Neuronal Determinants of Respiratory Rhythmogenesis

描述（由申请人提供）：神经科学的一个主要问题是神经元网络如何产生负责持续健康和幸福的复杂行为；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复核（pBC）是一个双侧分布的腹侧延髓亚区，包含脑干中一个对呼吸节律产生至关重要的区域。这种节律在减少的准备中持续存在，如髓横片，其中包含pBC。这个特殊应用的目的是开发计算模型来阐明pBC水平上节律产生的机制，以及它如何与另一群更多的吻侧呼吸神经元相互作用。本研究的目的是：1)建立离子通道模型，以解释pBC中神经元的各种电生理反应，并研究神经元形态在决定这些反应中的关键因素；2)研究特定连接模式在引发新形式的网络爆发中的潜在作用；3)利用最小模型和离子通道模型来确定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导致这种现象的程度。计算方法对这项研究特别有用，因为单细胞和网络动力学是复杂的，很难单独通过实验方法进行机械分析。一些研究，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可控的方式进行。我们特别准备进行这项研究，因为我们之前制定了pBC节律产生的最小计算模型，最近开发了更复杂的基于横向切片神经元离子通道的模型，并与该领域的几个实验实验室建立了积极的合作关系。拟议的研究代表了对呼吸中枢模式产生电路计算模型发展的持续合作努力。我们的方法是创新的，因为我们的理念是从下到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对呼吸节律和模式的产生和控制有更全面的了解。我们的结果也将在一般情况下有助于从神经种群稳定节律产生的一般机制的知识体系的增长。

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.