Cervical spinal cord injury (SCI) disrupts neural pathways to respiratory motor neurons, diminishing breathing capacity. Since even modest breathing impairment greatly increases susceptibility to life-threatening lung infections, restorin lost breathing capacity will improve the quality and duration of life. With funding from this MERIT Award, we discovered that repetitive acute intermittent hypoxia (rAIH) triggers plasticity in spared neural pathways to respiratory motor neurons, thereby restoring lost breathing capacity. We propose to extend these findings by addressing fundamental gaps in our knowledge concerning mechanisms of rAIH-induced functional recovery in rats with cervical SCI. The fundamental hypothesis guiding this proposal is that completely different cellular mechanisms underlie rAIH-induced functional recovery in early (<4 weeks) versus chronic SCI (>4 weeks). We propose that rAIH elicits plasticity via adenosinergic mechanisms in early SCI, but serotonin-dependent (adenosine-constrained) mechanisms in chronic SCI. This surprising idea will change the way we think about respiratory plasticity following SCI. Indeed, the realization that mechanisms giving rise to rAIH-induced plasticity and functional recovery are time-dependent will profoundly alter our ability to harness rAIH as a therapeutic intervention in humans with respiratory insufficiency due to chronic SCI. Since AIH-induced respiratory plasticity is impaired by systemic inflammation and constrained by cross-talk inhibition from competing mechanisms of phrenic motor facilitation, we hypothesize that functional outcomes may be improved by diminishing these factors in chronic (not early) SCI. We propose to investigate rAIH-induced functional recovery with a highly novel, multi-disciplinary approach including: 1) plethysmography to assess breathing capacity;2) EMG telemetry of respiratory muscles;3) flow cytometry to assess changes in identified respiratory motor neurons;4) immuno-fluorescence to assess key proteins in situ;and 5) manipulation of respiratory motor neuron gene expression via RNA interference in vivo.
Three specific aims are proposed to test the hypotheses that: 1) adenosine- (early) and serotonin-dependent (chronic) mechanisms dominate rAIH- induced functional recovery at different times post-injury;a corollary is that spinal adenosine 2A receptor inhibition augments rAIH-induced functional recovery in chronic (not early) SCI;2) the contributions of different inspiratory muscles shift with time post-injury; and 3) systemic inflammation impairs rAIH-induced functional recovery in chronic (not early) SCI. Although rAIH has potential to be a safe, non-invasive treatment for SCI- induced respiratory impairment, any rational translation of this promising therapy will require detailed understanding of its underlying mechanisms, including complexities such as shifting mechanisms with time post-injury and factors that degrade its therapeutic efficacy. rAIH represents a promising new strategy to enhance function in patients with chronic SCI, where the prognosis for functional gains is bleak.

Public Health Relevance

Cervical spinal injury disrupts neural pathways in the spinal cord, often leading to death from inadequate breathing capacity. The prognosis for meaningful functional recovery is bleak. Our goal is to understand simple procedures to stimulate spinal cord plasticity as a means of strengthening spared neural pathways to the spinal nerve cells that drive breathing, thereby restoring lost breathing capacity.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL069064-11A1
Application #
8654482
Study Section
Special Emphasis Panel (ZRG1-CVRS-M (03))
Program Officer
Laposky, Aaron D
Project Start
2002-01-01
Project End
2018-01-31
Budget Start
2014-02-15
Budget End
2015-01-31
Support Year
11
Fiscal Year
2014
Total Cost
$719,953
Indirect Cost
$241,579
Name
University of Wisconsin Madison
Department
Biology
Type
Schools of Veterinary Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Fuller, David D; Mitchell, Gordon S (2017) Special Issue: Respiratory Neuroplasticity. Exp Neurol 287:91-92
Agosto-Marlin, Ibis M; Nichols, Nicole L; Mitchell, Gordon S (2017) Adenosine-dependent phrenic motor facilitation is inflammation resistant. J Neurophysiol 117:836-845
Nichols, Nicole L; Satriotomo, Irawan; Allen, Latoya L et al. (2017) Mechanisms of Enhanced Phrenic Long-Term Facilitation in SOD1G93A Rats. J Neurosci 37:5834-5845
Navarrete-Opazo, A; Dougherty, B J; Mitchell, G S (2017) Enhanced recovery of breathing capacity from combined adenosine 2A receptor inhibition and daily acute intermittent hypoxia after chronic cervical spinal injury. Exp Neurol 287:93-101
Fields, D P; Mitchell, G S (2017) Divergent cAMP signaling differentially regulates serotonin-induced spinal motor plasticity. Neuropharmacology 113:82-88
Dougherty, B J; Terada, J; Springborn, S R et al. (2017) Daily acute intermittent hypoxia improves breathing function with acute and chronic spinal injury via distinct mechanisms. Respir Physiol Neurobiol :
Dale, Erica A; Fields, Daryl P; Devinney, Michael J et al. (2017) Phrenic motor neuron TrkB expression is necessary for acute intermittent hypoxia-induced phrenic long-term facilitation. Exp Neurol 287:130-136
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
Nichols, Nicole L; Mitchell, Gordon S (2016) Quantitative assessment of integrated phrenic nerve activity. Respir Physiol Neurobiol 226:81-6
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

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