究神经元形态在决定这些反应中的关键因素的作用; 2）研究特定连接模式的潜在作用，以产生新形式的网络范围的爆发;以及3）利用最小模型以及离子通道模型来确定所提出的pFRG-pBC相互作用机制的可行性以及细胞异质性与阿片样物质结合可能引起这种现象的程度。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。一些研究，例如突触连接对网络动力学的影响的研究，目前在实验准备中很难以受控的方式进行。我们特别准备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，最近开发了更复杂的离子通道为基础的模型的神经元在横向切片，并在这一领域的几个实验室积极的合作关系。拟议的研究代表了一个持续的合作努力，朝着发展的计算模型的呼吸中枢模式生成电路。我们的方法是创新的，因为我们的理念是自下而上有条不紊地采取这种方法。我们已经与合作实验室建立了联系并取得了良好的记录，这种模型和实验之间的互动方法有望产生新的信息，并在细胞和网络水平上更全面地了解呼吸节律和模式的产生和控制。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，稳定的节奏产生的神经种群。

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 critically important for respiratory rhythm generation. This rhythm persists in reduced preparations, such as the transverse medullary slice, which contains the pBC. The objective of this particular application is to develop computational models to elucidate mechanisms for rhythm generation at the level of the pBC and how it interacts with another population of more rostral respiratory neurons. The aims of this proposal are 1) to develop ion channel models that can account for the varied repertoire of electrophysiological responses of neuron in the pBC and investigate to what role neuron morphology is a critical factor in determining these responses; 2) to investigate a potential role for specific patterns of connectivity to give rise to a new form of network-wide bursting; and 3) to utilize minimal models as well as ion channel models to determine the feasibility of proposed mechanisms of pFRG-pBC interactions and the extent to which cellular heterogeneity, in combination with opioids, may give rise to this phenomena. 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. Some studies, such as studies of the impact of synaptic connectivity on network dynamics, are currently quite difficult to perform in a controlled manner in experimental preparations. We are particularly well prepared to undertake this proposed research, since we previously formulated minimal computational models of pBC rhythm generation, have recently developed more complex ion-channel based models of neurons in the transverse slice, and have active collaborative relationships with several experimental laboratories in this field. The proposed research represents a continuing collaborative effort towards the development of a computational model of the respiratory central pattern generating circuitry. Our approach is innovative in that our philosophy is to pursue this approach methodically, from the bottom up. We have established ties and a proven track record with collaborative laboratories, and this interactive approach between model and experiment is expected to yield novel information and a more complete understanding of the generation and control of respiratory rhythm and pattern at cellular and network levels. Our results will also contribute in general to a growing body of knowledge on general mechanisms of stable rhythm generation from neural populations.