Neuronal Determinants of Respiratory Rhythmogenesis

描述（申请人摘要）： 呼吸节律的发生是一个复杂的系统，具有复杂的神经动力学 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存在，包括整体 脑干-脊髓和横切面。虽然这些减少 这些准备工作极大地推进了呼吸节律发生的研究， 细胞水平，甚至这些简化的制剂的神经动力学 还没有完全被理解。本申请的目的是 为了充分了解体外和体外呼吸节律发生的机制， 和体内制备;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大脑中的神经元产生的。 显示适应性离子通道性质的前Botzinger复合物（pBc），和 这群人通过兴奋和抑制性联系 其他呼吸区域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，而且使 呼吸节律在细胞间变异性存在的情况下更稳健， 外部干扰。我们的具体目标是：1）确定固有离子 通道特性和外在突触输入调节突发频率， 呼吸pBc神经元的持续时间和动作电位放电率; 2） 确定细胞异质性和突触特性如何影响 呼吸节律的同步性和稳定性;以及3）确定 基于起搏器和基于网络的呼吸节律模式的作用 通过扩展我们的模型来考虑整个脑干脊髓， 准备.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， 最终导致临床干预的新药理学技术， 预防婴儿猝死综合征、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道疾病 控制失败。

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.