My long-term objective is to understand the mechanisms generating and modulating respiratory rhythm. l will exploit a novel optical method for exciting small numbers of targeted neurons (<10) to dissect the neural microcircuit in the preBvtzinger Complex, a key site for generation of respiratory rhythm. Breathing is an essential continuous behavior in mammals. Disruption of brainstem centers regulating breathing underlies disorders such as sleep apnea, Rett syndrome, central congenital hypoventilation syndrome (CCHS) and possibly sudden infant death syndrome (SIDS). Neurologic disorders such as Parkington's disease, multiple systems atrophy and amyotropic lateral sclerosis are associated with sleep- disordered breathing. Our current understanding of the neuronal structures underlying respiration and their synaptic and electrical connectivity is limited, and as such a serious hindrance to understanding the neural control of breathing in health and disease. A critical element for generation of the inspiratory phase of respiration is the preBvtzinger Complex (preBvtC), hypothesized to be the site of the inspiratory oscillator. Because the preBvtC is comprised of a heterogeneous population of neurons, and displays no obvious gross anatomical organization, it has been difficult to distinguish the structure of the preBvtC neuronal network and to determine how this structure supports the function of respiration. If breathing is to be understood in normal and in pathological conditions, the mechanisms for respiratory rhythmogenesis must be revealed. Here, in slices from the brainstem that contain the preBvtzinger Complex and generate a respiratory rhythm, I will study the mechanisms underlying the triggering of inspiratory bursts of motor nerve activity. Using advanced optical techniques, I will simultaneously stimulate one to several preBvtzinger Complex inspiratory neurons. I provide preliminary data that activation of 3-9 preBvtzinger Complex inspiratory neurons can trigger an inspiratory motor nerve burst. I propose to validate, refine and extend these experiments to elucidate the structure and function of preBvtC, a key element of the neural circuit controlling breathing. By exploiting advanced optical methods, I can achieve my ultimate goal of obtaining a dataset sufficient for representative and testable modeling that incorporates detailed preBvtC circuit topology, necessary for a deep understanding of this vital behavior. The data obtained here has the potential to provide an extraordinary window into understanding mechanisms of respiratory rhythm.

Public Health Relevance

The preBvtzinger Complex (preBvtC) is an essential element of the brainstem circuitry underlying breathing. Disruption of the preBvtC is proposed to underlie disorders such as sleep apnea, Rett syndrome, and sudden infant death syndrome and has been associated with sleep-disordered breathing in neurologic disorders such as Parkinson's disease, multiple system atrophy, and amyotropic lateral sclerosis. Knowledge of the preBvtC network structure will greatly aid our understanding of how respiration is generated and further our efforts to tackle the health-related issues that follow central disruption of breathing.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F02B-M (20))
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Gnadt, James W
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University of California Los Angeles
Schools of Medicine
Los Angeles
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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
Kam, Kaiwen; Worrell, Jason W; Janczewski, Wiktor A et al. (2013) Distinct inspiratory rhythm and pattern generating mechanisms in the preBotzinger complex. J Neurosci 33:9235-45