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 Corticospinal-motor neuronal plasticity promotes exercise-mediated recovery in humans with spinal cord injury

Brain ◽  
2020 ◽  
Vol 143 (5) ◽  
pp. 1368-1382 ◽  
Author(s):  
Hang Jin Jo ◽  
Monica A Perez
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Transcranial Magnetic Stimulation ◽  
Functional Recovery ◽  
Magnetic Stimulation ◽  
Primary Motor Cortex ◽  
Lumbar Spinal Cord ◽  
Non Invasive ◽  
Cord Injury ◽  
Stimulation Of

Abstract Rehabilitative exercise in humans with spinal cord injury aims to engage residual neural networks to improve functional recovery. We hypothesized that exercise combined with non-invasive stimulation targeting spinal synapses further promotes functional recovery. Twenty-five individuals with chronic incomplete cervical, thoracic, and lumbar spinal cord injury were randomly assigned to 10 sessions of exercise combined with paired corticospinal-motor neuronal stimulation (PCMS) or sham-PCMS. In an additional experiment, we tested the effect of PCMS without exercise in 13 individuals with spinal cord injury with similar characteristics. During PCMS, 180 pairs of stimuli were timed to have corticospinal volleys evoked by transcranial magnetic stimulation over the primary motor cortex arrive at corticospinal-motor neuronal synapses of upper- or lower-limb muscles (depending on the injury level), 1–2 ms before antidromic potentials were elicited in motor neurons by electrical stimulation of a peripheral nerve. Participants exercised for 45 min after all protocols. We found that the time to complete subcomponents of the Graded and Redefined Assessment of Strength, Sensibility and Prehension (GRASSP) and the 10-m walk test decreased on average by 20% after all protocols. However, the amplitude of corticospinal responses elicited by transcranial magnetic stimulation and the magnitude of maximal voluntary contractions in targeted muscles increased on overage by 40–50% after PCMS combined or not with exercise but not after sham-PCMS combined with exercise. Notably, behavioural and physiological effects were preserved 6 months after the intervention in the group receiving exercise with PCMS but not in the group receiving exercise combined with sham-PCMS, suggesting that the stimulation contributed to preserve exercise gains. Our findings indicate that targeted non-invasive stimulation of spinal synapses might represent an effective strategy to facilitate exercise-mediated recovery in humans with different degrees of paralysis and levels of spinal cord injury.

scholarly journals Non-invasive approaches to functional recovery after spinal cord injury: Therapeutic targets and multimodal device interventions

2021 ◽  
Vol 339 ◽  
pp. 113612
Author(s):  
Claudio Pizzolato ◽  
Mehmet A. Gunduz ◽  
Dinesh Palipana ◽  
Jingnan Wu ◽  
Gary Grant ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Functional Recovery ◽  
Therapeutic Targets ◽  
Non Invasive ◽  
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 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.

scholarly journals Non-invasive brain stimulation to promote motor and functional recovery following spinal cord injury

2017 ◽  
Vol 12 (12) ◽  
pp. 1933 ◽  
Author(s):  
Hatice Kumru ◽  
Aysegul Gunduz ◽  
John Rothwell ◽  
Joan Vidal
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Functional Recovery ◽  
Brain Stimulation ◽  
Non Invasive ◽  
Cord Injury

scholarly journals Allogeneic Neural Stem Cell Transplant Promotes Functional Recovery of Locomotion After Complete Transected Spinal Cord Injury Predominantly by Secreting Neurotrophic Factors

2021 ◽  
Author(s):  
Shuo Liu ◽  
Caixia Fan ◽  
Yuanyuan Xie ◽  
Liudi Wang ◽  
Yanyan Cui ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Functional Recovery ◽  
Neurotrophic Factors ◽  
Culture Medium ◽  
Collagen Scaffold ◽  
Locomotor Recovery ◽  
Cord Injury ◽  
Neuronal Replacement

Abstract ObjectiveCell-based therapy is a promising strategy for spinal cord injury (SCI) repair, but faced the challenges to direct the neuronal differentiation of appropriate neuron subtypes for achieving the neuronal replacement. We investigated whether allogeneic beforehand in vitro differentiated neural stem cells (NSCs) could relieve the adverse effects of regeneration inhibitory niche and promote motor functional recovery by accomplishing neuronal replacement after transplant into SCI rats. MethodsCollagen scaffold combined with digested NSCs, NSC sphere, differentiated neurons, and sphere of differentiated neurons were transplanted into completely transected SCI in rats and therapeutic outcomes were investigated. Next, we enriched complex of neurotrophic factors secreted from culture medium of NSCs, neurons, and sphere of neurons and a total of 2 mg total enriched protein combined with collagen scaffold were transplanted into SCI to further assay whether allogeneic NSCs transplant promotes the recovery of SCI predominantly by secreting neurotrophic factors. ResultsNSCs differentiated into neurons in density-dependent manner in vitro and sphere of NSCs could counteract myelin-induced inhibition of neuronal differentiation. Collagen scaffold combined with digested NSCs, NSC sphere, differentiated neurons, and sphere of differentiated neurons were transplanted into completely transected SCI in rats. Overall the cell treatment groups had a much better locomotor recovery, tissue remodeling, and newborn neuron formation than alone collagen scaffold treatment, compared with alone collagen material transplant and control group. However, unexpectedly, the differentiated cell treatment (differentiated neurons and sphere of differentiated neurons transplants) did not present striking better locomotor recovery than the undifferentiated NSCs and sphere of NSCs treatments, only sphere of neurons showed a slight increase in BBB score compared to other cell treatments. Next, we enriched complex of neurotrophic factors secreted from culture medium of NSCs, neurons, and sphere of neurons. BBB score analysis showed that the secreted neurotrophic factors from NSCs, neurons, and sphere of neurons would promote functional recovery of SCI to the same extent. ConclusionAllogeneic NSCs transplant promotes functional recovery of SCI predominantly by secreting neurotrophic factors, not direct neuronal replacement of differentiated neurons from transplanted cells.

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