Emergence and Coordination of Rhythmic Activity in Respiratory Neurons and Networks

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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.