Neural Control of Breathing

PROJECT SUMMARY/ ABSTRACT 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 neuro- degenerative diseases, such as Parkinson's disease, multiple systems atrophy, and amyotrophic lateral sclerosis, are associated with sleep disordered breathing that appear to result from the loss of neurons in brain areas controlling breathing. If breathing is to be understood in normal and in pathological conditions, the mechanisms for breathing central pattern generation must be revealed. We focus on two brainstem sites essential for generation of the normal breathing pattern, the preBötzinger Complex and the retrotrapezoid nucleus/parafacial respiratory group. We propose a broad series of experiments both in vivo and in vitro in rodents using state-of-the-art techniques to significantly advance our under- standing of respiratory rhythm and pattern generation to provide an extraordinary window into the mechanisms underlying the neural control of breathing. Such advancements will be foundational for development of highly novel therapies for treating human diseases of breathing.