Dynamics of Rhythm Generation in Respiration and Beyond

哺乳动物与环境相互作用的各种有节奏的基本运动源于神经元网络的活动。例如，实验揭示了哺乳动物脑干中存在一个神经元节律产生系统，该系统维持稳定的呼吸节律，而在哺乳动物脊髓中存在另一个神经元节律产生系统，驱动四肢运动，两者都受反馈控制。这个研究项目将带来新的见解，并产生新的预测，关于神经元的内在特性，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节。将研究的特定问题是特定离子电流的作用和呼吸神经元之间连接的特定模式在产生同步爆发，或在静止和活跃时期之间的活动交替，以及在呼吸的不同阶段之间切换；特定的反馈控制目标和信号在变化的环境或代谢需求下调节呼吸神经元活动的有效性；节律性神经元活动和机械约束和反馈信号对自上而下驱动变化下运动步态阶段持续时间不对称性的相对贡献；如果与脊髓损伤相关的自上而下驱动丧失，可能的机制可以产生运动节律的恢复。这些领域的结果将通过对实验数据约束下的神经网络模型的数学分析来实现。模型将由非线性常微分方程的耦合系统组成，不同的模型组件通常以不同的速率演化。快速/缓慢分解和几何奇异摄动理论、分岔分析、平均、映射推导和直接模拟技术都将应用于开发新的见解和预测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。呼吸和运动是许多有节奏的神经机械过程之一，这些过程可以在没有直接自愿输入的情况下维持。重要的研究工作提高了我们对呼吸和运动节律产生和改变的机制的理解，以响应不断变化的环境和代谢条件，但这种节律产生和反馈调节的许多方面仍然未知。本研究项目将利用受实验数据约束的数学模型的发展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性问题。在呼吸的背景下，本研究将考虑驱动与呼吸相关的肌肉运动的关键节律性活跃脑干神经元的活动模式的协调，以及这些神经元与调节网络活动以处理变化需求的反馈控制的相互作用。这些步骤将与两个神经科学实验室合作进行，提供直接访问实验数据和模型预测测试。在肢体运动的背景下，本项目将重点研究一个结合神经元节律产生系统和它驱动的机械肢体的模型，该模型将与肌肉动作相关的反馈信号发送回节律产生器。该领域的研究将包括分析这些神经元和机械成分的相互作用如何产生肢体运动的特性，以及如果发生与脊髓损伤相关的损伤，可以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，以恢复患有此类损伤的个体的运动。

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.