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

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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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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Nimodipine Promotes Functional Recovery After Spinal Cord Injury in Rats

Frontiers in Pharmacology ◽

10.3389/fphar.2021.733420 ◽

2021 ◽

Vol 12 ◽

Author(s):

Fangliang Guo ◽

Xiaolong Zheng ◽

Ziyu He ◽

Ruoying Zhang ◽

Song Zhang ◽

...

Keyword(s):

Spinal Cord ◽

Motor Neurons ◽

Hind Limb ◽

Term Treatment ◽

Bladder Function ◽

Lumbar Spinal Cord ◽

Long Term Treatment ◽

Cord Injury ◽

Lumbar Spinal

Spinal cord injury (SCI) is a devastating condition that results in severe motor, sensory, and autonomic dysfunction. The L-/T-type calcium channel blocker nimodipine (NMD) exerts a protective effect on neuronal injury; however, the protective effects of long-term administration of NMD in subjects with SCI remain unknown. Thus, the aim of this study was to evaluate the role of long-term treatment with NMD on a clinically relevant SCI model. Female rats with SCI induced by 25 mm contusion were subcutaneously injected with vehicle or 10 mg/kg NMD daily for six consecutive weeks. We monitored the motor score, hind limb grip strength, pain-related behaviors, and bladder function in this study to assess the efficacy of NMD in rats with SCI. Rats treated with NMD showed improvements in locomotion, pain-related behaviors, and spasticity-like symptoms, but not in open-field spontaneous activity, hind limb grip strength or bladder function. SCI lesion areas and perilesional neuronal numbers, gliosis and calcitonin gene-related peptide (CGRP+) fiber sprouting in the lumbar spinal cord and the expression of K+–Cl− cotransporter 2 (KCC2) on lumbar motor neurons were also observed to further explore the possible protective mechanisms of NMD. NMD-treated rats showed greater tissue preservation with reduced lesion areas and increased perilesional neuronal sparing. NMD-treated rats also showed improvements in gliosis, CGRP+ fiber sprouting in the lumbar spinal cord, and KCC2 expression in lumbar motor neurons. Together, these results indicate that long-term treatment with NMD improves functional recovery after SCI, which may provide a potential therapeutic strategy for the treatment of SCI.

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Effects of chronic spinal cord injury on relationships among ion channel and receptor mRNAs in mouse lumbar spinal cord

10.1101/357665 ◽

2018 ◽

Cited By ~ 1

Author(s):

Virginia B. Garcia ◽

Matthew D. Abbinanti ◽

Ronald M. Harris-Warrick ◽

David J. Schulz

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Ion Channel ◽

Motor Neurons ◽

Receptor Expression ◽

Lumbar Spinal Cord ◽

Mrna Levels ◽

Absolute Quantitation ◽

Cord Injury ◽

Lumbar Spinal

ABSTRACTSpinal cord injury (SCI) causes widespread changes in gene expression of the spinal cord, even in the undamaged spinal cord below the level of the lesion. Less is known about changes in the correlated expression of genes after SCI. We investigated gene co-expression networks among voltage-gated ion channel and neurotransmitter receptor mRNA levels using quantitative RT-PCR in longitudinal slices of the mouse lumbar spinal cord in control and chronic SCI animals. These longitudinal slices were made from the ventral surface of the cord, thus forming slices relatively enriched in motor neurons or interneurons. We performed absolute quantitation of mRNA copy number for 50 ion channel or receptor transcripts from each sample, and used multiple correlation analyses to detect patterns in correlated mRNA levels across all pairs of genes. The majority of channels and receptors changed in expression as a result of chronic SCI, but did so differently across slice levels. Furthermore, motor neuron enriched slices experienced an overall loss of correlated channel and receptor expression, while interneuron slices showed a dramatic increase in the number of positively correlated transcripts. These correlation profiles suggest that spinal cord injury induces distinct changes across cell types in the organization of gene co-expression networks for ion channels and transmitter receptors.

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Identification of 17 highly expressed genes within mouse lumbar spinal cord anterior horn region from an in-situ hybridization atlas of 3430 genes: implications for motor neuron disease

Neurology International ◽

10.4081/ni.2014.5367 ◽

2014 ◽

Vol 6 (2) ◽

Cited By ~ 8

Author(s):

Michael A. Meyer

Keyword(s):

Spinal Cord ◽

Motor Neuron ◽

Motor Neuron Disease ◽

Motor Neurons ◽

Ventral Horn ◽

Janus Kinase ◽

Anterior Horn ◽

Lumbar Spinal Cord ◽

Spinal Motor ◽

Lumbar Spinal

In an effort to find possible new gene candidates involved in the causation of amyotrophic lateral sclerosis (ALS), a prior version of the on-line brain gene expression atlas GENSAT was extensively searched for selectively intense expression within spinal motor neurons. Using autoradiographic data of in-situ hybridization from 3430 genes, a search for selectively intense activity was made for the anterior horn region of murine lumbar spinal cord sectioned in the axial plane. Of 3430 genes, a group of 17 genes was found to be highly expressed within the anterior horn suggesting localization to its primary cellular constituent, the alpha spinal motor neuron. For some genes, an inter-relationship to ALS was already known, such as for heavy, medium, and light neurofilaments, and peripherin. Other genes identified include: Gamma Synuclein, GDNF, SEMA3A, Extended Synaptotagmin-like protein 1, LYNX1, HSPA12a, Cadherin 22, PRKACA, TPPP3 as well as Choline Acetyltransferase, Janus Kinase 1, and the Motor Neuron and Pancreas Homeobox 1. Based on this study, Fibroblast Growth Factor 1 was found to have a particularly selective and intense localization pattern to the ventral horn and may be a good target for development of motor neuron disease therapies; further research is needed.

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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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Changes in serotonin-induced potentials during spinal cord development

Journal of Neurophysiology ◽

10.1152/jn.1993.69.4.1338 ◽

1993 ◽

Vol 69 (4) ◽

pp. 1338-1349 ◽

Cited By ~ 55

Author(s):

L. Ziskind-Conhaim ◽

B. S. Seebach ◽

B. X. Gao

Keyword(s):

Spinal Cord ◽

Direct Action ◽

Membrane Resistance ◽

Ventral Horn ◽

Repetitive Firing ◽

Lumbar Spinal Cord ◽

Receptor Subtypes ◽

Gamma Aminobutyric Acid ◽

Spinal Neurons ◽

Lumbar Spinal

1. Motoneuron responses to serotonin (5-hydroxytryptamine, 5-HT), and the growth pattern of 5-HT projections into the ventral horn were studied in the isolated spinal cord of embryonic and neonatal rats. 2. 5-HT projections first appeared in lumbar spinal cord at days 16-17 of gestation (E16-E17) and were localized in the lateral and ventral funiculi. By E18, the projections had grown into the ventral horn, and at 1-2 days after birth they were in close apposition to motoneuron somata. 3. At E16-E17, slow-rising depolarizing potentials of 1-4 mV were recorded intracellularly in lumbar motoneurons in response to bath application of 5-HT. These potentials were not apparent after E18; at that time 5-HT generated long-lasting depolarizations with an average amplitude of 6 mV, and an increase of 11% in membrane resistance. Starting at E18, 5-HT also induced high-frequency fast-rising potentials that were blocked by antagonists of glutamate, gamma-aminobutyric acid, and glycine. 4. Motoneuron responses to 5-HT increased significantly after birth, when 5-HT produced an average depolarization of 19 mV and repetitive firing of action potentials. 5. Tetrodotoxin and high Mg2+ did not reduce the amplitude of the long-lasting depolarizations, which suggested that they were produced by direct action of 5-HT on motoneuron membrane. 6. At all developmental ages, 5-HT reduced the amplitude of dorsal root-evoked potentials. The suppressed responses were neither due to 5-HT-induced depolarization nor the result of a decrease in motoneuron excitability. 7. The pharmacological profile of 5-HT-induced potentials was studied with the use of various agonists and antagonists of 5-HT. The findings indicated that the actions of 5-HT on spinal neurons were mediated via multiple 5-HT receptor subtypes. 8. Our results suggested that 5-HT excited spinal neurons before 5-HT projections grew into the ventral horn. The characteristics of 5-HT-induced potentials changed, however, at the time when the density of 5-HT projections increased in the motor nuclei.

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Noradrenergic synapses and effects of noradrenaline on interneurons in the ventral horn of the cat spinal cord

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y77-057 ◽

1977 ◽

Vol 55 (3) ◽

pp. 399-412 ◽

Cited By ~ 29

Author(s):

Larry M. Jordan ◽

David A. McCrea ◽

John D. Steeves ◽

John E. Menzies

Keyword(s):

Spinal Cord ◽

Close Contact ◽

Cell Types ◽

Muscle Afferents ◽

Ventral Horn ◽

Lumbar Spinal Cord ◽

High Threshold ◽

Depressant Action ◽

Motor Nuclei ◽

Lumbar Spinal

Histochemical and electrophysiological procedures were carried out to determine the cell types in the ventral horn which are in close contact with noradrenergic terminals and to identify the types of neurons in the ventral horn which are influenced by noradrenaline (NA). Fluorescence histochemical studies revealed that noradrenaline-containing fibers rarely form intimate contacts with alpha motoneurons, whereas many small interneurons which are closely invested with fluorescent fibers can be found near the motoneurons. The effects of microiontophoretically applied NA on interneurons were examined in the lateral motor areas of the lumbar spinal cord ventral horn. NA had a substantial depressant action on 43% of cells in chloralose-anesthetized and decerebrate cats; it excited 6% of the cells, and was without effect on the rest. The cells which were depressed by NA could be excited by electrical stimulation of high threshold muscle afferents or skin afferents, and they could be influenced from a variety of exteroceptive and proprioceptive inputs. Owing to considerable convergence on the affected interneurons, no distinct population of NA-sensitive interneurons could be identified. Many of the interneurons strongly depressed by NA were found near the motor nuclei. The hypothesis is presented that inhibitory actions of NA on interneurons in the motor nuclei might explain its hyperpolarizing action on motoneurons.

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Therapeutic Hypothermia Improves Hind Limb Motor Outcome and Attenuates Oxidative Stress and Neuronal Damage in the Lumbar Spinal Cord Following Cardiac Arrest

Antioxidants ◽

10.3390/antiox9010038 ◽

2020 ◽

Vol 9 (1) ◽

pp. 38

Author(s):

Ji Hyeon Ahn ◽

Tae-Kyeong Lee ◽

Bora Kim ◽

Jae-Chul Lee ◽

Hyun-Jin Tae ◽

...

Keyword(s):

Oxidative Stress ◽

Spinal Cord ◽

Therapeutic Hypothermia ◽

Hind Limb ◽

Neuronal Damage ◽

Ventral Horn ◽

Lumbar Spinal Cord ◽

Neuronal Protection ◽

Endogenous Antioxidants ◽

Lumbar Spinal

Hypothermia enhances outcomes of patients after resuscitation after cardiac arrest (CA). However, the underlying mechanism is not fully understood. In this study, we investigated effects of hypothermic therapy on neuronal damage/death, microglial activation, and changes of endogenous antioxidants in the anterior horn in the lumbar spinal cord in a rat model of asphyxial CA (ACA). A total of 77 adult male Sprague–Dawley rats were randomized into five groups: normal, sham ACA plus (+) normothermia, ACA + normothermia, sham ACA + hypothermia, and ACA + hypothermia. ACA was induced for 5 min by injecting vecuronium bromide. Therapeutic hypothermia was applied after return of spontaneous circulation (ROSC) via rapid cooling with isopropyl alcohol wipes, which was maintained at 33 ± 0.5 °C for 4 h. Normothermia groups were maintained at 37 ± 0.2 °C for 4 h. Neuronal protection, microgliosis, oxidative stress, and changes of endogenous antioxidants were evaluated at 12 h, 1 day, and 2 days after ROSC following ACA. ACA resulted in neuronal damage from 12 h after ROSC and evoked obvious degeneration/loss of spinal neurons in the ventral horn at 1 day after ACA, showing motor deficit of the hind limb. In addition, ACA resulted in a gradual increase in microgliosis with time after ACA. Therapeutic hypothermia significantly reduced neuronal loss and attenuated hind limb dysfunction, showing that hypothermia significantly attenuated microgliosis. Furthermore, hypothermia significantly suppressed ACA-induced increases of superoxide anion production and 8-hydroxyguanine expression, and significantly increased superoxide dismutase 1 (SOD1), SOD2, catalase, and glutathione peroxidase. Taken together, hypothermic therapy was found to have a substantial impact on changes in ACA-induced microglia activation, oxidative stress factors, and antioxidant enzymes in the ventral horn of the lumbar spinal cord, which closely correlate with neuronal protection and neurological performance after ACA.

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