PMID- 27466333
OWN - NLM
STAT- MEDLINE
DCOM- 20170710
LR  - 20240327
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 36
IP  - 30
DP  - 2016 Jul 27
TI  - Sustained Hypoxia Elicits Competing Spinal Mechanisms of Phrenic Motor 
      Facilitation.
PG  - 7877-85
LID - 10.1523/JNEUROSCI.4122-15.2016 [doi]
AB  - Acute intermittent hypoxia (AIH) induces phrenic long-term facilitation (pLTF), a 
      form of spinal motor plasticity. Competing mechanisms give rise to phrenic motor 
      facilitation (pMF; a general term including pLTF) depending on the severity of 
      hypoxia within episodes. In contrast, moderate acute sustained hypoxia (mASH) 
      does not elicit pMF. By varying the severity of ASH and targeting competing 
      mechanisms of pMF, we sought to illustrate why moderate AIH (mAIH) elicits pMF 
      but mASH does not. Although mAIH elicits serotonin-dependent pLTF, mASH does not; 
      thus, mAIH-induced pLTF is pattern sensitive. In contrast, severe AIH (sAIH) 
      elicits pLTF through adenosine-dependent mechanisms, likely from greater 
      extracellular adenosine accumulation. Because serotonin- and adenosine-dependent 
      pMF interact via cross talk inhibition, we hypothesized that pMF is obscured 
      because the competing mechanisms of pMF are balanced and offsetting during mASH. 
      Here, we demonstrate the following: (1) blocking spinal A2A receptors with MSX-3 
      reveals mASH-induced pMF; and (2) sASH elicits A2A-dependent pMF. In anesthetized 
      rats pretreated with intrathecal A2A receptor antagonist injections before mASH 
      (PaO2 = 40-54 mmHg) or sASH (PaO2 = 25-36 mmHg), (1) mASH induced a 
      serotonin-dependent pMF and (2) sASH induced an adenosine-dependent pMF, which 
      was enhanced by spinal serotonin receptor inhibition. Thus, competing adenosine- 
      and serotonin-dependent mechanisms contribute differentially to pMF depending on 
      the pattern/severity of hypoxia. Understanding interactions between these 
      mechanisms has clinical relevance as we develop therapies to treat severe 
      neuromuscular disorders that compromise somatic motor behaviors, including 
      breathing. Moreover, these results demonstrate how competing mechanisms of 
      plasticity can give rise to pattern sensitivity in pLTF. SIGNIFICANCE STATEMENT: 
      Intermittent hypoxia elicits pattern-sensitive spinal plasticity and improves 
      motor function after spinal injury or during neuromuscular disease. Specific 
      mechanisms of pattern sensitivity in this form of plasticity are unknown. We 
      provide evidence that competing mechanisms of phrenic motor facilitation mediated 
      by adenosine 2A and serotonin 2 receptors are differentially expressed, depending 
      on the pattern/severity of hypoxia. Understanding how these distinct mechanisms 
      interact during hypoxic exposures differing in severity and duration will help 
      explain interesting properties of plasticity, such as pattern sensitivity, and 
      may help optimize therapies to restore motor function in patients with 
      neuromuscular disorders that compromise movement.
CI  - Copyright (c) 2016 the authors 0270-6474/16/367877-09$15.00/0.
FAU - Devinney, Michael J
AU  - Devinney MJ
AUID- ORCID: 0000-0003-3906-6421
AD  - Department of Comparative Biosciences, University of Wisconsin, Madison, 
      Wisconsin 53706, and.
FAU - Nichols, Nicole L
AU  - Nichols NL
AUID- ORCID: 0000-0003-3837-0069
AD  - Department of Comparative Biosciences, University of Wisconsin, Madison, 
      Wisconsin 53706, and.
FAU - Mitchell, Gordon S
AU  - Mitchell GS
AUID- ORCID: 0000-0002-8489-1861
AD  - Department of Comparative Biosciences, University of Wisconsin, Madison, 
      Wisconsin 53706, and Department of Physical Therapy, Center for Respiratory 
      Research and Rehabilitation and McKnight Brain Institute, University of Florida, 
      Gainesville, Florida 32610 gsmitche@phhp.ufl.edu.
LA  - eng
GR  - R00 HL119606/HL/NHLBI NIH HHS/United States
GR  - R01 HL080209/HL/NHLBI NIH HHS/United States
GR  - T32 HL007654/HL/NHLBI NIH HHS/United States
GR  - T32 GM008692/GM/NIGMS NIH HHS/United States
GR  - T32 GM007507/GM/NIGMS NIH HHS/United States
GR  - R37 HL069064/HL/NHLBI NIH HHS/United States
GR  - R01 HL111598/HL/NHLBI NIH HHS/United States
GR  - R01 HL069064/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
SB  - IM
MH  - Animals
MH  - *Central Pattern Generators
MH  - Chronic Disease
MH  - Hypoxia/*physiopathology
MH  - *Long-Term Potentiation
MH  - Male
MH  - *Motor Neurons
MH  - Movement
MH  - Nerve Net/physiopathology
MH  - Neuronal Plasticity
MH  - Phrenic Nerve/*physiopathology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Spinal Cord/*physiopathology
PMC - PMC4961775
OTO - NOTNLM
OT  - hypoxia
OT  - long-term facilitation
OT  - motor control
OT  - pattern sensitivity
OT  - phrenic
OT  - spinal cord
EDAT- 2016/07/29 06:00
MHDA- 2017/07/14 06:00
PMCR- 2017/01/27
CRDT- 2016/07/29 06:00
PHST- 2015/10/11 00:00 [received]
PHST- 2016/05/23 00:00 [accepted]
PHST- 2016/07/29 06:00 [entrez]
PHST- 2016/07/29 06:00 [pubmed]
PHST- 2017/07/14 06:00 [medline]
PHST- 2017/01/27 00:00 [pmc-release]
AID - 36/30/7877 [pii]
AID - 4122-15 [pii]
AID - 10.1523/JNEUROSCI.4122-15.2016 [doi]
PST - ppublish
SO  - J Neurosci. 2016 Jul 27;36(30):7877-85. doi: 10.1523/JNEUROSCI.4122-15.2016.