Factors that undermine the neural system controlling breathing diminish the capacity to compensate for pathology, threatening life itself. Plasticity is an essential feature of neural systems, including the neural system controlling breathing. The fundamental hypothesis guiding this proposal is that systemic inflammation impairs respiratory motor plasticity, undermining the ability to compensate for multiple pathologies, including chronic lung disease, traumatic, ischemic and degenerative neural disorders, and obstructive sleep apnea. We propose to investigate mechanisms whereby inflammation impairs a well-studied model of respiratory motor plasticity, phrenic long-term facilitiation (pLTF) following acute intermittent hypoxia. We will contrast inflammation induced by lipopolysaccharide (LPS) with that induced by one day of severe intermittent hypoxia (sIH); sIH simulates aspects of obstructive sleep apnea, a widespread clinical disorder with major implications for human health. Exciting preliminary data suggest that both LPS and sIH block pLTF via spinal inflammation. Since LPS and sIH elicit differential gene expression in different spinal cell types, yet have similar effects on pLTF, we propose a unifying hypothesis whereby multiple inflammatory molecules converge on a common downstream signaling cascade that constrains respiratory motor plasticity. An innovative, multidisciplinary approach will be used to test our hypotheses; experimental approaches include: phrenic nerve recordings in anesthetized rats, diaphragm EMG recordings in unanesthetized rats, immunohistochemical analysis of proteins in labeled phrenic motor neurons, analysis of inflammatory gene expression in freshly-isolated spinal astrocytes and microglia, and flow cytometry to assess proteins in identified cell types. Five specific hypotheses will be tested to advance our understanding: 1) Systemic LPS and sIH elicit spinal inflammation, thereby impairing phrenic and diaphragm LTF; 2) LPS and sIH differentially impair distinct pathways to phrenic motor facilitation (pMF). We will determine LPS and sIH effects on ERK- dependent (eg. pLTF), Akt-dependent and ERK/Akt-dependent pMF; 3) LPS and sIH elicit distinct inflammatory profiles. sIH affects only spinal microglia, whereas LPS also affects astrocytes; 4) Despite different inflammatory profiles, LPS and sIH impair pLTF by a common downstream mechanism involving p38 MAP kinase activation in phrenic motor neurons; and 5) Spinal p38 activity increases protein phosphatase 2A activity in phrenic motor neurons, thereby inhibiting ERK and constraining pLTF. Understanding mechanisms whereby inflammation undermines respiratory plasticity is of fundamental importance since inflammation may diminish the capacity for natural, compensatory plasticity during pathological states. Our long-range goal is to harness and promote respiratory plasticity as a therapeutic strategy to treat devastating breathing disorders, such as during cervical spinal injury or motor neuron disease.

Public Health Relevance

All lung and CNS disorders that challenge the ability to generate adequate breathing are associated with inflammation, including chronic lung diseases, traumatic, ischemic and degenerative neural disorders, and obstructive sleep apnea. Although these pathologies have profound consequences for public health, virtually nothing is known concerning the impact of inflammation on the neural system controlling breathing. Our goal is to investigate mechanisms whereby inflammation undermines a well-studied model of respiratory motor plasticity known as long-term facilitation since this knowledge may guide the development of novel therapeutic strategies to treat breathing disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL111598-04
Application #
8791340
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Laposky, Aaron D
Project Start
2012-01-15
Project End
2016-12-31
Budget Start
2015-01-01
Budget End
2015-12-31
Support Year
4
Fiscal Year
2015
Total Cost
$569,963
Indirect Cost
$188,637
Name
University of Wisconsin Madison
Department
Biology
Type
Schools of Veterinary Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Turner, Sara; Streeter, Kristi A; Greer, John et al. (2018) Pharmacological modulation of hypoxia-induced respiratory neuroplasticity. Respir Physiol Neurobiol 256:4-14
Huxtable, Adrianne G; Kopp, Elizabeth; Dougherty, Brendan J et al. (2018) Cyclooxygenase enzyme activity does not impair respiratory motor plasticity after one night of intermittent hypoxia. Respir Physiol Neurobiol 256:21-28
Devinney, Michael J; Mitchell, Gordon S (2018) Spinal activation of protein kinase C elicits phrenic motor facilitation. Respir Physiol Neurobiol 256:36-42
Agosto-Marlin, Ibis M; Nichols, Nicole L; Mitchell, Gordon S (2018) Systemic inflammation inhibits serotonin receptor 2-induced phrenic motor facilitation upstream from BDNF/TrkB signaling. J Neurophysiol 119:2176-2185
Dougherty, Brendan J; Kopp, Elizabeth S; Watters, Jyoti J (2017) Nongenomic Actions of 17-? Estradiol Restore Respiratory Neuroplasticity in Young Ovariectomized Female Rats. J Neurosci 37:6648-6660
Hocker, Austin D; Stokes, Jennifer A; Powell, Frank L et al. (2017) The impact of inflammation on respiratory plasticity. Exp Neurol 287:243-253
Agosto-Marlin, Ibis M; Nichols, Nicole L; Mitchell, Gordon S (2017) Adenosine-dependent phrenic motor facilitation is inflammation resistant. J Neurophysiol 117:836-845
Kharbush, Rima J; Gutwillig, Allison; Hartzler, Kate E et al. (2017) Antinociceptive and respiratory effects following application of transdermal fentanyl patches and assessment of brain ?-opioid receptor mRNA expression in ball pythons. Am J Vet Res 78:785-795
Cheng, Kevin P; Kiernan, Elizabeth A; Eliceiri, Kevin W et al. (2016) Blue Light Modulates Murine Microglial Gene Expression in the Absence of Optogenetic Protein Expression. Sci Rep 6:21172
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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