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The European Journal of Neuroscience Jun 2009Lumbar motoneurons can be activated monosynaptically by two glutamatergic synaptic inputs: the segmental dorsal root (DR) and the descending ventrolateral funiculus... (Comparative Study)
Comparative Study
Lumbar motoneurons can be activated monosynaptically by two glutamatergic synaptic inputs: the segmental dorsal root (DR) and the descending ventrolateral funiculus (VLF). To determine whether their N-methyl-d-aspartate (NMDA) receptors are independent, we used (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine-hydrogen-maleate (MK-801), known to induce a use-dependent irreversible block of NMDA receptors (NMDARs). In the presence of MK-801 (in bath) and non-NMDA antagonists (in bath, to isolate NMDARs pharmacologically), we first stimulated the DR. After MK-801 blockade of DR synaptic input, the VLF was stimulated. Its response was found to be not significantly different from its control value, suggesting that the DR stimulus activated very few, if any, receptors also activated by VLF stimulation. Similar findings were obtained if the stimulation order was reversed. Both inputs also elicited a polysynaptic NMDAR-mediated response. Evoking the DR polysynaptic response in the presence of MK-801 eliminated the corresponding VLF response; the reverse did not occur. Surprisingly, when MK-801 was washed from the bath, both the DR and the VLF responses could recover, although the recovery of the DR monosynaptic and polysynaptic responses was reliably greater than those associated with the VLF. Recovery was prevented if extrasynaptic receptors were activated by bath-applied NMDA in the presence of MK-801, consistent with the possibility that recovery was due to movement of extrasynaptic receptors into parts of the membrane accessible to transmitter released by DR and VLF stimulation. These novel findings suggest that segmental glutamatergic inputs to motoneurons are more susceptible to plastic changes than those from central nervous system white matter inputs at this developmental stage.
Topics: Animals; Animals, Newborn; Dizocilpine Maleate; Motor Neurons; Neuronal Plasticity; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Synapses; Synaptic Transmission
PubMed: 19490018
DOI: 10.1111/j.1460-9568.2009.06769.x -
Experimental & Molecular Medicine Mar 2009A subset of patients of amyotrophic lateral sclerosis (ALS) present with mutation of Cu/Zn superoxide dismutase 1 (SOD1), and such mutants caused an ALS- like disorder...
A subset of patients of amyotrophic lateral sclerosis (ALS) present with mutation of Cu/Zn superoxide dismutase 1 (SOD1), and such mutants caused an ALS- like disorder when expressed in rodents. These findings implicated SOD1 in ALS pathogenesis and made the transgenic animals a widely used ALS model. However, previous studies of these animals have focused largely on motor neuron damage. We report herein that the spinal cords of mice expressing a human SOD1 mutant (hSOD1-G93A), besides showing typical destruction of motor neurons and axons, exhibit significant damage in the sensory system, including Wallerian-like degeneration in axons of dorsal root and dorsal funiculus, and mitochondrial damage in dorsal root ganglia neurons. Thus, hSOD1-G93A mutation causes both motor and sensory neuropathies, and as such the disease developed in the transgenic mice very closely resembles human ALS.
Topics: Amyotrophic Lateral Sclerosis; Animals; Axons; Disease Models, Animal; Ganglia, Spinal; Humans; Mice; Mice, Transgenic; Mitochondria; Motor Neurons; Mutation; Nerve Degeneration; Sensory Receptor Cells; Spinal Cord; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 19293633
DOI: 10.3858/emm.2009.41.3.017 -
Journal of Veterinary Science Dec 2008Due to the therapeutic potential of gene therapy for neuronal injury, many studies of neurotrophic factors, vectors, and animal models have been performed. The presumed...
Due to the therapeutic potential of gene therapy for neuronal injury, many studies of neurotrophic factors, vectors, and animal models have been performed. The presumed dog beta-nerve growth factor (pdbeta-NGF) was generated and cloned and its expression was confirmed in CHO cells. The recombinant pdbeta-NGF protein reacted with a human beta-NGF antibody and showed bioactivity in PC12 cells. The pdbeta-NGF was shown to have similar bioactivity to the dog beta-NGF. The recombinant pdbeta-NGF plasmid was administrated into the intrathecal space in the gene therapy group. Twenty-four hours after the vector inoculation, the gene therapy group and the positive control group were intoxicated with excess pyridoxine for seven days. Each morning throughout the test period, the dogs' body weight was taken and postural reaction assessments were made. Electrophysiological recordings were performed twice, once before the experiment and once after the test period. After the experimental period, histological analysis was performed. Dogs in the gene therapy group had no weight change and were normal in postural reaction assessments. Electrophysiological recordings were also normal for the gene therapy group. Histological analysis showed that neither the axons nor the myelin of the dorsal funiculus of L4 were severely damaged in the gene therapy group. In addition, the dorsal root ganglia of L4 and the peripheral nerves (sciatic nerve) did not experience severe degenerative changes in the gene therapy group. This study is the first to show the protective effect of NGF gene therapy in a dog model.
Topics: Amino Acid Sequence; Animals; Base Sequence; CHO Cells; Central Nervous System Diseases; Cloning, Molecular; Cricetinae; Cricetulus; Cytomegalovirus; Dog Diseases; Dogs; Female; Genetic Therapy; Genetic Vectors; Male; Molecular Sequence Data; Nerve Growth Factor; Pyridoxine
PubMed: 19043311
DOI: 10.4142/jvs.2008.9.4.367 -
Journal of Anatomy Nov 2008Developing sensory axons grow into the spinal cord in a three-step process: the axons extend toward and into the cord, then branch rostrally and caudally to establish a...
Developing sensory axons grow into the spinal cord in a three-step process: the axons extend toward and into the cord, then branch rostrally and caudally to establish a longitudinal pathway, and finally grow into the grey matter. This study investigated regulation by cAMP of the longitudinal extension of this pathway within the spinal cord. The cAMP pathway was pharmacologically altered in chicken embryos to determine its effects on the establishment of the longitudinal extension of the dorsal funiculus. A forskolin-induced increase in cAMP in ovo inhibited longitudinal growth by sensory afferents. Furthermore, blocking cAMP activation of protein kinase A (PKA) in ovo with H-89 substantially increased longitudinal extension. These results demonstrate a specific role for the cAMP/PKA pathway in the initial longitudinal spinal afferent growth in the chicken embryo.
Topics: Afferent Pathways; Animals; Axons; Chick Embryo; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Isoquinolines; Neurons, Afferent; Sensory Receptor Cells; Signal Transduction; Spinal Cord; Sulfonamides
PubMed: 19014362
DOI: 10.1111/j.1469-7580.2008.00981.x -
Journal of Neurotrauma Aug 2008Cervical spinal cord injury (SCI) can severely impair reaching and grasping ability, and several descending systems, including the rubrospinal tract and corticospinal...
Cervical spinal cord injury (SCI) can severely impair reaching and grasping ability, and several descending systems, including the rubrospinal tract and corticospinal tract, have been implicated in the control of reach-to-grasp movements. The primary aim of this study was to characterize further the forelimb deficits associated with a cervical dorsolateral funiculotomy, which ablates the rubrospinal tract but spares the dorsal and ventral corticospinal tract in the rat. Adult female rats that preferred to use their right forelimb to reach for single pellets received a lesion to the right cervical dorsolateral funiculus between the C3-4 dorsal roots. Gross forelimb motor function was assessed by measuring spontaneous forelimb usage during exploration in a cylinder, and fine motor function was assessed using staircase and single pellet reaching tests. Single pellet reaching was further evaluated by qualitative and quantitative kinematic scoring of the movement components. Histological analysis included the quantification of spared white matter. Cervical dorsolateral funiculotomy produced marked deficits in reaching performance on both the single pellet and staircase reaching tests, with transient deficits in gross forelimb usage in the cylinder. Quantitative kinematics also revealed a reduction in digit abduction during the reach, which persisted throughout the 8-week post-SCI period. Tests of reach-to-grasp function, therefore, were more sensitive than a test of gross forelimb usage after cervical dorsolateral funiculotomy and did not show recovery over the 8-week survival period. We suggest that the staircase test is a useful screening tool for intervention studies because of its ease of implementation, and that the single pellet test is valuable for examining reaching accuracy and detailed kinematics.
Topics: Animals; Cervical Vertebrae; Cordotomy; Disease Models, Animal; Extrapyramidal Tracts; Female; Functional Laterality; Hand Strength; Motor Skills; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries
PubMed: 18721108
DOI: 10.1089/neu.2007.0419 -
Journal of Veterinary Science Jun 2008To construct a sensory neuropathy model, excess pyridoxine (150 mg/kg s.i.d.) was injected subcutaneously in dogs over a period of 7 days. During the administrations... (Comparative Study)
Comparative Study
To construct a sensory neuropathy model, excess pyridoxine (150 mg/kg s.i.d.) was injected subcutaneously in dogs over a period of 7 days. During the administrations period, the dogs experienced body weight reduction and proprioceptive loss involving the hindquarters. After pyridoxine administration was completed, electrophysiological recordings showed that the M wave remained at a normal state, but the H-reflex of the treated dogs disappeared at 7 days. The dorsal funiculus of L(4) was disrupted irregularly in the axons and myelin with vacuolation. The dorsal root ganglia of L(4), and sciatic and tibial nerves showed degenerative changes and vacuolation. However, the lateral and ventral funiculi of L(4) showed a normal histopathologic pattern. Although this subcutaneous administration method did not cause systemic toxicity and effectively induced sensory neuropathy, this study confirmed the possibility of producing a pyridoxine-induced sensory neuropathy model in dogs with short-term administration.
Topics: Animals; Body Weight; Disease Models, Animal; Dogs; Electrophysiology; Neurodegenerative Diseases; Proprioception; Pyridoxine
PubMed: 18487933
DOI: 10.4142/jvs.2008.9.2.127 -
Neuroscience Mar 2008Injuries to the cauda equina/conus medullaris portion of the spinal cord can result in motor, sensory, and autonomic dysfunction, and neuropathic pain. In rats,...
Injuries to the cauda equina/conus medullaris portion of the spinal cord can result in motor, sensory, and autonomic dysfunction, and neuropathic pain. In rats, unilateral avulsion of the motor efferents from the lumbosacral spinal cord results in at-level allodynia, along with a corresponding glial and inflammatory response in the dorsal horn of the spinal cord segments immediately rostral to the lesion. Here, we investigated the fate of intramedullary primary sensory projections following a motor efferent lesion. The lumbosacral (L6 and S1) ventral roots were unilaterally avulsed from the rat spinal cord (VRA; n=9). A second experimental group had the avulsed roots acutely reimplanted into the lateral funiculus (Imp; n=5), as this neural repair strategy is neuroprotective, and promotes the functional reinnervation of peripheral targets. A laminectomy-only group served as controls (Lam; n=7). At 8 weeks post-lesion, immunohistochemical examination showed a 42% reduction (P<0.001) in the number of RT97-positive axons in the ascending tracts of the dorsal funiculus of the L4-5 spinal segment in VRA rats. Evidence for degenerating myelin was also present. Reimplantation of the avulsed roots ameliorated axon and myelin degeneration. Axons in the descending dorsal corticospinal tract were unaffected in all groups, suggesting a specificity of this lesion for spinal primary sensory afferents. These results show for the first time that a lesion restricted to motor roots can induce the degeneration of intramedullary sensory afferents. Importantly, reimplantation of the lesioned motor roots ameliorated sensory axon degeneration. These data further support the therapeutic potential for reimplantation of avulsed ventral roots following trauma to the cauda equina/conus medullaris.
Topics: Animals; Calcium-Binding Proteins; Cauda Equina; Disease Models, Animal; Female; Functional Laterality; Glial Fibrillary Acidic Protein; Indoles; Microfilament Proteins; Myelin Basic Protein; Nerve Degeneration; Nerve Regeneration; Neurofilament Proteins; Rats; Rats, Sprague-Dawley; Recovery of Function; Replantation; Spinal Cord Injuries; Spinal Nerve Roots
PubMed: 18291596
DOI: 10.1016/j.neuroscience.2007.11.043 -
Pain Aug 2008Peripheral nerve injuries that provoke neuropathic pain are associated with microglial activation in the spinal cord. We have investigated the characteristics of spinal...
Peripheral nerve injuries that provoke neuropathic pain are associated with microglial activation in the spinal cord. We have investigated the characteristics of spinal microglial activation in three distinct models of peripheral neuropathic pain in the rat: spared nerve injury (SNI), chronic constriction injury, and spinal nerve ligation. In all models, dense clusters of cells immunoreactive for the microglial marker CD11b formed in the ipsilateral dorsal horn 7 days after injury. Microglial expression of ionised calcium binding adapter molecule 1 (Iba1) increased by up to 40% and phosphorylation of p38 mitogen-activated protein kinase, a marker of microglial activity, by 45%. Expression of the lysosomal ED1-antigen indicated phagocytic activity of the cells. Unlike the peripheral nerve lesions, rhizotomy produced only a weak microglial reaction within the spinal gray matter but a strong activation of microglia and phagocytes in the dorsal funiculus at lumbar and thoracic spinal cord levels. This suggests that although degeneration of central terminals is sufficient to elicit microglial activation, it does not account for the inflammatory response in the dorsal horn after peripheral nerve injury. Early intrathecal treatment with low-dose methotrexate, beginning at the time of injury, decreased microglial activation, reduced p38 phosphorylation, and attenuated pain-like behavior after SNI. In contrast, systemic or intrathecal delivery of the glucocorticoid dexamethasone did not inhibit the activation of microglia or reduce pain-like behavior. We confirm that microglial activation is crucial for the development of pain after nerve injury, and demonstrates that suppression of this cellular immune response is a promising approach for preventing neuropathic pain.
Topics: Animals; Behavior, Animal; Immunosuppressive Agents; Male; Methotrexate; Microglia; Neuralgia; Peripheral Nerve Injuries; Peripheral Nerves; Rats; Rats, Sprague-Dawley; Spinal Cord; Treatment Outcome
PubMed: 18215468
DOI: 10.1016/j.pain.2007.11.019 -
Journal of Veterinary Internal Medicine 2007Adult dogs with degenerative myelopathy (DM) have progressive ataxia and paresis of the pelvic limbs, leading to paraplegia and euthanasia. Although most commonly...
BACKGROUND
Adult dogs with degenerative myelopathy (DM) have progressive ataxia and paresis of the pelvic limbs, leading to paraplegia and euthanasia. Although most commonly reported in German Shepherd dogs, high disease prevalence exists in other breeds.
OBJECTIVE
Our aim was the clinical and histopathologic characterization of familial degenerative myelopathy (FDM) in Pembroke Welsh Corgi (PWC) dogs.
ANIMALS
Twenty-one PWCs were prospectively studied from initial diagnosis until euthanasia.
METHODS
Neurologic examination, blood tests, cerebrospinal fluid (CSF) analysis, electrodiagnostic testing, and spinal imaging were performed. Concentrations of 8-iso-prostaglandin F2alpha (8-isoprostane) were measured in CSF. Routine histochemistry was used for neuropathology. Deoxyribonucleic acid and pedigrees were collected from 110 dogs.
RESULTS
Median duration of clinical signs before euthanasia was 19 months. Median age at euthanasia was 13 years. All dogs were nonambulatory paraparetic or paraplegic, and 15 dogs had thoracic limb weakness at euthanasia. Electrodiagnostic testing and spinal imaging were consistent with noncompressive myelopathy. No significant difference was detected in 8-isoprostane concentrations between normal and FDM-affected dogs. Axonal and myelin degeneration of the spinal cord was most severe in the dorsal portion of the lateral funiculus. Pedigree analysis suggested a familial disease.
CONCLUSIONS AND CLINICAL IMPORTANCE
Clinical progression of FDM in PWC dogs was similar to that observed in other breeds but characterized by a longer duration. Spinal cord pathology predominates as noninflammatory axonal degeneration. Oxidative stress injury associated with 8-isoprostane production is not involved in the pathogenesis of FDM-affected PWC dogs. A familial disease is suspected.
Topics: Animals; DNA; Dog Diseases; Dogs; Female; Genetic Predisposition to Disease; Male; Pedigree; Spinal Cord Diseases
PubMed: 18196743
DOI: 10.1892/07-059.1 -
The Journal of Veterinary Medical... Dec 2007Canine ganglioradiculitis (sensory neuropathy) was examined pathologically in two dogs (dog Nos. 1 and 2). The affected dogs had 1 and 2 years clinical courses from the...
Canine ganglioradiculitis (sensory neuropathy) was examined pathologically in two dogs (dog Nos. 1 and 2). The affected dogs had 1 and 2 years clinical courses from the onset, respectively. As common clinical signs, both cases showed progressive ataxia, difficulty in prehending food, visual deficit, and several sensory abnormalities. Gross observation after tissue fixation revealed whitish discoloration in the dorsal column of the spinal cords. The histological lesions were mainly distributed in the spinal dorsal roots, ganglions, and dorsal columns. In the spinal dorsal roots and ganglions, there were striking myelin loss, mild infiltration of mononuclear cells, and proliferation of small spindle cells. In the dorsal funiculus, there were moderate to severe diffuse myelin-loss and axonal degeneration. Immunohistochemistry for substance P (SP) revealed marked reduction of SP-immunopositive granules in the spinal substantia gelatinosa of affected dogs. By immunohistochemistry, CD3-positive cells were observed in the dorsal roots of dog No. 2, while CD3-positive cells were rare in those of dog No. 1. In the spinal ganglion of dog No. 1 there were many CD3- and MHC class II-positive cells. By indirect immunofluorescence assay using sera from affected dogs, no autoantibodies against canine nerve tissues were detected. The clinicopathological features of the present cases are almost consistent with those in previous reports of canine sensory neuropathies, while the etiology remains unclear.
Topics: Animals; Dog Diseases; Dogs; Female; Muscle, Skeletal; Polyradiculoneuropathy; Spinal Cord; Spinal Nerve Roots
PubMed: 18176020
DOI: 10.1292/jvms.69.1247