Central chemoreceptors monitor brain CO2-pH and provide an essential component of the drive to breathe, operating with peripheral chemoreceptors that rapidly sense arterial O2 and CO2-pH. Asthma is a common often life-threatening disorder associated with changes in PaO2, PaCO2, and the drive to breathe, yet little is known about circuits that link chemoresponsive brain regions to the respiratory network for motor pattern generation or the roles of these pathways during acute asthma attacks. The goal of this project is to identify functional connectivity among three brainstem chemoresponsive regions and the pontomedullary network for breathing, and to test model-based predictions on network mechanisms for regulating the drive to breathe during hypocapnia and acute challenge-evoked exacerbations in an established sensitized animal model of asthma.
Aim 1 addresses the hypothesis that central chemoresponsive neurons in the retrotrapezoid nucleus/parafacial respiratory group, the rostral medullary raphi, and nucleus of the solitary tract regulate the respiratory motor pattern generator through multiple pathways, including circuits shared by baroreceptor and peripheral chemoreceptor reflexes.
Aim 2 targets mechanisms of central chemoreceptor modulation of peripheral chemoreceptor influences on breathing during hypocapnia. Hypocapnia and hypoxemia frequently accompany acute asthma attacks. Reduced chemosensitivity to hypoxia is a likely contributing factor in patients with near-fatal episodes. Thus, Aim 3 pursues the hypothesis that chemoreceptor reflex circuit mechanisms are appropriated and reconfigured during antigen challenge-evoked exacerbations. The experimental approach combines advanced multi-electrode array technologies, computational methods for network analysis and predictive modeling, circuit interrogation by selective activation of central and peripheral chemoreceptors and other challenges. Expected outcomes include a new conceptual framework on respiratory network architecture, evidence for adaptive chemoreceptor reflex circuit mechanisms that control breathing during hypocapnic hypoxia, and the first network-scale assessment of identified central and peripheral reflex circuit functions during acute antigen-challenge evoked episodes in an animal model system of asthma.
Asthma is a common and often life-threatening disorder associated with changes in breathing pattern, ventilation, and altered levels of O2 and CO2. Central chemoreceptors monitor brain CO2-pH and provide an essential component of the drive to breathe, operating with peripheral chemoreceptors that rapidly sense arterial O2 and CO2-pH. The goal of this project is to identify functional connections among chemoresponsive brainstem regions and the central pattern generator for breathing and to test computer model-based predictions on network mechanisms for regulating the drive to breathe during hypocapnia and during acute antigen-challenge evoked exacerbations in an animal model system of asthma.
|Nuding, Sarah C; Segers, Lauren S; Iceman, Kimberly E et al. (2015) Functional connectivity in raphé-pontomedullary circuits supports active suppression of breathing during hypocapnic apnea. J Neurophysiol 114:2162-86|
|Segers, L S; Nuding, S C; Ott, M M et al. (2015) Peripheral chemoreceptors tune inspiratory drive via tonic expiratory neuron hubs in the medullary ventral respiratory column network. J Neurophysiol 113:352-68|
|O'Connor, Russell; Segers, Lauren S; Morris, Kendall F et al. (2012) A joint computational respiratory neural network-biomechanical model for breathing and airway defensive behaviors. Front Physiol 3:264|
|Morris, K F; Nuding, S C; Segers, L S et al. (2010) Respiratory and Mayer wave-related discharge patterns of raphe and pontine neurons change with vagotomy. J Appl Physiol 109:189-202|
|Dick, Thomas E; Baekey, David M; Paton, Julian F R et al. (2009) Cardio-respiratory coupling depends on the pons. Respir Physiol Neurobiol 168:76-85|
|Dick, Thomas E; Shannon, Roger; Lindsey, Bruce G et al. (2008) Pontine respiratory-modulated activity before and after vagotomy in decerebrate cats. J Physiol 586:4265-82|
|Lindsey, Bruce G; Gerstein, George L (2006) Two enhancements of the gravity algorithm for multiple spike train analysis. J Neurosci Methods 150:116-27|
|Dick, Thomas E; Shannon, Roger; Lindsey, Bruce G et al. (2005) Arterial pulse modulated activity is expressed in respiratory neural output. J Appl Physiol 99:691-8|
|Dick, Thomas E; Morris, Kendall F (2004) Quantitative analysis of cardiovascular modulation in respiratory neural activity. J Physiol 556:959-70|
|Morris, Kendall F; Gozal, David (2004) Persistent respiratory changes following intermittent hypoxic stimulation in cats and human beings. Respir Physiol Neurobiol 140:1-8|
Showing the most recent 10 out of 33 publications