Dynamics of Rhythm Generation in Respiration and Beyond

呼吸及其他节律产生的动力学

• 批准号: 1021701
• 负责人: Jonathan Rubin
• 金额: $ 35万
• 依托单位: University of Pittsburgh
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1021701&HistoricalAwards=false
• 关键词: Dynamics; Rhythm; Generation; Respiration; Beyond

A variety of rhythmic movements fundamental to mammalian interactions with the environment emerge from activity in networks of neurons. For example, experiments have revealed the existence of a neuronal rhythm-generating system in the mammalian brainstem that maintains a stable respiratory rhythm and another in the mammalian spinal cord that drives limbed locomotion, both subject to feedback control. This research project will lead to new insights, and generate new predictions, about how the intrinsic properties of neurons, the characteristics of their interactions, and the features of feedback signals contribute to the generation and modulation of these and other neuronal rhythms. Particular issues that will be investigated are the roles of specific ionic currents and the specific patterns of connections between respiratory neurons in generating synchronized bursting, or alternation of activity between silent and active periods, and in switching between different phases of respiration; the effectiveness of particular feedback control targets and signals in regulating respiratory neuron activity under changing environmental or metabolic demands; the relative contributions of rhythmic neuronal activity and of mechanical constraints and feedback signals to asymmetries in locomotor gait phase durations seen in response to changes in top-down drive; and possible mechanisms that can yield recovery of locomotor rhythms if loss of top-down drive associated with spinal cord injury occurs. Results in these areas will be achieved through the mathematical analysis of neuronal network models constrained by experimental data. The models will consist of coupled systems of nonlinear ordinary differential equations, with different model components often evolving at disparate rates. Techniques of fast/slow decomposition and geometric singular perturbation theory, bifurcation analysis, averaging, map derivation, and direct simulation will all be applied to develop new insights and predictions about the dynamics of respiratory and locomotor rhythms as well as general principles of neuronal rhythmogenesis.Respiration and locomotion are among the many rhythmic neuro-mechanical processes that can be maintained without direct voluntary inputs. Significant research efforts have advanced our understanding of the mechanisms through which respiratory and locomotor rhythms are produced and altered in response to changing environmental and metabolic conditions, yet many aspects of this rhythm generation and feedback regulation remain unknown. This research project will address several such open questions using the development of mathematical models constrained by experimental data as well as computer simulations and mathematical analysis of these models. In the context of respiration, this research will consider coordination of activity patterns of key rhythmically active brainstem neurons that drive muscle movements associated with respiration as well as the interaction of these neurons with feedback controls that adjust network activity to handle changing demands. These steps will be performed in collaboration with two neuroscience labs, providing direct access to experimental data and testing of model predictions. In the setting of limbed locomotion, this project will focus on a model that combines a neuronal rhythm generation system and a mechanical limb that it drives, which sends feedback signals, related to muscle actions, back to the rhythm generator. The research in this area will include analysis of how the interactions of these neuronal and mechanical components generate the properties of limbed locomotion as well as of mechanisms that can yield recovery of locomotor rhythms if damage associated with spinal cord injury occurs, which may help guide the development of therapeutic interventions currently under investigation to restore locomotion in individuals with such injuries.

哺乳动物与环境相互作用的基础是各种有节奏的运动，这些运动来自神经元网络的活动。例如，实验揭示了哺乳动物脑干中存在一个维持稳定呼吸节奏的神经元节律生成系统，而哺乳动物脊髓中存在另一个驱动肢体运动的神经元节律生成系统，这两个系统都受到反馈控制。这项研究项目将导致新的见解，并产生新的预测，关于神经元的内在属性，它们相互作用的特征，以及反馈信号的特征如何有助于这些和其他神经元节律的产生和调制。将研究的特别问题包括：特定的离子电流和呼吸神经元之间连接的特定模式在产生同步爆发或静止期和活动期之间的活动交替以及在不同呼吸时相之间切换方面的作用；在不断变化的环境或代谢需求下，特定的反馈控制靶点和信号在调节呼吸神经元活动方面的有效性；节律性神经元活动以及机械约束和反馈信号对运动步态持续时间不对称的相对贡献，以应对自上而下驱动的变化；以及如果发生与脊髓损伤相关的自上而下驱动的丧失，能够恢复运动节律的可能机制。这些领域的结果将通过对受实验数据约束的神经网络模型进行数学分析来实现。这些模型将由非线性常微分方程组的耦合系统组成，不同的模型组件通常以不同的速度发展。快/慢分解和几何奇异摄动理论、分支分析、平均、映射推导和直接模拟技术都将被应用于开发关于呼吸和运动节律的动力学以及神经元节律发生的一般原理的新的见解和预测。呼吸和运动是许多可以在没有直接自愿输入的情况下保持的有节奏的神经机械过程。大量的研究工作促进了我们对呼吸和运动节律产生和改变以响应不断变化的环境和代谢条件的机制的理解，然而这种节律产生和反馈调节的许多方面仍然未知。这项研究项目将通过开发受实验数据约束的数学模型以及对这些模型的计算机模拟和数学分析来解决几个这样的开放问题。在呼吸的背景下，这项研究将考虑关键的有节奏地活跃的脑干神经元的活动模式的协调，这些神经元驱动与呼吸相关的肌肉运动，以及这些神经元与反馈控制的相互作用，反馈控制调整网络活动以应对不断变化的需求。这些步骤将与两个神经科学实验室合作执行，提供对实验数据的直接访问和对模型预测的测试。在肢体运动的设定中，这个项目将重点放在一个模型上，该模型结合了神经元节奏生成系统和它驱动的机械肢体，机械肢体将与肌肉动作相关的反馈信号发送回节奏生成器。这方面的研究将包括分析这些神经元和机械组件的相互作用如何产生肢体运动的特性，以及在与脊髓损伤相关的损伤发生时能够产生运动节律恢复的机制，这可能有助于指导目前正在研究的治疗干预措施的发展，以恢复此类损伤的个体的运动。