Neuronal Determinants of Respiratory Rhythmogenesis

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): A major issue in neuroscience is how networks of neurons generate complex behaviors responsible for sustained health and well being; the neural control system for breathing is one such network. Evidence over the past decade suggests that the pre-Botzinger Complex (pBC), a bilaterally distributed subregion of the ventrolateral medulla, contains a region of the brainstem critically important for respiratory rhythm generation. This rhythm persists in reduced preparations, such as the transverse medullary slice, which contains the pBC. The objective of this particular application is to develop computational models to elucidate mechanisms for rhythm generation at the level of the pBC and how it interacts with another population of more rostral respiratory neurons. The aims of this proposal are 1) to develop ion channel models that can account for the varied repertoire of electrophysiological responses of neuron in the pBC and investigate to what role neuron morphology is a critical factor in determining these responses; 2) to investigate a potential role for specific patterns of connectivity to give rise to a new form of network-wide bursting; and 3) to utilize minimal models as well as ion channel models to determine the feasibility of proposed mechanisms of pFRG-pBC interactions and the extent to which cellular heterogeneity, in combination with opioids, may give rise to this phenomena. Computational approaches are particularly useful for this investigation because the single cell and network dynamics are complex and difficult to analyze mechanistically by experimental approaches alone. Some studies, such as studies of the impact of synaptic connectivity on network dynamics, are currently quite difficult to perform in a controlled manner in experimental preparations. We are particularly well prepared to undertake this proposed research, since we previously formulated minimal computational models of pBC rhythm generation, have recently developed more complex ion-channel based models of neurons in the transverse slice, and have active collaborative relationships with several experimental laboratories in this field. The proposed research represents a continuing collaborative effort towards the development of a computational model of the respiratory central pattern generating circuitry. Our approach is innovative in that our philosophy is to pursue this approach methodically, from the bottom up. We have established ties and a proven track record with collaborative laboratories, and this interactive approach between model and experiment is expected to yield novel information and a more complete understanding of the generation and control of respiratory rhythm and pattern at cellular and network levels. Our results will also contribute in general to a growing body of knowledge on general mechanisms of stable rhythm generation from neural populations.