Functional regeneration of respiratory pathways after spinal cord injury.
Journal - Nature (England )
Spinal cord injuries often occur at the cervical level above the phrenic motor pools, which innervate the diaphragm. The effects of impaired breathing are a leading cause of death from spinal cord injuries, underscoring the importance of developing strategies to restore respiratory activity. Here we show that, after cervical spinal cord injury, the expression of chondroitin sulphate proteoglycans (CSPGs) associated with the perineuronal net (PNN) is upregulated around the phrenic motor neurons. Digestion of these potently inhibitory extracellular matrix molecules with chondroitinase ABC (denoted ChABC) could, by itself, promote the plasticity of tracts that were spared and restore limited activity to the paralysed diaphragm. However, when combined with a peripheral nerve autograft, ChABC treatment resulted in lengthy regeneration of serotonin-containing axons and other bulbospinal fibres and remarkable recovery of diaphragmatic function. After recovery and initial transection of the graft bridge, there was an unusual, overall increase in tonic electromyographic activity of the diaphragm, suggesting that considerable remodelling of the spinal cord circuitry occurs after regeneration. This increase was followed by complete elimination of the restored activity, proving that regeneration is crucial for the return of function. Overall, these experiments present a way to markedly restore the function of a single muscle after debilitating trauma to the central nervous system, through both promoting the plasticity of spared tracts and regenerating essential pathways.©2011 Macmillan Publishers Limited. All rights reserved
|ISSN : ||1476-4687|
|Mesh Heading : ||Animals Axons Chondroitin ABC Lyase Chondroitin Sulfate Proteoglycans Diaphragm Disease Models, Animal Electromyography Extracellular Matrix Nerve Net Nerve Regeneration Neuronal Plasticity Phrenic Nerve Rats Spinal Cord Injuries physiology metabolism metabolism physiology metabolism physiology physiology cytology physiology surgery transplantation|
|Mesh Heading Relevant : ||Respiration physiology physiopathology|
Light-induced rescue of breathing after spinal cord injury.
Journal - The Journal of neuroscience : the official journal of the Society for Neuroscience (United States )
Paralysis is a major consequence of spinal cord injury (SCI). After cervical SCI, respiratory deficits can result through interruption of descending presynaptic inputs to respiratory motor neurons in the spinal cord. Expression of channelrhodopsin-2 (ChR2) and photostimulation in neurons affects neuronal excitability and produces action potentials without any kind of presynaptic inputs. We hypothesized that after transducing spinal neurons in and around the phrenic motor pool to express ChR2, photostimulation would restore respiratory motor function in cervical SCI adult animals. Here we show that light activation of ChR2-expressing animals was sufficient to bring about recovery of respiratory diaphragmatic motor activity. Furthermore, robust rhythmic activity persisted long after photostimulation had ceased. This recovery was accomplished through a form of respiratory plasticity and spinal adaptation which is NMDA receptor dependent. These data suggest a novel, minimally invasive therapeutic avenue to exercise denervated circuitry and/or restore motor function after SCI.
|ISSN : ||1529-2401|
|Mesh Heading : ||Animals Anterior Horn Cells Diaphragm Disease Models, Animal Female Neural Pathways Neuronal Plasticity Paralysis Periodicity Phototherapy Rats Rats, Sprague-Dawley Receptors, N-Methyl-D-Aspartate Respiration Respiratory Insufficiency Rhodopsin Spinal Cord Spinal Cord Injuries Treatment Outcome metabolism physiopathology innervation physiology metabolism physiopathology radiation effects physiology radiation effects metabolism physiopathology therapy metabolism etiology physiopathology metabolism radiation effects metabolism physiopathology radiation effects metabolism physiopathology|
|Mesh Heading Relevant : ||radiation effects methods radiation effects therapy therapy|
MK-801 upregulates NR2A protein levels and induces functional recovery of the ipsilateral hemidiaphragm following acute C2 hemisection in adult rats.
Journal - The journal of spinal cord medicine (United States )
BACKGROUND: C2 hemisection results in paralysis of the ipsilateral hemidiaphragm. Recent data indicate that an upregulation of the N-methyl-D-aspartate (NMDA) receptor 2A subunit following chronic C2 hemisection is associated with spontaneous hemidiaphragmatic recovery following injury. MK-801, an antagonist of the NMDA receptor, upregulates the NR2A subunit in neonatal rats. HYPOTHESIS: We hypothesized that administration of MK-801 to adult, acute C2-hemisected rats would result in an increase of NR2A in the spinal cord. Furthermore, we hypothesized that upregulation of NR2A would be associated with recovery of the ipsilateral hemidiaphragm as in the chronic studies. DESIGN: To develop a dose-response curve, adult rats were treated with varying doses of MK-801 and their spinal cords harvested and assessed for NR2A as well as AMPA GluR1 and GluR2 subunit protein levels. In the second part of this study, C2-hemisected animals received MK-801. Following treatment, the animals were assessed for recovery of the hemidiaphragm through electromyographic recordings and their spinal cords assessed for NR2A, GluR1, and GluR2. RESULTS: Treatment with MK-801 leads to an increase of the NR2A subunit in the spinal cords of adult noninjured rats. There were no changes in the expression of GluR1 and GluR2 in these animals. Administration of MK-801 to C2-hemisected rats resulted in recovery of the ipsilateral hemidiaphragm, an increase of NR2A, and a decrease of GluR2. CONCLUSION: Our findings strengthen the evidence that the NR2A subunit plays a substantial role in mediating recovery of the paralyzed hemidiaphragm following C2 spinal cord hemisection.
|ISSN : ||1079-0268|
|Mesh Heading : ||Analysis of Variance Animals Diaphragm Dizocilpine Maleate Dose-Response Relationship, Drug Electromyography Female Functional Laterality Neuroprotective Agents Rats Rats, Sprague-Dawley Receptors, N-Methyl-D-Aspartate Recovery of Function Time Factors Up-Regulation drug effects innervation drug therapy pathology physiopathology drug effects|
|Mesh Heading Relevant : ||Spinal Cord Injuries physiopathology therapeutic use physiology therapeutic use metabolism drug effects|