Emergence and Coordination of Rhythmic Activity in Respiratory Neurons and Networks

哺乳动物的呼吸在一生中是有规律的，不需要有意识的控制。这种异常强健的行为源于大脑深处神经元网络的活动，它们相互作用，产生协调、有节奏的输出，驱动呼吸。虽然这个过程的某些方面已经被很好地理解，但实验已经揭示了超越现有理论的特征，这个项目将应用新的建模和分析方法来研究这些影响。将研究的第一组问题涉及呼吸神经元输出的特定模式出现的方式，在发育过程中发生变化，并受到反馈信号的影响。第二个研究方向将集中在活动如何在一群呼吸神经元之间传播和协调，这是有效驱动发起每个呼吸循环的肌肉所必需的。其他研究途径将涉及跨多个神经元群体的全系统协调机制，这些神经元群体相互作用，在一系列条件下产生完整的呼吸周期。这项工作将与实验学家合作完成，该项目的结果将导致改进模型，以解释呼吸实验的结果，并将产生新的预测。除了加强对呼吸功能和功能障碍的理解外，该项目还将产生广泛的影响：研究协调活动传播的理论方法将与其他神经网络以及疾病、意见和信息的传播相关，而分析以不同速度发展的过程的方法也将适用于其他环境。为这项研究做出贡献的学员将获得使用计算方法解决神经科学中数据驱动问题的经验。所开发的方法和发现将有助于通过当地小组会议和课程培训学生，并将通过出版物、报告和模式分享更广泛地传播。神经元网络的节律性活动是一系列重复性行为的基础，如行走、抓挠和呼吸。该项目将通过关注哺乳动物脑干中与呼吸相关的神经网络来解决节律的产生、协调和控制。在这些神经网络产生的节律中，在每个呼吸周期中，多个神经元群在特定的相对时间和特定的活动模式中轮流激活，并且每个神经元群的活动在出现时迅速同步。这项工作将分析具有复杂动态特征的活动（称为爆发）如何在特定神经元中产生，并随后在呼吸的吸气阶段扩散到特定脑干区域的人群。对爆发模式的分析将跨越多个开发阶段进行，将涉及对具有在几个不同时间尺度上演化的组件的系统动力学进行新颖的数学分析。由此产生的理论进展将对具有多时间尺度动力学的其他生物和物理系统的研究产生影响。利用数学和计算方法，也将获得新的结果，关于网络中爆发的协调如何依赖于相关神经元之间的连接模式以及这些神经元通过突触进行交流的特性。这些进展也将更广泛地适用于其他过程，这些过程涉及将活动从一小部分局部起始地点传播到网络中。最后，该项目将包括跨多个神经元群体的活动协调调查，以产生功能性呼吸输出，包括由于环境或代谢需求而导致的反馈信号变化下的灵活性和鲁棒性问题。这些步骤将以新的实验数据为指导，将涉及与实验学家的合作，并将在基本理解和预测某些呼吸功能障碍的变化方面取得进展。该项目将包括各种各样的研究生和本科生，他们将获得有价值的研究培训，将影响教育工作，并将导致结果的传播和模型共享。该奖项由MPS数学科学部（DMS）通过数学生物学项目和BIO/IOS通过神经系统集群共同资助。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Breathing in mammals occurs regularly throughout life without the need for conscious control. This remarkably robust behavior results from the activity of networks of neurons deep in the brain that interact to produce coordinated, rhythmic outputs that drive breathing. Although certain aspects of this process are well understood, experiments have revealed features that go beyond existing theories, and this project will apply new modeling and analysis approaches to investigate these effects. A first set of issues that will be studied relates to the ways that specific patterns of respiratory neuron outputs emerge, change across development, and are affected by feedback signals. A second direction of investigation will focus on how activity spreads and becomes coordinated across a population of respiratory neurons, as needed to effectively drive the muscles that initiate each breathing cycle. Additional avenues for research will involve the mechanisms of system-wide coordination across multiple populations of neurons that interact to produce the full breathing cycle over a range of conditions. The work will be completed in collaboration with experimentalists, and results of the project will lead to improved models to explain results of respiratory experiments and will generate new predictions. In addition to enhancing understanding of respiratory function and dysfunction, this project will have broad implications: theoretical methods developed to study the spread of coordinated activity will be relevant to other neural networks and to the spread of disease, opinion and information, while approaches for analyzing processes that evolve at very different rates will apply to other settings as well. Trainees contributing to this research will gain experience in using computational methods to address data-driven questions in neuroscience. Methods and findings developed will contribute to the training of students via local group meetings and courses and will be disseminated more broadly via publications, presentations, and model sharing.Rhythmic activity of networks of neurons underlies a wide range of repetitive behaviors such as walking, scratching, and breathing. This project will address rhythm generation, coordination, and control via a focus on neuronal networks in the mammalian brainstem associated with respiration. In the rhythms that these networks produce, multiple populations of neurons take turns activating at specific relative times and with specific activity patterns within each breathing cycle, and the activity within each population rapidly synchronizes when it arises. This work will analyze how activity with complex dynamic features, called bursting, arises in specific neurons and subsequently spreads across the population in a particular brainstem region during the inspiratory phase of breathing. Analysis of the bursting patterns, which will be done across multiple stages of development, will involve novel mathematical analysis of the dynamics of systems with components that evolve on several distinct timescales. The resulting theoretical advances will have implications for the study of other biological and physical systems with multiple timescale dynamics. New results will also be attained, using mathematical and computational methods, about how the coordination of bursting across the network depends on the pattern of connections across the neurons involved and the properties of the synapses through which these neurons communicate. These advances will also have broader applicability to other processes involving the spread of activity in a network from a small set of local initiation sites. Finally, this project will include investigation of coordination of activity across multiple neuronal populations to produce functional respiratory outputs, including issues of flexibility and robustness under changes in feedback signals due to environmental or metabolic demands. These steps will be guided by novel experimental data, will involve collaboration with experimentalists, and will result in advances in basic understanding as well as predictions about alterations underlying certain respiratory dysfunctions. The project will include diverse graduate students and undergraduates who will gain valuable research training, will impact educational efforts, and will lead to dissemination of results and model sharing.This award is funded jointly by the MPS Division of Mathematical Sciences (DMS) through the Mathematical Biology Program and BIO/IOS through the Neural Systems Cluster.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.