Multi-scale modeling of the neural control of respiration

Bartholomew James Bacak

doi:10.17918/etd-6635

The generation of respiration in mammals begins in the lower brainstem where groups of neurons, that together comprise the respiratory central pattern generator (CPG), interact to produce a motor output that controls breathing. The pre-Bötzinger complex (pre-BötC) in the ventrolateral respiratory column (VRC) is believed to be a major contributor to rhythmic inspiratory activity that interacts with other neural compartments within the VRC as well as with other brainstem areas, including the pons. Though there has been a substantial push to understand the exact cellular and network mechanisms operating within the pre-BötC, as well as the way it is incorporated into the larger respiratory network, there is still much to be resolved. The overarching goal of the work presented in this dissertation is to contribute to our understanding of the neural control of respiration at several hierarchical levels. It is my hope that better insight into the complexities of these multiscale neural control mechanisms will provide a more complete framework for understanding various respiratory pathologies, and ultimately guide the development of novel therapies that will improve patient outcomes. I applied techniques from the fields of mathematics and computer science to develop computational models that reproduced results from electrophysiological recordings (done by our collaborators) and generated verifiable predictions. The scale of my modeling work encompasses the interaction of neurons in a single population, several interconnected populations of neurons that encompass the core of the mammalian respiratory network, and an integration of the respiratory network into a larger control system that includes afferent feedback loops. At each level I address specific, but related, topics that add to the general understanding of the neural control of respiration. The aims of my thesis address specific issues at each of the scales mentioned above. These issues may be summarized as follows: (i) the characteristic rhythmic bursting behavior observed in the pre-BötC, which was studied at the cellular levels with a particular interest in how this behavior impacts respiratory rhythmogenesis; (ii) a respiratory network connectome that defines interactions between several populations of neurons that together form the VRC, which produces an alternating pattern of inspiration, post-inspiration and expiration, and, how such a pattern may be affected by changes in chemical environment, e.g. elevated carbon dioxide or diminished oxygen concentrations; and (iii) the role of afferent feedback to the VRC, from the pons and lungs, which was studied in the context of respiratory phase switching mechanisms.

Multi-scale modeling of the neural control of respiration

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Multi-scale modeling of the neural control of respiration

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