Central mechanisms of respiratory control caudal to the obex

© 2016 Dr. Sarah Elizabeth JonesThe current literature regarding the generation of respiratory rhythm is not contiguous, with a large disconnect between the results and interpretations of various research studies. Much literature focuses on, and supports the theory that, rhythmogenesis is dependent on the integrity of the pre-Bötzinger complex (pre-BötC), with rhythm independent of and not reliant upon more caudal medullary structures. Whilst much evidence supports this viewpoint, it cannot accommodate the vast array of respiratory literature, including numerous studies which have shown that respiratory motor activities can be generated in the absence of the pre-BötC, including the documentation of phrenic motor activity (inspiratory activity) recorded in animals following cervical transection. Therefore, the fundamental questions; which parts of the ventrolateral medulla and spinal cord are necessary and which parts sufficient to generate respiratory rhythm, still exist. The aim of the current body of work was to try and close one of the gaps in our knowledge and understanding of respiratory rhythmogenesis, this gap being: the role of the most caudal areas of the medulla and the spinal cord. The current work investigates the anatomical and physiological contribution of the caudal medullary reticular formation (cMRF) to the central control of breathing. I show novel ascending anatomical connectivity of two caudal medullary areas; the nucleus retroambiguus (NRA) and the dorsal respiratory group (DRG) each projecting to key areas of the respiratory central pattern generator (rCPG) in rat. I show for the first time that the DRG extends laterally to the nucleus of the solitary tract (NTS) and plays an ongoing role in respiratory motor patterning, whilst the NRA acts purely as a relay. I used a novel technique, a-priori transections in the in-situ perfused brainstem preparation, to probe the degenerate potential of the caudal medulla and explore the sufficiency of reduced circuit systems in the brainstem. I found no degenerate rhythmogenic circuitry in the caudal medulla under physiological conditions. However, I show that the pre-BötC is responsible for the generation of a low amplitude burstlet-type rhythm which paces respiratory rhythm, yet requires more rostral pontine structures in order for the burstlet-type rhythm to be converted into a full amplitude, eupneic breathing pattern. This finding challenges the contemporary models of rhythm generation which place all essential circuitry for eupnea in the medulla, and will be an important avenue for future research. Finally, I demonstrate for the first time, that under hypoxic conditions the spinal cord delivers an ascending tonic excitatory drive to the rCPG, supporting the idea of intrinsic spinal oxygen sensing. My results infer that the networks involved in the control of breathing extend both further caudal and rostral than previously believed