Breathing is a remarkable behavior fundamental to life that mediates gas exchange to support metabolism and regulate pH. A reliable, non-stop, robust rhythmic pattern of respiratory muscle activity is essential for breathing in mammals. Failure to maintain a normal breathing pattern in humans suffering from sleep apnea, apnea of prematurity, congenital central hypoventilation syndrome, hyperventilation syndrome, Rett syndrome, and perhaps Sudden Infant Death Syndrome, leads to serious adverse health consequences, even death. Various neurodegenerative diseases, such as Parkinson's disease, multiple systems atrophy, and amyotrophic lateral sclerosis, are associated with sleep disordered breathing that we hypothesize results from the loss of neurons in brain areas controlling respiration. If breathing is to be understood in normal and in pathological conditions, the mechanisms for respiratory central pattern generation must be revealed. We focus on two brain sites essential for generation of the normal breathing pattern, the preBtzinger Complex and the retrotrapezoid nucleus/parafacial respiratory group. We propose a broad series of experiments both in vivo and in vitro in rodents using advanced techniques including: viral delivery to express genetically encoded opsins or DREADDs in key subpopulations of neurons in these regions; advanced optical techniques to determine the contributions of the preBtzinger Complex microcircuit to rhythm generation; state-of-the-art neuroanatomical techniques to establish, in appropriate and necessary detail, the interconnectivity of the brainstem respiratory pattern generator. The data from these experiments will provide an extraordinary window into the mechanisms underlying respiratory rhythm and pattern generation.
In humans, continuous breathing from birth is essential to life and requires that the nervous system generate a reliable and robust rhythmic pattern that drives inspiratory and expiratory muscles appropriate for the regulation of blood gases and pH. The proposed studies will significantly advance our understanding of the neural mechanisms generating respiratory pattern and shed light on human disorders of breathing.
|Huckstepp, Robert T R; Cardoza, Kathryn P; Henderson, Lauren E et al. (2018) Distinct parafacial regions in control of breathing in adult rats. PLoS One 13:e0201485|
|Yang, Cindy F; Feldman, Jack L (2018) Efferent projections of excitatory and inhibitory preBötzinger Complex neurons. J Comp Neurol 526:1389-1402|
|Yackle, Kevin; Schwarz, Lindsay A; Kam, Kaiwen et al. (2017) Breathing control center neurons that promote arousal in mice. Science 355:1411-1415|
|Huckstepp, Robert Tr; Henderson, Lauren E; Cardoza, Kathryn P et al. (2016) Interactions between respiratory oscillators in adult rats. Elife 5:|