scholarly journals Intraspinal Grafting of Serotonergic Neurons Modifies Expression of Genes Important for Functional Recovery in Paraplegic Rats

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Krzysztof Miazga ◽  
Hanna Fabczak ◽  
Ewa Joachimiak ◽  
Małgorzata Zawadzka ◽  
Łucja Krzemień-Ojak ◽  
...  
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Functional Recovery ◽  
Serotonergic Neurons ◽  
Locomotor Recovery ◽  
Thoracic Level ◽  
Hindlimb Muscles ◽  
Complete Transection ◽  
Expression Of Genes ◽  
Influence Functional

Serotonin (5-hydroxytryptamine; 5-HT) plays an important role in control of locomotion, partly through direct effects on motoneurons. Spinal cord complete transection (SCI) results in changes in 5-HT receptors on motoneurons that influence functional recovery. Activation of 5-HT2A and 5-HT7 receptors improves locomotor hindlimb movements in paraplegic rats. Here, we analyzed the mRNA of 5-HT2A and 5-HT7 receptors (encoded by Htr2a and Htr7 genes, resp.) in motoneurons innervating tibialis anterior (TA) and gastrocnemius lateralis (GM) hindlimb muscles and the tail extensor caudae medialis (ECM) muscle in intact as well as spinal rats. Moreover, the effect of intraspinal grafting of serotonergic neurons on Htr2a and Htr7 gene expression was examined to test the possibility that the graft origin 5-HT innervation in the spinal cord of paraplegic rats could reverse changes in gene expression induced by SCI. Our results indicate that SCI at the thoracic level leads to changes in Htr2a and Htr7 gene expression, whereas transplantation of embryonic serotonergic neurons modifies these changes in motoneurons innervating hindlimb muscles but not those innervating tail muscles. This suggests that the upregulation of genes critical for locomotor recovery, resulting in limb motoneuron plasticity, might account for the improved locomotion in grafted animals.

Exosomes loaded with PTEN siRNA leads to functional recovery after complete transection of the spinal cord by specifically targeting the damaged area

Cytotherapy ◽  
2019 ◽  
Vol 21 (5) ◽  
pp. e7-e8 ◽  
Author(s):  
D. Offen ◽  
N. Perets ◽  
S. Guo ◽  
O. Betzer ◽  
R. Popovtzer ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Functional Recovery ◽  
Complete Transection

Treadmill training promotes spinal changes leading to locomotor recovery after partial spinal cord injury in cats

2013 ◽  
Vol 109 (12) ◽  
pp. 2909-2922 ◽  
Author(s):  
Marina Martinez ◽  
Hugo Delivet-Mongrain ◽  
Serge Rossignol
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Treadmill Training ◽  
Locomotor Training ◽  
Locomotor Recovery ◽  
Thoracic Level ◽  
Spinal Circuitry ◽  
Cord Injury ◽  
Locomotor Deficits ◽  
Spinal Hemisection

After a spinal hemisection at thoracic level in cats, the paretic hindlimb progressively recovers locomotion without treadmill training but asymmetries between hindlimbs persist for several weeks and can be seen even after a further complete spinal transection at T13. To promote optimal locomotor recovery after hemisection, such asymmetrical changes need to be corrected. In the present study we determined if the locomotor deficits induced by a spinal hemisection can be corrected by locomotor training and, if so, whether the spinal stepping after the complete spinal cord transection is also more symmetrical. This would indicate that locomotor training in the hemisected period induces efficient changes in the spinal cord itself. Sixteen adult cats were first submitted to a spinal hemisection at T10. One group received 3 wk of treadmill training, whereas the second group did not. Detailed kinematic and electromyographic analyses showed that a 3-wk period of locomotor training was sufficient to improve the quality and symmetry of walking of the hindlimbs. Moreover, after the complete spinal lesion was performed, all the trained cats reexpressed bilateral and symmetrical hindlimb locomotion within 24 h. By contrast, the locomotor pattern of the untrained cats remained asymmetrical, and the hindlimb on the side of the hemisection was still deficient. This study highlights the beneficial role of locomotor training in facilitating bilateral and symmetrical functional plastic changes within the spinal circuitry and in promoting locomotor recovery after an incomplete spinal cord injury.

Limited functional recovery in rats with complete spinal cord injury after transplantation of whole-layer olfactory mucosa

2010 ◽  
Vol 12 (2) ◽  
pp. 122-130 ◽  
Author(s):  
Masanori Aoki ◽  
Haruhiko Kishima ◽  
Kazuhiro Yoshimura ◽  
Masahiro Ishihara ◽  
Masaki Ueno ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Lamina Propria ◽  
Motor Function ◽  
Functional Recovery ◽  
Olfactory Mucosa ◽  
Respiratory Mucosa ◽  
Locomotor Recovery ◽  
Cord Injury ◽  
Complete Spinal Cord Injury

Object The olfactory mucosa (OM) consists of 2 layers, the epithelium and the lamina propria. Attempts have been made to restore motor function in rat models of spinal cord injury (SCI) by transplanting olfactory ensheathing cells from the lamina propria, but there has been no attempt to transplant the OM in animal models. To investigate the potential of the OM to restore motor function, the authors developed a rat model of SCI and delayed transplantation of syngenic OM. Methods Two weeks after complete transection of the spinal cord at the T-10 level in Wistar rats, pieces of syngenic whole-layer OM were transplanted into the lesion. Rats that underwent respiratory mucosa transplantation were used as controls. The authors evaluated the locomotor activity according to the Basso-Beattie-Bresnahan scale for 8 weeks after transplantation. Obtained spinal cords were analyzed histologically. Results The OM transplantation rats showed significantly greater hindlimb locomotor recovery than the respiratory mucosa–transplanted rats. However, the recovery was limited according to the Basso-Beattie-Bresnahan scale. In the histological examination, the serotonergic raphespinal tract was regenerated. The pseudocyst cavity volume in the vicinity of the SCI lesion correlated negatively with the functional recovery. Conclusions Transplantation of whole-layer OM in rats contributes to functional recovery from SCI, but the effect is limited. In addition to OM transplantation, other means would be necessary for better outcomes in clinical situations.

scholarly journals Restoring Function After Severe Spinal Cord Injury Through Bioluminescence-Driven Optogenetics

2019 ◽  
Author(s):  
Eric D. Petersen ◽  
Erik D. Sharkey ◽  
Akash Pal ◽  
Lateef O. Shafau ◽  
Jessica R. Zenchak ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Neuron ◽  
Functional Recovery ◽  
Rational Approach ◽  
Lumbar Spinal Cord ◽  
Locomotor Recovery ◽  
Non Invasive ◽  
Cord Injury ◽  
Neuronal Connections

The ability to manipulate specific neuronal populations of the spinal cord following spinal cord injury (SCI) could prove highly beneficial for rehabilitation in patients through maintaining and strengthening still existing neuronal connections and/or facilitating the formation of new connections. A non-invasive and highly specific approach to neuronal stimulation is bioluminescent-optogenetics (BL-OG), where genetically expressed light emitting luciferases are tethered to light sensitive channelrhodopsins (luminopsins, LMO); neurons are activated by the addition of the luciferase substrate coelenterazine (CTZ). This approach utilizes ion channels for current conduction while activating the channels through application of a small chemical compound, thus allowing non-invasive stimulation and recruitment of all targeted neurons. Rats were transduced in the lumbar spinal cord with AAV2/9 to express the excitatory LMO3 under control of a pan-neuronal or motor neuron-specific promoter. A day after contusion injury of the thoracic spine, rats received either CTZ or vehicle every other day for 2 weeks. Activation of either interneuron or motor neuron populations below the level of injury significantly improved locomotor recovery lasting beyond the time of stimulation. Utilizing histological and gene expression methods we identified neuronal plasticity as a likely mechanism underlying the functional recovery. These findings provide a foundation for a rational approach to spinal cord injury rehabilitation, thereby advancing approaches for functional recovery after SCI.

scholarly journals Intramuscular Neurotrophin-3 normalizes low threshold spinal reflexes, reduces spasms and improves mobility after bilateral corticospinal tract injury in rats

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Claudia Kathe ◽  
Thomas Haynes Hutson ◽  
Stephen Brendan McMahon ◽  
Lawrence David Falcon Moon
Keyword(s):  
Spinal Cord ◽  
Viral Vector ◽  
Spinal Injury ◽  
Spinal Reflexes ◽  
Locomotor Recovery ◽  
Sensorimotor Processing ◽  
Complete Transection ◽  
Neurotrophin 3 ◽  
Underlying Causes ◽  
Low Threshold

Brain and spinal injury reduce mobility and often impair sensorimotor processing in the spinal cord leading to spasticity. Here, we establish that complete transection of corticospinal pathways in the pyramids impairs locomotion and leads to increased spasms and excessive mono- and polysynaptic low threshold spinal reflexes in rats. Treatment of affected forelimb muscles with an adeno-associated viral vector (AAV) encoding human Neurotrophin-3 at a clinically-feasible time-point after injury reduced spasticity. Neurotrophin-3 normalized the short latency Hoffmann reflex to a treated hand muscle as well as low threshold polysynaptic spinal reflexes involving afferents from other treated muscles. Neurotrophin-3 also enhanced locomotor recovery. Furthermore, the balance of inhibitory and excitatory boutons in the spinal cord and the level of an ion co-transporter in motor neuron membranes required for normal reflexes were normalized. Our findings pave the way for Neurotrophin-3 as a therapy that treats the underlying causes of spasticity and not only its symptoms.

A Selective P2Y Purinergic Receptor Agonist 2-MesADP Enhances Locomotor Recovery after Acute Spinal Cord Injury

2020 ◽  
Vol 83 (2) ◽  
pp. 195-212
Author(s):  
Ziru Zhao ◽  
Xiao Hu ◽  
Zhourui Wu ◽  
Qi Chen ◽  
Qihui Shao
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Neuronal Apoptosis ◽  
Purinergic Receptor ◽  
Expression Patterns ◽  
Gene Profiling ◽  
Locomotor Recovery ◽  
Wnt Signal Pathway ◽  
Cord Injury

Introduction: Spinal cord injury (SCI) causes most severe motor and sensory dysfunctions. In Chinese traditional medicine, the agonist of a purinergic receptor is believed to have a positive effect on SCIs, and 2-Methylthio-adenosine-5′-diphosphate (2-MesADP) is a selective agonist of the P2Y purinergic receptor. Methods: To investigate its therapeutic function and molecular mechanism in SCI, transcriptome analysis associated with weighted gene co-expression network analysis (WGCNA) was carried out at various time points after T9 crush injury. Results: 2-MesADP demonstrated recovery of limb motor function at the 6 weeks after injury, accompanied by neuronal regeneration and axon remyelination at 2 and 6 weeks. Furthermore, gene profiling revealed alternated gene expression with the treatment of 2-MesADP. These genes were assigned to a total of 38 modules, followed by gene ontology analysis; of these, 18 represented neuronal apoptosis and regeneration, immune response, synaptic transmission, cell cycle, and angiogenesis. In the neuronal apoptosis and regeneration module, Nefh, NeuroD6, and Dcx in the 2-MesADP group were noticed due to their interesting expression pattern. The gene expression patterns of Mag, Mog, and Cnp, which played key roles in myelination, were significantly changed with the treatment of 2-MesADP. Wnt signal pathway was the most important pathway in 2-MesADP treatment for acute SCI. Conclusion: 2-MesADP enhanced locomotor recovery in mouse SCI by altering the expression of neuronal apoptosis and remyelination-related genes and Wnt signaling pathways.

scholarly journals Noradrenergic Components of Locomotor Recovery Induced by Intraspinal Grafting of the Embryonic Brainstem in Adult Paraplegic Rats

2020 ◽  
Vol 21 (15) ◽  
pp. 5520
Author(s):  
Anna Kwaśniewska ◽  
Krzysztof Miazga ◽  
Henryk Majczyński ◽  
Larry M. Jordan ◽  
Małgorzata Zawadzka ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Central Canal ◽  
Locomotor Performance ◽  
Adult Rats ◽  
Locomotor Recovery ◽  
Hindlimb Muscles ◽  
Hindlimb Movement ◽  
Caudal Spinal Cord ◽  
Adrenergic Receptor Agonist

Intraspinal grafting of serotonergic (5-HT) neurons was shown to restore plantar stepping in paraplegic rats. Here we asked whether neurons of other phenotypes contribute to the recovery. The experiments were performed on adult rats after spinal cord total transection. Grafts were injected into the sub-lesional spinal cord. Two months later, locomotor performance was tested with electromyographic recordings from hindlimb muscles. The role of noradrenergic (NA) innervation was investigated during locomotor performance of spinal grafted and non-grafted rats using intraperitoneal application of α2 adrenergic receptor agonist (clonidine) or antagonist (yohimbine). Morphological analysis of the host spinal cords demonstrated the presence of tyrosine hydroxylase positive (NA) neurons in addition to 5-HT neurons. 5-HT fibers innervated caudal spinal cord areas in the dorsal and ventral horns, central canal, and intermediolateral zone, while the NA fiber distribution was limited to the central canal and intermediolateral zone. 5-HT and NA neurons were surrounded by each other’s axons. Locomotor abilities of the spinal grafted rats, but not in control spinal rats, were facilitated by yohimbine and suppressed by clonidine. Thus, noradrenergic innervation, in addition to 5-HT innervation, plays a potent role in hindlimb movement enhanced by intraspinal grafting of brainstem embryonic tissue in paraplegic rats.

scholarly journals Activation of Neuroprotective Microglia and Astrocytes at the Lesion Site and in the Adjacent Segments Is Crucial for Spontaneous Locomotor Recovery after Spinal Cord Injury

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1943
Author(s):  
Alexandra Kisucká ◽  
Katarína Bimbová ◽  
Mária Bačová ◽  
Ján Gálik ◽  
Nadežda Lukáčová
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Lesion Site ◽  
Post Injury ◽  
Reactive Microglia ◽  
Locomotor Recovery ◽  
Cord Injury ◽  
Polarization States ◽  
Anti Inflammatory ◽  
Adjacent Segments

Microglia and astrocytes play an important role in the regulation of immune responses under various pathological conditions. To detect environmental cues associated with the transformation of reactive microglia (M1) and astrocytes (A1) into their polarization states (anti-inflammatory M2 and A2 phenotypes), we studied time-dependent gene expression in naive and injured spinal cord. The relationship between astrocytes and microglia and their polarization states were studied in a rat model after Th9 compression (40g/15 min) in acute and subacute stages at the lesion site, and both cranially and caudally. The gene expression of microglia/macrophages and M1 microglia was strongly up-regulated at the lesion site and caudally one week after SCI, and attenuated after two weeks post-SCI. GFAP and S100B, and A1 astrocytes were profoundly expressed predominantly two weeks post-SCI at lesion site and cranially. Gene expression of anti-inflammatory M2a microglia (CD206, CHICHI, IL1rn, Arg-1), M2c microglia (TGF-β, SOCS3, IL4R α) and A2 astrocytes (Tgm1, Ptx3, CD109) was greatly activated at the lesion site one week post-SCI. In addition, we observed positive correlation between neurological outcome and expression of M2a, M2c, and A2 markers. Our findings indicate that the first week post‑injury is critical for modulation of reactive microglia/astrocytes into their neuroprotective phenotypes.

scholarly journals Transneuronal delivery of hyper-interleukin-6 enables functional recovery after severe spinal cord injury in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Marco Leibinger ◽  
Charlotte Zeitler ◽  
Philipp Gobrecht ◽  
Anastasia Andreadaki ◽  
Günter Gisselmann ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Brain Stem ◽  
Functional Recovery ◽  
Cortical Neurons ◽  
Locomotor Recovery ◽  
Stat3 Signaling ◽  
Cord Injury ◽  
Severed Axons ◽  
The Brain

AbstractSpinal cord injury (SCI) often causes severe and permanent disabilities due to the regenerative failure of severed axons. Here we report significant locomotor recovery of both hindlimbs after a complete spinal cord crush. This is achieved by the unilateral transduction of cortical motoneurons with an AAV expressing hyper-IL-6 (hIL-6), a potent designer cytokine stimulating JAK/STAT3 signaling and axon regeneration. We find collaterals of these AAV-transduced motoneurons projecting to serotonergic neurons in both sides of the raphe nuclei. Hence, the transduction of cortical neurons facilitates the axonal transport and release of hIL-6 at innervated neurons in the brain stem. Therefore, this transneuronal delivery of hIL-6 promotes the regeneration of corticospinal and raphespinal fibers after injury, with the latter being essential for hIL-6-induced functional recovery. Thus, transneuronal delivery enables regenerative stimulation of neurons in the deep brain stem that are otherwise challenging to access, yet highly relevant for functional recovery after SCI.

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