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至关重要的区域。这种节律持续存在于减少的准备工作中，例如包含PBC的横向髓质切片。这一特殊应用的目标是开发计算模型，以阐明在PBC水平上的节律产生机制，以及它如何与另一组更多嘴呼吸神经元相互作用。这项建议的目的是1)建立离子通道模型，可以解释PBC中神经元的不同电生理反应，并研究神经元形态在决定这些反应中的关键作用；2)研究特定的连接模式在引起新形式的全网络爆发中的潜在作用；以及3)利用最小模型和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类药物结合可能在多大程度上引起这种现象。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。一些研究，例如突触连通性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。我们已经为开展这项拟议的研究做好了准备，因为我们以前建立了PBC节律产生的最小计算模型，最近开发了更复杂的基于离子通道的横切片神经元模型，并与该领域的几个实验实验室建立了积极的合作关系。拟议的研究代表了为开发呼吸中枢模式产生电路的计算模型而进行的持续合作努力。我们的方法是创新的，因为我们的哲学是自下而上有条不紊地追求这种方法。我们已经与合作实验室建立了联系和经过验证的记录，这种模型和实验之间的互动方法预计将产生新的信息，并在细胞和网络水平上更全面地理解呼吸节律和模式的产生和控制。我们的结果总体上也将有助于从神经群体中产生稳定节律的一般机制的不断增长的知识体系。

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.