Nerve Regeneration Restores Supraspinal Control of Bladder Function after Complete Spinal Cord Injury

Lee, Yu Shang; Lin, Ching Yi; Jiang, Hai; DePaul, Marc A.; Lin, Vernon W.; Silver, Jerry

doi:10.1523/jneurosci.1116-12.2013

Cited by 94 publications

(106 citation statements)

References 70 publications

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“…In these animals, AAV-ChR2 was mixed with control AAV-EBFP to enable comparison with a second treatment group (AAV-ChR2/AAVSox11 mixture; described below). Previous work has established that, in the absence of therapeutic intervention, intact CST axons display a limited ability to sprout across the spinal midline and compensate for lost CST input (Lee et al, 2014;Du et al, 2015;Wang et al, 2015). As expected, animals treated with AAV-EBFP control showed minimal midline crossing of CST axons in the cervical spinal cord (Fig.…”

Section: Optogenetic Assessment Of Functional Connectivity By Newly Smentioning

confidence: 53%

“…However, behavioral gains are often modest, and it can be unclear whether they result from direct synaptic input from newly grown axons, as opposed to plasticity in the target field or in upstream relays (Onifer et al, 2011). In other cases, behavioral effects are undetectable or even negative (Takeoka et al, 2011;Lu et al, 2014b;Geoffroy et al, 2015). For example, we found that overexpression of Sox11, a pro-regenerative transcription factor, improves corticospinal axon growth in the injured spinal cord but that behavioral outcomes were neutral in some tasks and slightly worsened in others .…”

Section: Introductionmentioning

confidence: 62%

“…Notably, because various approaches have succeeded in promoting axon regeneration and sprouting after CNS injury, effects on animal behavior are at best partially beneficial Zou et al, 2015) and can also be neutral (Lu et al, 2012a,b;Geoffroy et al, 2015) or even negative (Takeoka et al, 2011;Wang et al, 2015). Thus, the ability of growth-stimulated axons to synaptically integrate into target tissue is emerging as a key question in the field (Pernet and Schwab, 2014;Ramer et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…AAV9 -CaMKIIChR2(H134R)-EYFP was obtained from the University of North Carolina Viral Vector Core. AAV8 -EBFP-2A-mCherry and AAV8 -Sox11-2A-mCherry, modified with H2B fusion protein to render the mCherry localized to nuclei (Kanda et al, 1998), were from the University of Miami viral vector core as described previously . Mice were tested weekly on a horizontal ladder (30 cm long, 1 cm rung spacing) task before and after pyramidotomy and adeno-associated virus (AAV) injection in the motor cortex .…”

Section: Animals and Behavioral Testingmentioning

confidence: 99%

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Optogenetic Interrogation of Functional Synapse Formation by Corticospinal Tract Axons in the Injured Spinal Cord

et al. 2016

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To restore function after injury to the CNS, axons must be stimulated to extend into denervated territory and, critically, must form functional synapses with appropriate targets. We showed previously that forced overexpression of the transcription factor Sox11 increases axon growth by corticospinal tract (CST) neurons after spinal injury. However, behavioral outcomes were not improved, raising the question of whether the newly sprouted axons are able to form functional synapses. Here we developed an optogenetic strategy, paired with single-unit extracellular recordings, to assess the ability of

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Section: Optogenetic Assessment Of Functional Connectivity By Newly Smentioning

confidence: 53%

Section: Introductionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Animals and Behavioral Testingmentioning

confidence: 99%

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Optogenetic Interrogation of Functional Synapse Formation by Corticospinal Tract Axons in the Injured Spinal Cord

et al. 2016

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“…However, injured axons are unable to regenerate across the site of injury in the central nervous system because of the presence of an array of inhibitory cues present within the scar (For a review, see 5,6), in particular chondroitin sulphate proteoglycans (CSPGs) (7)(8)(9)(10). Digestion of CSPGs with the bacterial enzyme chondroitinase ABC (ChABC), following local delivery to the spinal cord, has led to axon regeneration, plastic neuronal rearrangements and functional recovery following section or crush injury in laboratory animal SCI models (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Encouragingly, these findings have also been found using clinically relevant contusive injury rodent models (22,23) and large animal models such as cats and squirrel monkeys (19,24,25).…”

Section: Introductionmentioning

confidence: 99%

Canine olfactory ensheathing cells from the olfactory mucosa can be engineered to produce active chondroitinase ABC

Carwardine

Wong

Fawcett

et al. 2016

Journal of the Neurological Sciences

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A multitude of factors must be overcome following spinal cord injury (SCI) in order to achieve clinical improvement in patients. It is thought that by combining promising therapies these diverse factors could be combatted with the aim of producing an overall improvement in function. Chondroitin sulphate proteoglycans (CSPGs) present in the glial scar that forms following SCI present a significant block to axon regeneration. Digestion of CSPGs by chondroitinase ABC (ChABC) leads to axon regeneration, neuronal plasticity and functional improvement in preclinical models of SCI. However, the enzyme activity decays at body temperature within 24-72 hours, limiting the translational potential of ChABC as a therapy. Olfactory ensheathing cells (OECs) have shown huge promise as a cell transplant therapy in SCI. Their beneficial effects have been demonstrated in multiple small animal SCI models as well as in naturally occurring SCI in canine patients. In the present study, we have genetically modified canine OECs from the mucosa to constitutively produce enzymatically active ChABC. We have developed a lentiviral vector that can deliver a mammalian modified version of the ChABC gene to mammalian cells, including OECs. Enzyme production was quantified using the Morgan-Elson assay that detects the breakdown products of CSPG digestion in cell supernatants. We confirmed our findings by immunolabelling cell supernatant samples using Western blotting. OECs normal cell function was unaffected by genetic modification as demonstrated by normal microscopic morphology and the presence of the low affinity neurotrophin receptor (p75 NGF ) following viral transduction. We have developed the means to allow production of active ChABC in combination with a promising cell transplant therapy for SCI repair.

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Autonomic Consequences of Spinal Cord Injury

Hou

Rabchevsky

2014

Comprehensive Physiology

163

112

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Spinal cord injury (SCI) results not only in motor and sensory deficits but also in autonomic dysfunctions. The disruption of connections between higher brain centers and the spinal cord, or the impaired autonomic nervous system itself, manifests a broad range of autonomic abnormalities. This includes compromised cardiovascular, respiratory, urinary, gastrointestinal, thermoregulatory, and sexual activities. These disabilities evoke potentially life-threatening symptoms that severely interfere with the daily living of those with SCI. In particular, high thoracic or cervical SCI often causes disordered hemodynamics due to deregulated sympathetic outflow. Episodic hypertension associated with autonomic dysreflexia develops as a result of massive sympathetic discharge often triggered by unpleasant visceral or sensory stimuli below the injury level. In the pelvic floor, bladder and urethral dysfunctions are classified according to upper motor neuron versus lower motor neuron injuries; this is dependent on the level of lesion. Most impairments of the lower urinary tract manifest in two interrelated complications: bladder storage and emptying. Inadequate or excessive detrusor and sphincter functions as well as detrusor-sphincter dyssynergia are examples of micturition abnormalities stemming from SCI. Gastrointestinal motility disorders in spinal cord injured-individuals are comprised of gastric dilation, delayed gastric emptying, and diminished propulsive transit along the entire gastrointestinal tract. As a critical consequence of SCI, neurogenic bowel dysfunction exhibits constipation and/or incontinence. Thus, it is essential to recognize neural mechanisms and pathophysiology underlying various complications of autonomic dysfunctions after SCI. This overview provides both vital information for better understanding these disorders and guides to pursue novel therapeutic approaches to alleviate secondary complications.

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Nerve Regeneration Restores Supraspinal Control of Bladder Function after Complete Spinal Cord Injury

Cited by 94 publications

References 70 publications

Optogenetic Interrogation of Functional Synapse Formation by Corticospinal Tract Axons in the Injured Spinal Cord

Optogenetic Interrogation of Functional Synapse Formation by Corticospinal Tract Axons in the Injured Spinal Cord

Canine olfactory ensheathing cells from the olfactory mucosa can be engineered to produce active chondroitinase ABC

Autonomic Consequences of Spinal Cord Injury

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