Breathing is a remarkable behavior that mediates gas exchange to support metabolism and regulate pH. A reliable and robust rhythm is essential for breathing in mammals. Failure to maintain a normal breathing rhythm 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 underlying circuits and the functional contribution of each neuronal subtype to respiratory rhythmogenesis must be revealed. We focus on two brain sites essential for generation of the normal breathing pattern, the preB?tzinger Complex and the retrotrapezoid nucleus/parafacial respiratory group. We will exploit: i) a novel method for rapid changes in excitability of genetically targeted neurons to affect respiration, and;ii) newly developed techniques for the study of neuronal projections. Using a viral delivery system, we will express genetically encoded fluorescent proteins or the allatostatin receptor in targeted subpopulations of neurons in these key regions. Rapid changes in the excitability of these neuronal subpopulations by administration of allatostatin in anesthetized or behaving rodents should produce noticeable, even profound perturbations in breathing that will illuminate their functional roles. Defining the detailed anatomical organization of the respiratory central pattern generator is essential to advance our understanding of the neural control of breathing and determining the perturbations that arise from selectively suppressing neuronal subtypes will provide a unique and extraordinary window into understanding mechanisms of central respiratory rhythm and pattern generation.

Public Health Relevance

In humans, continuous breathing from birth is essential to life and requires that the nervous system generate a reliable and robust rhythm that drives inspiratory and expiratory muscles. The proposed studies will significantly advance our understanding of the neural mechanisms generating respiratory rhythm and shed light on human disorders of breathing.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Laposky, Aaron D
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Yackle, Kevin; Schwarz, Lindsay A; Kam, Kaiwen et al. (2017) Breathing control center neurons that promote arousal in mice. Science 355:1411-1415
Cui, Yan; Kam, Kaiwen; Sherman, David et al. (2016) Defining preBötzinger Complex Rhythm- and Pattern-Generating Neural Microcircuits In Vivo. Neuron 91:602-14
Huckstepp, Robert Tr; Henderson, Lauren E; Cardoza, Kathryn P et al. (2016) Interactions between respiratory oscillators in adult rats. Elife 5:
Sung, Kevin; Ding, Yichen; Ma, Jianguo et al. (2016) Simplified three-dimensional tissue clearing and incorporation of colorimetric phenotyping. Sci Rep 6:30736
Li, Peng; Janczewski, Wiktor A; Yackle, Kevin et al. (2016) The peptidergic control circuit for sighing. Nature 530:293-297
Feldman, Jack L; Kam, Kaiwen (2015) Facing the challenge of mammalian neural microcircuits: taking a few breaths may help. J Physiol 593:3-23
Huckstepp, Robert T R; Cardoza, Kathryn P; Henderson, Lauren E et al. (2015) Role of parafacial nuclei in control of breathing in adult rats. J Neurosci 35:1052-67
Dick, T E; Dutschmann, M; Feldman, J L et al. (2015) Facts and challenges in respiratory neurobiology. Respir Physiol Neurobiol :
Feldman, Jack L; Del Negro, Christopher A; Gray, Paul A (2013) Understanding the rhythm of breathing: so near, yet so far. Annu Rev Physiol 75:423-52
Kam, Kaiwen; Worrell, Jason W; Ventalon, Cathie et al. (2013) Emergence of population bursts from simultaneous activation of small subsets of preBotzinger complex inspiratory neurons. J Neurosci 33:3332-8

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