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Neuronal Determinants of Respiratory Rhythmogenesis

呼吸节律发生的神经元决定因素

基本信息

批准号：
7061723
负责人：
ROBERT J BUTERA
金额：
$ 12.69万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-05-01 至 2008-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7061723
关键词：
cell cell interaction cell morphology computational neuroscience electrophysiology medulla oblongata membrane channels model design /development neuroregulation pulmonary respiration respiration regulatory center synapses

项目摘要

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.

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福祉的复杂行为；呼吸的神经控制系统就是这样一种网络。过去十年的证据表明，前博辛格复合体（pBC）是腹外侧延髓的双侧分布亚区域，包含脑干中对于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，例如含有 pBC 的横向髓质切片。这一特定应用的目的是开发计算模型，以阐明 pBC 水平的节律生成机制以及它如何与另一群更多的嘴侧呼吸神经元相互作用。该提案的目的是 1) 开发离子通道模型，该模型可以解释 pBC 中神经元电生理反应的各种变化，并研究神经元形态在决定这些反应中的关键因素； 2）研究特定连接模式的潜在作用，以产生新形式的网络范围爆发； 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相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非常复杂，并且很难仅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影响的研究，目前在实验准备中很难以受控方式进行。我们为开展这项拟议的研究做好了充分的准备，因为我们之前制定了 pBC 节律生成的最小计算模型，最近开发了更复杂的基于离子通道的横向切片神经元模型，并与该领域的几个实验实验室建立了积极的合作关系。拟议的研究代表了对开发呼吸中枢模式生成电路的计算模型的持续合作努力。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追求这种方法。我们与合作实验室建立了联系并拥有良好的跟踪记录，模型和实验之间的这种交互方法预计将产生新的信息，并更全面地了解细胞和网络水平上呼吸节律和模式的生成和控制。我们的结果总体上还将有助于增加关于神经群体稳定节律生成的一般机制的知识体系。