This proposal is to understand processes by which motoneurons innervating respiratory muscles function properly. Phrenic motoneurons integrate rhythmic, tonic and episodic inputs to produce an output that results in contraction of the diaphragm that subserves breathing, phonation, emesis, defecation, etc. Hypoglossal motoneurons control tongue muscles for swallowing, chewing, phonation and breathing, where they affect upper airway resistance.
The aim of this application is to understand the control of the excitability of these neurons as they subserve breathing. Modulation of AMPA receptor function mediating inspiratory drive in these motoneurons by phosphorylation and dephosphorylation is postulated by a critical component in control of respiratory motor output. Electrophysiological studies will be done under in vitro conditions where we will record from neonatal rodent motoneurons while they receive endogenous respiratory-relative drive, conditions advantageous for determination of synaptic and cellular mechanisms specifically related to respiratory function. Histological studies will determine the presence within the phrenic and hypoglossal nuclei of kinases and phosphatases that can underlie phosphorylation of AMPA receptors of associated proteins. Pathologies of breathing such as sleep apnea, central alveolar hyperventilation, central inspiratory muscle fatigue and (perhaps) sudden infant death syndrome result from failure to generate adequate respiratory muscle activity; the degree that these failures occur at motoneurons is unknown. Therapeutic and/or abusive drugs that affect breathing, e.g., anesthetics or opiates, produce effects that may be ameliorated by pharmacological manipulation. Understanding the synaptic physiology of the control of breathing, in specific respiratory motoneurons, is essential for further rational development of therapies and treatments for breathing dysfunctions. Principles governing the control of respiratory rhythm generating neurons which also process rhythmic inputs mediated by AMPA receptors these. These results may reveal modulatory mechanisms common to other motoneurons, particularly those controlling muscle involved in rhythmic activities (e.g., locomotion, mastication, and nystagmus). The properties of different neuron types may be regulated phenotypically to optimize neuronal performance based on function. This proposal will provide the basis for such an interpretation concerning phrenic and hypoglossal motoneurons. Our unique advantage of making measurements in the context of behavior may reveal critical elements underlying control of neuronal excitability and its modulation in the normal transactions of the intact living brain.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Respiratory and Applied Physiology Study Section (RAP)
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Chiu, Arlene Y
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Dick, T E; Dutschmann, M; Feldman, J L et al. (2018) Facts and challenges in respiratory neurobiology. Respir Physiol Neurobiol 258:104-107
Babiec, Walter E; Faull, Kym F; Feldman, Jack L (2012) Cyclothiazide-induced persistent increase in respiratory-related activity in vitro. J Physiol 590:4897-915
Saywell, Shane A; Babiec, Walter E; Neverova, Natalia V et al. (2010) Protein kinase G-dependent mechanisms modulate hypoglossal motoneuronal excitability and long-term facilitation. J Physiol 588:4431-9
Neverova, Natalia V; Saywell, Shane A; Nashold, Lisa J et al. (2007) Episodic stimulation of alpha1-adrenoreceptors induces protein kinase C-dependent persistent changes in motoneuronal excitability. J Neurosci 27:4435-42
Feldman, Jack L; Neverova, Natalia V; Saywell, Shane A (2005) Modulation of hypoglossal motoneuron excitability by intracellular signal transduction cascades. Respir Physiol Neurobiol 147:131-43
Bocchiaro, Christopher M; Feldman, Jack L (2004) Synaptic activity-independent persistent plasticity in endogenously active mammalian motoneurons. Proc Natl Acad Sci U S A 101:4292-5
Saywell, Shane A; Feldman, Jack L (2004) Dynamic interactions of excitatory and inhibitory inputs in hypoglossal motoneurones: respiratory phasing and modulation by PKA. J Physiol 554:879-89
Feldman, Jack L; Mitchell, Gordon S; Nattie, Eugene E (2003) Breathing: rhythmicity, plasticity, chemosensitivity. Annu Rev Neurosci 26:239-66
Bocchiaro, Christopher M; Saywell, Shane A; Feldman, Jack L (2003) Dynamic modulation of inspiratory drive currents by protein kinase A and protein phosphatases in functionally active motoneurons. J Neurosci 23:1099-103
Parkis, Marjorie A; Feldman, Jack L; Robinson, Dean M et al. (2003) Oscillations in endogenous inputs to neurons affect excitability and signal processing. J Neurosci 23:8152-8

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