Neuronal Determinants of Respiratory Rhythmogenesis

描述(申请人摘要)：潜在的神经回路 呼吸节律的发生是一个具有复杂神经动力学的复杂系统 涉及哺乳动物脑干内的各种神经元群体。这 节律在减少的体外制剂中持续，包括全组 脑干-脊髓和横切片。虽然这些减少了 准备工作极大地促进了呼吸节律发生的研究。 即使是这些减量制剂的细胞水平和神经元动力学 还没有完全被理解。此特定应用程序的目标是 充分了解两者在体外呼吸节律发生的机制 和体内准备；我们的特殊方法是使用计算 模型和定量数据分析技术。我们假设 呼吸节律的吸气相是由 显示自适应离子通道属性的Pre-Botzinger络合物(PBC)，以及 这个群体通过兴奋性和抑制性连接相互作用 其他呼吸区在体内产生完整的呼吸节律。 我们进一步假设兴奋性突触连接的性质 在PBC内不仅协调吸气相，而且还使 呼吸节律在存在细胞间变异性和 外部干扰。我们的具体目标是：1)决定本征离子 通道特性和外源性突触输入调节突发频率和 吸气性PBC神经元的时程和动作电位放电率； 确定细胞异质性和突触属性如何影响 呼吸节律的同步性和稳定性；以及3)决定 基于起搏器和基于网络的呼吸节律模式的作用 通过将我们的模型扩展到考虑整体脑干脊髓来生成 准备工作。这项研究将增加我们对基本细胞的理解 和呼吸节律产生的突触机制，并可能 最终导致新的药理技术用于临床干预和 预防婴儿猝死综合症、睡眠呼吸暂停和 早产儿呼吸暂停、中央肺泡综合征和其他形式的呼吸系统疾病 控制失灵。

DESCRIPTION (Applicant's abstract): The neuronal circuitry underlying respiratory rhythm genesis is a complex system with complex neuronal dynamics involving various neuronal populations within the mammalian brainstem. This rhythm persists in reduced in vitro preparations, including the en bloc brainstem-spinal cord and the transverse slice. While these reduced preparations have greatly advanced the study of respiratory rhythm genesis at the cellular level, the neuronal dynamics of even these reduced preparations are not completely understood. The objective of this particular application is to fully understand mechanisms for respiratory rhythm genesis in both in vitro and in vivo preparations; our particular approach is the use of computational models and quantitative data analysis techniques. We hypothesize that the aspiratory phase of the respiratory rhythm is generated by neurons in the pre-Botzinger complex (pBc) that display adaptive ion channel properties, and that this population interacts via excitatory and inhibitory connections with other respiratory regions to produce the complete respiratory rhythm in vivo. We further hypothesize that the nature of the excitatory synaptic connectivity within the pBc not only coordinates the aspiratory phase but also makes the respiratory rhythm more robust in the presence of cell-to-cell variability and external disturbances. Our specific aims are 1) determine how intrinsic ion channel properties and extrinsic synaptic input regulate burst frequency and duration and action potential firing rates of aspiratory pBc neurons; 2) determine how cellular heterogeneity and synaptic properties affect the synchronization and stability of the respiratory rhythm; and 3) determine the role of pacemaker-based and network-based modes of respiratory rhythm generation by extending our model to consider the en bloc brainstem spinal cord preparation. This research will increase our understanding of basic cellular and synaptic mechanisms underlying respiratory rhythm generation and may ultimately lead to new pharmacological techniques for clinical intervention and prophylaxis for such disorders as sudden infant death syndrome, sleep apnea and apnea of prematurity, central alveolar syndrome, and other forms of respiratory control failure.