Acute intermittent hypoxia elicits a unique form of plasticity in the neural control of breathing, respiratory long-term facilitation (LTF). The resulting plasticity is unique in the sense that an equal cumulative duration of sustained hypoxia does not elicit the same underlying mechanisms. We propose to investigate cellular mechanisms giving rise to LTF in phrenic nerve activity (pLTF) in vivo, and to determine some of the mechanisms that distinguish sustained and intermittent hypoxia. Our working model is that intermittent (but not sustained) hypoxia increases synthesis of brain-derived neurotrophic factor (BDNF) within phrenic motoneurons. We propose that BDNF activates extracellular regulated kinases (ERK 1/2), members of the MAP kinase family, within phrenic motoneurons. ERK 1/2 subsequently strengthens the synapse between brainstem premotor neurons and phrenic neurons, thereby establishing pLTF. We suggest that sustained hypoxia is unique in that it also activates protein phosphatases, which halt the mechanisms leading to increased BDNF synthesis. Thus, pLTF is observed following intermittent, but not sustained, hypoxia, largely through the differential regulation of phosphatase activity. We will pursue four specific aims to test the hypotheses that: 1) Intermittent (but not sustained) hypoxia increases BDNF synthesis near respiratory motoneurons; 2) Increased BDNF synthesis within phrenic motoneurons is necessary for pLTF; 3) Increased ERK 1/2 MAP kinase activation following intermittent hypoxia is necessary for pLTF; and 4) Sustained (but not intermittent) hypoxia activates protein phosphatases within phrenic motoneurons and halts the mechanisms leading to increased BDNF synthesis, ERK 1/2 activation and pLTF. A strength of this proposal is the multidisciplinary approach, including the application of modern molecular biological techniques such as RNA interference, towards an understanding of respiratory neuroplasticity in vivo. A thorough understanding of mechanisms leading to respiratory plasticity may provide the rationale for new therapeutic approaches to the treatment of devastating respiratory control disorders such as obstructive sleep apnea, respiratory insufficiency following spinal cord injury, Rhett Syndrome and Sudden Infant Death Syndrome.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL080209-04
Application #
7434358
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Twery, Michael
Project Start
2005-07-18
Project End
2009-12-31
Budget Start
2008-07-01
Budget End
2009-12-31
Support Year
4
Fiscal Year
2008
Total Cost
$344,900
Indirect Cost
Name
University of Wisconsin Madison
Department
Biology
Type
Schools of Veterinary Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Satriotomo, I; Nichols, N L; Dale, E A et al. (2016) Repetitive acute intermittent hypoxia increases growth/neurotrophic factor expression in non-respiratory motor neurons. Neuroscience 322:479-88
Devinney, Michael J; Nichols, Nicole L; Mitchell, Gordon S (2016) Sustained Hypoxia Elicits Competing Spinal Mechanisms of Phrenic Motor Facilitation. J Neurosci 36:7877-85
Nichols, Nicole L; Mitchell, Gordon S (2016) Quantitative assessment of integrated phrenic nerve activity. Respir Physiol Neurobiol 226:81-6
Navarrete-Opazo, A; Vinit, S; Dougherty, B J et al. (2015) Daily acute intermittent hypoxia elicits functional recovery of diaphragm and inspiratory intercostal muscle activity after acute cervical spinal injury. Exp Neurol 266:1-10
Nichols, Nicole L; Satriotomo, Irawan; Harrigan, Daniel J et al. (2015) Acute intermittent hypoxia induced phrenic long-term facilitation despite increased SOD1 expression in a rat model of ALS. Exp Neurol 273:138-50
Nichols, Nicole L; Vinit, Stéphane; Bauernschmidt, Lorene et al. (2015) Respiratory function after selective respiratory motor neuron death from intrapleural CTB-saporin injections. Exp Neurol 267:18-29
Gonzalez-Rothi, Elisa J; Lee, Kun-Ze; Dale, Erica A et al. (2015) Intermittent hypoxia and neurorehabilitation. J Appl Physiol (1985) 119:1455-65
Fields, D P; Springborn, S R; Mitchell, G S (2015) Spinal 5-HT7 receptors induce phrenic motor facilitation via EPAC-mTORC1 signaling. J Neurophysiol 114:2015-22
Devinney, Michael J; Fields, Daryl P; Huxtable, Adrianne G et al. (2015) Phrenic long-term facilitation requires PKCθ activity within phrenic motor neurons. J Neurosci 35:8107-17
MacFarlane, P M; Vinit, S; Mitchell, G S (2014) Spinal nNOS regulates phrenic motor facilitation by a 5-HT2B receptor- and NADPH oxidase-dependent mechanism. Neuroscience 269:67-78

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