Neuromuscular interaction is required for neurotrophins-mediated locomotor recovery following treadmill training in rat spinal cord injury

Recent results have shown that exercise training promotes the recovery of injured rat distal spinal cords, but are still unclear about the function of skeletal muscle in this process. Herein, rats with incomplete thoracic (T10) spinal cord injuries (SCI) with a dual spinal lesion model were subjected to four weeks of treadmill training and then were treated with complete spinal transection at T8. We found that treadmill training retained hind limb motor function after incomplete SCI, even with a heavy load after complete spinal transection. Moreover, treadmill training alleviated the secondary injury in distal lumbar spinal motor neurons, and enhanced BDNF/TrkB expression in the lumbar spinal cord. To discover the influence of skeletal muscle contractile activity on motor function and gene expression, we adopted botulinum toxin A (BTX-A) to block the neuromuscular activity of the rat gastrocnemius muscle. BTX-A treatment inhibited the effects of treadmill training on motor function and BDNF/TrKB expression. These results indicated that treadmill training through the skeletal muscle-motor nerve-spinal cord retrograde pathway regulated neuralplasticity in the mammalian central nervous system, which induced the expression of related neurotrophins and promoted motor function recovery.

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The Effect Of Treadmill Training On Igf-1 Levels In Rat Skeletal Muscle And Lumbar Spinal Cord Following Spinal Cord Injury

Medicine & Science in Sports & Exercise ◽

10.1249/01.mss.0000274218.19035.a9 ◽

2007 ◽

Vol 39 (Supplement) ◽

pp. S313

Author(s):

Min Liu ◽

Jennifer E. Stevens ◽

Glenn A. Walter ◽

Prodip Bose ◽

Floyd J. Thompson ◽

...

Keyword(s):

Skeletal Muscle ◽

Spinal Cord ◽

Spinal Cord Injury ◽

Treadmill Training ◽

Lumbar Spinal Cord ◽

Rat Skeletal Muscle ◽

Cord Injury ◽

Lumbar Spinal

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Robotic loading during treadmill training enhances locomotor recovery in rats spinally transected as neonates

Journal of Neurophysiology ◽

10.1152/jn.01099.2012 ◽

2013 ◽

Vol 110 (3) ◽

pp. 760-767 ◽

Cited By ~ 5

Author(s):

Pamela Anne See ◽

Ray D. de Leon

Keyword(s):

Spinal Cord ◽

Weight Bearing ◽

Gait Training ◽

Ventral Horn ◽

Treadmill Training ◽

Lumbar Spinal Cord ◽

Step Cycle ◽

Locomotor Recovery ◽

Cord Injury ◽

Lumbar Spinal

Loading on the limbs has a powerful influence on locomotion. In the present study, we examined whether robotic-enhanced loading during treadmill training improved locomotor recovery in rats that were spinally transected as neonates. A robotic device applied a force on the ankle of the hindlimb while the rats performed bipedal stepping on a treadmill. The robotic force enhanced loading during the stance phase of the step cycle. One group of spinally transected rats received 4 wk of bipedal treadmill training with robotic loading while another group received 4 wk of bipedal treadmill training but without robotic loading. The two groups exhibited similar stepping performance during baseline tests of bipedal treadmill stepping. However, after 4 wk, the spinally transected rats that received bipedal treadmill training with robotic loading performed significantly more weight-bearing steps than the bipedal treadmill training only group. Bipedal treadmill training with robotic loading enhanced the ankle trajectory and ankle velocity during the step cycle. Based on immunohistochemical analyses, the expression of the presynaptic marker, synaptophysin, was significantly greater in the ventral horn of the lumbar spinal cord of the rats that received bipedal treadmill training with robotic loading. These findings suggested that robotic loading during bipedal treadmill training improved the ability of the lumbar spinal cord to generate stepping. The results have implications for the use of robotic-enhanced gait training therapies that encourage motor learning after spinal cord injury.

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Multi-pronged neuromodulation intervention engages the residual motor circuitry to facilitate walking in a rat model of spinal cord injury

Nature Communications ◽

10.1038/s41467-021-22137-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Marco Bonizzato ◽

Nicholas D. James ◽

Galyna Pidpruzhnykova ◽

Natalia Pavlova ◽

Polina Shkorbatova ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Rat Model ◽

Stress Responses ◽

Learning Algorithm ◽

Lumbar Spinal Cord ◽

Cord Injury ◽

Potential Synergy ◽

Lumbar Spinal ◽

Deep Brain

AbstractA spinal cord injury usually spares some components of the locomotor circuitry. Deep brain stimulation (DBS) of the midbrain locomotor region and epidural electrical stimulation of the lumbar spinal cord (EES) are being used to tap into this spared circuitry to enable locomotion in humans with spinal cord injury. While appealing, the potential synergy between DBS and EES remains unknown. Here, we report the synergistic facilitation of locomotion when DBS is combined with EES in a rat model of severe contusion spinal cord injury leading to leg paralysis. However, this synergy requires high amplitudes of DBS, which triggers forced locomotion associated with stress responses. To suppress these undesired responses, we link DBS to the intention to walk, decoded from cortical activity using a robust, rapidly calibrated unsupervised learning algorithm. This contingency amplifies the supraspinal descending command while empowering the rats into volitional walking. However, the resulting improvements may not outweigh the complex technological framework necessary to establish viable therapeutic conditions.

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Nonsteroidal Anti-Inflammatory Drugs and Their Neuroprotective Role After an Acute Spinal Cord Injury: A Systematic Review of Animal Models

Global Spine Journal ◽

10.1177/2192568220901689 ◽

2020 ◽

pp. 219256822090168

Author(s):

Mark J. Lambrechts ◽

James L. Cook

Keyword(s):

Systematic Review ◽

Spinal Cord ◽

Animal Models ◽

Motor Function ◽

Spinal Cord Injuries ◽

Inclusion Criteria ◽

Improve Motor Function ◽

Cord Injury ◽

Inflammatory Drugs ◽

Anti Inflammatory

Study Design: Systematic review. Objective: Spinal cord injuries (SCIs) resulting in motor deficits can be devastating injuries resulting in millions of health care dollars spent per incident. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a potential class of drugs that could improve motor function after an SCI. This systematic review utilizes PRISMA guidelines to evaluate the effectiveness of NSAIDs for SCI. Methods: PubMed/MEDLINE, CINAHL, PsycINFO, Embase, and Scopus were reviewed linking the keywords of “ibuprofen,” “meloxicam,” “naproxen,” “ketorolac,” “indomethacin,” “celecoxib,” “ATB-346,” “NSAID,” and “nonsteroidal anti-inflammatory drug” with “spinal.” Results were reviewed for relevance and included if they met inclusion criteria. The SYRCLE checklist was used to assess sources of bias. Results: A total of 2960 studies were identified in the PubMed/MEDLINE database using the above-mentioned search criteria. A total of 461 abstracts were reviewed in Scopus, 340 in CINAHL, 179 in PsycINFO, and 7632 in Embase. A total of 15 articles met the inclusion criteria. Conclusions: NSAIDs’ effectiveness after SCI is largely determined by its ability to inhibit Rho-A. NSAIDs are a promising therapeutic option in acute SCI patients because they appear to decrease cord edema and inflammation, increase axonal sprouting, and improve motor function with minimal side effects. Studies are limited by heterogeneity, small sample size, and the use of animal models, which might not replicate the therapeutic effects in humans. There are no published human studies evaluating the safety and efficacy of these drugs after a traumatic cord injury. There is a need for well-designed prospective studies evaluating ibuprofen or indomethacin after adult spinal cord injuries.

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Locomotor Training Increases Synaptic Structure With High NGL-2 Expression After Spinal Cord Hemisection

Neurorehabilitation and Neural Repair ◽

10.1177/1545968319829456 ◽

2019 ◽

Vol 33 (3) ◽

pp. 225-231 ◽

Cited By ~ 3

Author(s):

Kazu Kobayakawa ◽

Kyleigh Alexis DePetro ◽

Hui Zhong ◽

Bau Pham ◽

Masamitsu Hara ◽

...

Keyword(s):

Spinal Cord ◽

Motor Neurons ◽

Ventral Horn ◽

Lumbar Spinal Cord ◽

Locomotor Training ◽

Synaptic Structure ◽

Cord Injury ◽

Lumbar Spinal ◽

Spinal Cord Hemisection ◽

Activity Dependent

Background. We previously demonstrated that step training leads to reorganization of neuronal networks in the lumbar spinal cord of rodents after a hemisection (HX) injury and step training, including increases excitability of spinally evoked potentials in hindlimb motor neurons. Methods. In this study, we investigated changes in RNA expression and synapse number using RNA-Seq and immunohistochemistry of the lumbar spinal cord 23 days after a mid-thoracic HX in rats with and without post-HX step training. Results. Gene Ontology (GO) term clustering demonstrated that expression levels of 36 synapse-related genes were increased in trained compared with nontrained rats. Many synaptic genes were upregulated in trained rats, but Lrrc4 (coding NGL-2) was the most highly expressed in the lumbar spinal cord caudal to the HX lesion. Trained rats also had a higher number of NGL-2/synaptophysin synaptic puncta in the lumbar ventral horn. Conclusions. Our findings demonstrate clear activity-dependent regulation of synapse-related gene expression post-HX. This effect is consistent with the concept that activity-dependent phenomena can provide a mechanistic drive for epigenetic neuronal group selection in the shaping of the reorganization of synaptic networks to learn the locomotion task being trained after spinal cord injury.

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1H-MRS in spinal cord injury: acute and chronic metabolite alterations in rat brain and lumbar spinal cord

European Journal of Neuroscience ◽

10.1111/j.1460-9568.2010.07562.x ◽

2011 ◽

Vol 33 (4) ◽

pp. 678-688 ◽

Cited By ~ 14

Author(s):

Matthias Erschbamer ◽

Johanna Öberg ◽

Eric Westman ◽

Rouslan Sitnikov ◽

Lars Olson ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Rat Brain ◽

Lumbar Spinal Cord ◽

1H Mrs ◽

Cord Injury ◽

Lumbar Spinal

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The Effect of Treadmill Training on IGF-I Expression in Skeletal Muscle Following Spinal Cord Injury

Medicine & Science in Sports & Exercise ◽

10.1249/00005768-200605001-01149 ◽

2006 ◽

Vol 38 (Supplement) ◽

pp. S61

Author(s):

Min Liu ◽

Jennifer E. Stevens ◽

Prodip Bose ◽

Floyd J. Thompson ◽

Wilbur Oʼsteen ◽

...

Keyword(s):

Skeletal Muscle ◽

Spinal Cord ◽

Spinal Cord Injury ◽

Treadmill Training ◽

Cord Injury ◽

Igf I

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Tail Nerve Electrical Stimulation and Electro-Acupuncture Can Protect Spinal Motor Neurons and Alleviate Muscle Atrophy after Spinal Cord Transection in Rats

Neural Plasticity ◽

10.1155/2017/7351238 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 10

Author(s):

Yu-Ting Zhang ◽

Hui Jin ◽

Jun-Hua Wang ◽

Lan-Yu Wen ◽

Yang Yang ◽

...

Keyword(s):

Spinal Cord ◽

Electrical Stimulation ◽

Muscle Atrophy ◽

Motor Neurons ◽

Lumbar Spinal Cord ◽

Hindlimb Muscle ◽

Neurotrophin 3 ◽

Spinal Cord Segment ◽

Cord Injury ◽

Lumbar Spinal

Spinal cord injury (SCI) often results in death of spinal neurons and atrophy of muscles which they govern. Thus, following SCI, reorganizing the lumbar spinal sensorimotor pathways is crucial to alleviate muscle atrophy. Tail nerve electrical stimulation (TANES) has been shown to activate the central pattern generator (CPG) and improve the locomotion recovery of spinal contused rats. Electroacupuncture (EA) is a traditional Chinese medical practice which has been proven to have a neural protective effect. Here, we examined the effects of TANES and EA on lumbar motor neurons and hindlimb muscle in spinal transected rats, respectively. From the third day postsurgery, rats in the TANES group were treated 5 times a week and those in the EA group were treated once every other day. Four weeks later, both TANES and EA showed a significant impact in promoting survival of lumbar motor neurons and expression of choline acetyltransferase (ChAT) and ameliorating atrophy of hindlimb muscle after SCI. Meanwhile, the expression of neurotrophin-3 (NT-3) in the same spinal cord segment was significantly increased. These findings suggest that TANES and EA can augment the expression of NT-3 in the lumbar spinal cord that appears to protect the motor neurons as well as alleviate muscle atrophy.

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