Doctor of Philosophy (Ph.D.)
Breathing is essential for mammalian life. Although there is an emerging consensus that the inspiratory respiratory rhythm is generated in a lower brainstem region known as the preBotzinger Complex (preBotC), the mechanism of rhythmogenesis is still unclear. Additionally, the modulation of intrinsic currents within preBotC neurons has yet to be fully elucidated. This dissertation addresses both of these issues and relies on imaging, electrophysiological, and modeling techniques. The first chapter examines the size and composition of the preBotC. The chapter also decribes the means by which substance P (SP) excites the vast majority of preBotC neurons by illustrating the characteristics of the SP-activated current (/SP) in these neurons. In the subsequent chapter, we characterize a voltage-dependent potassium current that is involved in maintaining stable rhythms during normal fictive breathing. The third chapter presents a mathematical model of heterogeneous and rhythmogenic neurons that initiate network bursts. We show how this behavior relies on feedback synaptic connections within the network that reinforces activity, i.e., recurrent-excitation. We also compare model results to experimental data and make testable predictions. The final chapter elaborates on the discussion of /SP from the first chapter and presents evidence suggesting that a cyclic adenosine monophosphate (cAMP)-modulated non-specific cation channel may account for the depolarizing response in preBotC neurons from several neuromodulators. Altogether, this dissertation advances the field's understanding on several fronts. We have distinguished possible functional roles of neurons from electrophysiological characteristics, estimated the number of neurons necessary for rhythmogenesis, characterized /SP , and clarified the distribution of SP-sensitive receptors among inspiratory neurons. We have identified and characterized a voltage-dependent potassium currrent important for inspiratory activity and analyzed its role. We have also described in detail how rhythmic bursts form from recurrent excitation and how this relates to experimental data. Finally, we have identified and begun characterizing a potentially important and novel mechanism for the modulation of membrane potentials in critical inspiratory neurons.
© The Author
Hayes, John A., "Phenotypic properties and intrinsic currents of neurons involved in the neural generation of mammalian breathing" (2007). Dissertations, Theses, and Masters Projects. William & Mary. Paper 1539623329.