The fundamental hypothesis guiding this proposal is that chronic treatments, known to enhance serotonergic modulation of respiratory motor output, strengthen respiratory synaptic pathways to spinal (phrenic) motoneurons, thereby improving respiratory function during recovery from spinal cord injury. In specific, we will investigate the effects of Chronic Intermittent Hypoxia (CIH) and spinal deafferentation via Cervical Dorsal Rhizotomy (CDR) on synaptic pathways to phrenic motoneuronsprior to acute spinal hemisection orfollowing chronic spinal hemisection. Our laboratory has previously shown that both CIH and CDR enhance serotonergic modulation of phrenic motor output, but appear to do so by different mechanisms. We have also shown that spinal serotonin receptor activation enhances both functional and ineffective (crossed-spinal) synaptic pathways in rats. Thus, we will apply these unique models of serotonin-dependent respiratory plasticity to test the hypothesis that they will restore respiratory drive to phrenic motoneurons on the injured (hemisected) side, and enhance respiratory drive to phrenic motoneurons on the uninjured (non-hemisected) side.
In Aims 1 and 2, we will test the hypotheses that pretreatment with either CIH or CDR enhances evoked and spontaneous phrenic activity in intact and crossed-spinal pathways in anesthetized rats. In the:next three aims, we will apply CIH following chronic spinal hemisection to test the hypotheses that CIH enhances evoked and spontaneous phrenic activity in anesthetized rats (Aim 3), restores ventilatory responses to chemoreceptor stimulation in unanesthetized rats (Aim 4), and increases ventral spinal concentrations of brain derived neurotrophic factor below the hemisection (Aim 5). This study provides an unprecedented opportunity to determine whether two unique experimental treatments restore respiratory motor function below a well-defined cervical spinal injury, and provides the basis for highly novel therapeutic approaches in the treatment of respiratory insufficiency following spinal cord injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL069064-10
Application #
7994190
Study Section
Special Emphasis Panel (NSS)
Program Officer
Laposky, Aaron D
Project Start
2002-01-01
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2012-12-31
Support Year
10
Fiscal Year
2011
Total Cost
$397,288
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
Agosto-Marlin, Ibis M; Nichols, Nicole L; Mitchell, Gordon S (2016) Adenosine-Dependent Phrenic Motor Facilitation is Inflammation Resistant. J Neurophysiol :jn.00619.2016
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
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
Dougherty, Brendan J; Fields, Daryl P; Mitchell, Gordon S (2015) Mammalian target of rapamycin is required for phrenic long-term facilitation following severe but not moderate acute intermittent hypoxia. J Neurophysiol 114:1784-91
Navarrete-Opazo, Angela; Mitchell, Gordon S (2014) Therapeutic potential of intermittent hypoxia: a matter of dose. Am J Physiol Regul Integr Comp Physiol 307:R1181-97
Huxtable, A G; MacFarlane, P M; Vinit, S et al. (2014) Adrenergic α₁ receptor activation is sufficient, but not necessary for phrenic long-term facilitation. J Appl Physiol (1985) 116:1345-52

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