Lateral Funiculus Research Articles

Activity of 2′, 3′-Cyclic Nucleotide 3′-Phosphodiesterase (CNPase) in Spinal Cord with Spongy Change Induced by a Single Oral Dose of Aniline in Rats

A spongy change in the spinal cord white matter was observed in four-week-old rats treated with aniline. Although this change was found to be a result of the myelin sheath splitting at the ultrastructural level, the mechanism is unknown. This study was conducted to identify the mechanism of the spongy change in aniline-treated rats. The spongy change in the spinal cord white matter was first detected on day 5 in the histopathologic examination. The incidence and severity of the lesions, especially in the lateral and ventral funiculi of the thoracic spinal cord white matter, increased prominently from day 8 to day 10. In all rats, immunohistochemical staining by anti-2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) occurred along the cytoplasmic boundaries of the normal oligodendroglia. However, mild to moderate anti-CNPase staining extended to the swollen cytoplasm of the oligodendroglia in the aniline-treated rats from day 2 to day 4. In the electron microscopic examination, free ribosomes and rough endoplasmic reticula in the cytoplasm of the oligodendroglia increased on days 3 and 4. These changes were considered to be related to CNPase expression. However, CNPase expression decreased, whereas the spongy changes were detected from day 5. The reduction in CNPase expression may contribute to the changes in the myelin morphology observed in aniline intoxication.

Biomechanical study of the effect of degree of static compression of the spinal cord in ossification of the posterior longitudinal ligament

The authors evaluated the biomechanical effect of 3 different degrees of static compression in a model of the spinal cord in order to investigate the effect of cord compression in patients with ossification of the posterior longitudinal ligament (OPLL). A 3D finite element spinal cord model consisting of gray matter, white matter, and pia mater was established. As a simulation of OPLL-induced compression, a rigid plate compressed the anterior surface of the cord. The degrees of compression were 10, 20, and 40% of the anteroposterior (AP) diameter of the cord. The cord was supported from behind by the rigid body along its the posterior border, simulating the lamina. Stress distributions inside of the cord were evaluated. The stresses on the cord were very low under 10% compression. At 20% compression, the stresses on the cord increased very slightly. At 40% compression, the stresses on the cord became much higher than with 20% compression, and high stress distributions were observed in gray matter and the lateral and posterior funiculus. The stresses on the compressed layers were much higher than those on the uncompressed layer. The stress distributions at 10 and 20% compression of the AP diameter of the spinal cord were very low. The stress distribution at 40% compression was much higher. The authors conclude that a critical point may exist between 20 and 40% compression of the AP diameter of the cord such that when the degree of the compression exceeds this point, the stress distribution becomes much higher, and that this may contribute to myelopathy.

Transplantation of ciliary neurotrophic factor-expressing adult oligodendrocyte precursor cells promotes remyelination and functional recovery after spinal cord injury.

Demyelination contributes to the dysfunction after traumatic spinal cord injury (SCI). We explored whether the combination of neurotrophic factors and transplantation of adult rat spinal cord oligodendrocyte precursor cells (OPCs) could enhance remyelination and functional recovery after SCI. Ciliary neurotrophic factor (CNTF) was the most effective neurotrophic factor to promote oligodendrocyte (OL) differentiation and survival of OPCs in vitro. OPCs were infected with retroviruses expressing enhanced green fluorescent protein (EGFP) or CNTF and transplanted into the contused adult thoracic spinal cord 9 d after injury. Seven weeks after transplantation, the grafted OPCs survived and integrated into the injured spinal cord. The survival of grafted CNTF-OPCs increased fourfold compared with EGFP-OPCs. The grafted OPCs differentiated into adenomatus polyposis coli (APC(+)) OLs, and CNTF significantly increased the percentage of APC(+) OLs from grafted OPCs. Immunofluorescent and immunoelectron microscopic analyses showed that the grafted OPCs formed central myelin sheaths around the axons in the injured spinal cord. The number of OL-remyelinated axons in ventrolateral funiculus (VLF) or lateral funiculus (LF) at the injured epicenter was significantly increased in animals that received CNTF-OPC grafts compared with all other groups. Importantly, 75% of rats receiving CNTF-OPC grafts recovered transcranial magnetic motor-evoked potential and magnetic interenlargement reflex responses, indicating that conduction through the demyelinated axons in VLF or LF, respectively, was partially restored. More importantly, recovery of hindlimb locomotor function was significantly enhanced in animals receiving grafts of CNTF-OPCs. Thus, combined treatment with OPC grafts expressing CNTF can enhance remyelination and facilitate functional recovery after traumatic SCI.

Distribution of the Neuronal Gap Junction Protein Connexin36 in the Spinal Cord Enlargements of Developing and Adult Opossums, Monodelphis domestica

We use opossums Monodelphis domestica to study the development of mammalian motor systems. The immature forelimbs of the newborn perform rhythmic and alternating movements that are likely under spinal control. The hindlimbs start moving in the second week. Chemical synapses are scant in the spinal enlargements of neonatal opossums and the presence of electrochemical synapses has not been evaluated in this species or in other marsupials. As a first step aiming at evaluating the existence of such synapses in the neonatal spinal cord, we have investigated the presence of the exclusively neuronal gap junction protein connexin36 (Cx36) by immunohistochemistry in light microscopy. At birth, Cx36 immunoreactivity is moderate in the presumptive gray matter in both enlargements. Thereafter, it decreases gradually, except in the superficial dorsal horn where it increases to a plateau between P10 and P20. Cx36 labeling is detected in the presumptive white matter at birth, but then decreases except in the dorsal part of the lateral funiculus, where it is dense between P10 and P20. Cx36 has become virtually undetectable by P52. The presence of Cx36 in the spinal enlargements of postnatal opossums suggests that neurons might be linked by gap junctions at a time when chemical synapses are only beginning to form. The greater abundance of Cx36 observed transiently in the superficial dorsal horn suggests a stronger involvement of this protein in spinal sensory systems than in direct motor control of the limbs.

The role of the alpha5 beta1 integrin in axonal regeneration

Event Abstract Back to Event The role of the alpha5 beta1 integrin in axonal regeneration Tamás Bellák1*, Gábor Márton1 and Antal Nógrádi1 1 University of Szeged, Department of Ophthalmology, Faculty of Medicine, Hungary Injury to the spinal cord in humans and other mammals is not followed by the replacement of lost neurons or regrowth of injured axons, thus it leads to permanent, incurable functional deficits. Injured axons readily regenerate in the peripheral nervous system, while they show limited regenerative capacity in the central nervous system (CNS). Earlier research from our laboratory has shown that integrins play an important role in the regulation of axonal growth and survival of injured motoneurons destined to die. These results suggest that alteration of the integrin expression profile of injured CNS neurons may promote the regeneration of injured CNS axons, too. The right lateral funiculus was transected at the level of C5 segment in Sprague-Dawley rats. This limited lesion did not interfere with the majority of the vital spinal cord functions, but induced a functional motor deficit in the use of the ipsilateral forelimb. This procedure provided the opportunity to study the regeneration of some descending pathways, most importantly that of the rubrospinal tract. An alpha5 adenoviral vector construct was injected into the cord above the lesion. The survival of neurons in the red nucleus was determined and the extent of axonal growth analysed. These preliminary data suggest that this treatment model is a suitable application to study the effect of alpha5 beta1 integrin overexpression on axonal regeneration in the injured spinal cord. Conference: IBRO International Workshop 2010, Pécs, Hungary, 21 Jan - 23 Jan, 2010. Presentation Type: Poster Presentation Topic: Cellular neuroscience Citation: Bellák T, Márton G and Nógrádi A (2010). The role of the alpha5 beta1 integrin in axonal regeneration. Front. Neurosci. Conference Abstract: IBRO International Workshop 2010. doi: 10.3389/conf.fnins.2010.10.00003 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 14 Apr 2010; Published Online: 14 Apr 2010. * Correspondence: Tamás Bellák, University of Szeged, Department of Ophthalmology, Faculty of Medicine, Szeged, Hungary, tamasbellak@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Tamás Bellák Gábor Márton Antal Nógrádi Google Tamás Bellák Gábor Márton Antal Nógrádi Google Scholar Tamás Bellák Gábor Márton Antal Nógrádi PubMed Tamás Bellák Gábor Márton Antal Nógrádi Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

GABAB Mediated Regulation of Sympathetic Preganglionic Neurons: Pre- and Postsynaptic Sites of Action

Modulatory influences on sympathetic nervous system activity are diverse and far reaching, acting at select points in the complex pathways controlling sympathetic outflow to enable subtle changes or more global effects. Changes in the degree of sympathetic neuromodulation can have serious consequences on homeostatic variables such as heart rate, blood pressure and gut motility. At the level of the spinal cord, the sympathetic preganglionic neurons (SPNs) can be modulated by activation of presynaptic GABAB heteroreceptors on glutamatergic terminals and by postsynaptic GABAB receptors. Here we show that a low concentration of the GABAB agonist baclofen (1 μM) attenuated GABAergic inhibitory postsynaptic potentials in SPNs elicited from stimulation of either the central autonomic area or descending fibers in the lateral funiculus. This low baclofen concentration also elicited three categories of postsynaptic response: a large hyperpolarization with a decrease in input resistance, a moderate hyperpolarization with no change in input resistance and no response. Using cesium-loaded, tetraethylammonium chloride containing electrodes (to block potassium conductance), baclofen elicited moderate hyperpolarizations with no change in input resistance in 50% of SPNs; the remainder were unaffected. These modest hyperpolarizations were reduced in Ca2+ free solution or cadmium. Hyperpolarizing responses were also observed in interneurons in the vicinity of SPNs. These studies provide the first evidence for GABAB autoreceptors involved in inhibitory GABAergic transmission onto SPNs and for postsynaptic GABAB receptors on interneurons. The data also indicate that there is heterogeneity in the postsynaptic responses of SPNs.

Distribution of oxytocin-immunoreactive neuronal elements in the rat spinal cord

We investigated the distribution of oxytocin in rat spinal cord using immunocytochemistry and radioimmunoassay (RIA). Each segment of the spinal cord from cervical to coccygeal contained oxytocin-immunoreactive fibers. The Rexed laminae I and II of the dorsal horn showed moderate to intense immunoreactivity. A dense network was found around the central canal where some fibers apposed the ependyma. The autonomic centers of the spinal cord at the thoracolumbar and sacral segments were heavily innervated. Few fibers were found around the motoneurons. In the white matter, the immunoreactivity was localized mainly in the dorsal part of the lateral funiculus, in the pars funicularis of the nucleus intermediolateralis and in a longitudinal network of the lateral funiculus below the spinal cord surface. Some fibers from this network entered the pia mater. RIA measurements revealed that the cervical spinal cord had lower oxytocin content than that found in either the thoracic, lumbar, sacral or coccygeal region. Our results show that the distribution of oxytocin-immunoreactive fibers in the spinal cord correlates with anatomic locations related to nociceptive, autonomic and motor functions. We assume that oxytocin-containing axons play a role in secreting oxytocin directly into the liquor space of the spinal cord.

Dynamics of Fast and Slow Inhibition from Cerebellar Golgi Cells Allow Flexible Control of Synaptic Integration

Throughout the brain, multiple interneuron types influence distinct aspects of synaptic processing. Interneuron diversity can thereby promote differential firing from neurons receiving common excitation. In contrast, Golgi cells are the sole interneurons regulating granule cell spiking evoked by mossy fibers, thereby gating inputs to the cerebellar cortex. Here, we examine how this single interneuron class modifies activity in its targets. We find that GABA(A)-mediated transmission at unitary Golgi cell --> granule cell synapses consists of varying contributions of fast synaptic currents and sustained inhibition. Fast IPSCs depress and slow IPSCs gradually build during high-frequency Golgi cell activity. Consequently, fast and slow inhibition differentially influence granule cell spike timing during persistent mossy fiber input. Furthermore, slow inhibition reduces the gain of the mossy fiber --> granule cell input-output curve, while fast inhibition increases the threshold. Thus, a lack of interneuron diversity need not prevent flexible inhibitory control of synaptic processing.

Enkephalins, dynorphins, and β‐endorphin in the rat dorsal horn: An immunofluorescence colocalization study

To characterize neuronal pathways that release opioid peptides in the rat dorsal horn, multiple-label immunohistochemistry, confocal microscopy, and computerized co-localization measures were used to characterize opioid-containing terminals and cells. An antibody that selectively recognized beta-endorphin labeled fibers and neurons in the ventral horn as well as fibers in the lateral funiculus and lamina X, but practically no fibers in the dorsal horn. An anti-enkephalin antibody, which recognized Leu-, Met-, and Phe-Arg-Met-enkephalin, labeled the dorsolateral funiculus and numerous puncta in laminae I-III and V of the dorsal horn. An antibody against Phe-Arg-Met-enkephalin, which did not recognize Leu- and Met-enkephalin, labeled the same puncta. Antibodies against dynorphin and prodynorphin labeled puncta and fibers in laminae I, II, and V, as well as some fibers in the rest of the dorsal horn. Dynorphin and prodynorphin immunoreactivities colocalized in some puncta and fibers, but the prodynorphin antibody additionally labeled cell bodies. There was no co-localization of dynorphin (or prodynorphin) with enkephalin (or Phe-Arg-Met-enkephalin). Enkephalin immunoreactivity did not colocalize with the C-fiber markers calcitonin gene-related peptide (CGRP), substance P, and isolectin B4. In contrast, there was some colocalization of dynorphin and prodynorphin with CGRP and substance P, but not with isolectin B4. Both enkephalin and dynorphin partly colocalized with vesicular glutamate transporter 2, a marker of glutamatergic terminals. The prodynorphin-positive neurons in the dorsal horn were distinct from neurons expressing mu-opioid receptors, neurokinin 1 receptors, and protein kinase C-gamma. These results show that enkephalins and dynorphins are present in different populations of dorsal horn neurons. In addition, dynorphin is present in some C-fibers.

Three-Dimensional Finite Element Model of the Cervical Spinal Cord

A three-dimensional finite element investigation. To create a three-dimensional finite element model of the cervical spinal cord enlargement and to simulate a hyperextension injury of the cervical cord. Experimental studies are difficult to simulate the complex mechanism of spinal cord injuries. The introduction of three-dimensional modeling technique into neurotrauma studies is essential to further understand mechanical behavior of the nerve tissue during traumatic injuries. Geometrical reconstruction of cervical spinal cord enlargement was developed based on the morphologic features of each segment of the fresh human cervical cord. After the validation of the model, the pinching condition in the hyperextension injuries was simulated with compressive and extension forces applied on the cervical enlargement model. The average von Mises stress of the 9 anatomic regions, such as anterior funiculus, lateral part of the lateral funiculus, medial part of the lateral funiculus, lateral part of the posterior funiculus, medial part of the posterior funiculus, anterior horn, the bottom of anterior horn, the apex of posterior horn, the cervix cornu posterioris, and caput cornu posterioris was recorded. The force-displacement response of the spinal cord under compression and axial tension loading was close to the experimental results reported in the literature. The stress distribution of the spinal cord according to the numerical simulation and the morphologic features of the in vivo experiment were also in close agreement. Hyperextension injury simulation showed high localized stress at the anterior and posterior horn in the gray matter. The finite element method as a three-dimensional modeling technique can improve the understanding of the biomechanical behavior of the spinal cord. The results of hyperextension injury simulation of the cervical spinal cord probably account for the predominance of the hand weakness in patients with central cord injury.

Degenerative Myelopathy in Two Boxer Dogs

Degenerative myelopathy (DM) is a common, slowly progressive, debilitating disease reported in several dog breeds, including the German Shepherd Dog and Pembroke Welsh Corgi. Boxer dogs present occasionally for a thoracolumbar myelopathy for which no cause is identified on MRI or cerebrospinal fluid analysis. Despite a lack of a histologic description of DM in the Boxer in the veterinary literature, such dogs are presumed to have DM. Here we report 2 histologically confirmed cases of DM in the Boxer breed in which histologic studies disclosed marked degenerative changes in the spinal cord that were most prominent in the thoracic and cranial lumbar segments. Lesions consisted of myelin vacuolation and degeneration, myelophagocytosis, reactive astrocytosis, and ellipsoid formation most prominent in the lateral and ventral funiculi. We present a detailed histologic description of DM in the Boxer dog and compare it to DM in other purebred dogs.

Degenerative Myelopathy in 18 Pembroke Welsh Corgi Dogs

Postmortem examination was performed on 18 Pembroke Welsh Corgi dogs (mean age 12.7 years) with clinical signs and antemortem diagnostic tests compatible with a diagnosis of degenerative myelopathy. Tissue sections from specific spinal cord and brain regions were systematically evaluated in all dogs. Axonal degeneration and loss were graded according to severity and subsequently compared across different spinal cord segments and funiculi. White matter lesions were identified in defined regions of the dorsal, lateral, and ventral funiculi. The dorsolateral portion of the lateral funiculus was the most severely affected region in all cord segments. Spinal cord segment T12 exhibited the most severe axonal loss. Spinal nerve roots, peripheral nerves, and brain sections were within normal limits, with the exception of areas of mild astrogliosis in gray matter of the caudal medulla. Dogs with more severe lesions showed significant progression of axonal degeneration and loss at T12 and at cord segments cranial and caudal to T12. Severity of axonal loss in individual dogs positively correlated with the duration of clinical signs. The distribution of axonal degeneration resembled that reported in German Shepherd Dog degenerative myelopathy but differed with respect to the transverse and longitudinal extent of the lesions within more clearly defined funicular areas. Although these lesion differences might reflect disease longevity, they could also indicate a form of degenerative myelopathy unique to the Pembroke Welsh Corgi dog.

Mediolateral and rostrocaudal topographic organization of the sympathetic preganglionic cell pool in the spinal cord of Xenopus laevis

The sympathetic preganglionic cell pool in Xenopus laevis can be divided into four parts, i.e., the intercalated nucleus (IC) and the intermediolateral nucleus (IML) located respectively at the medial and the lateral borders of the lateral field, the lateral funiculus, and the ventral field within the thoracolumbar spinal segments. We compared the location of the preganglionic cells labeled following tracer application to the paravertebral sympathetic chain with those labeled following application to the celiac ganglion (CG), the adrenal gland (AG), and the splanchnic nerves (SNs) and found that their relative contribution differs depending on the sites. In tracer application to the paravertebral chain ganglia and the sympathetic trunk, 31.4-41.9% and 43.9-58.4% of labeled cells were detected respectively in the IC and in the IML, whereas application to the CG, AG, and on all the SNs, revealed that more than 84% of labeled cells were found in the IML and in the lateral funiculus with less than 8.6% in the IC. The contribution of the ventral field cells was less than 7.5% in all experiments. This type of topographic cytoarchitecture is a character shared with the mammalian preganglionic cell pool, but what distinguishes it from that of mammals is its systematic form throughout the entire longitudinal extent of the pool. In Xenopus, differences of mean soma areas and dendritic projections of labeled cells also suggest that the cell pools are distinguished not only by their location and axonal projections, but also by the morphology of their cells.

Degenerative Myelopathy in 18 Pembroke Welsh Corgi Dogs

Postmortem examination was performed on 18 Pembroke Welsh Corgi dogs (mean age 12.7 years) with clinical signs and antemortem diagnostic tests compatible with a diagnosis of degenerative myelopathy. Tissue sections from specific spinal cord and brain regions were systematically evaluated in all dogs. Axonal degeneration and loss were graded according to severity and subsequently compared across different spinal cord segments and funiculi. White matter lesions were identified in defined regions of the dorsal, lateral, and ventral funiculi. The dorsolateral portion of the lateral funiculus was the most severely affected region in all cord segments. Spinal cord segment T12 exhibited the most severe axonal loss. Spinal nerve roots, peripheral nerves, and brain sections were within normal limits, with the exception of areas of mild astrogliosis in gray matter of the caudal medulla. Dogs with more severe lesions showed significant progression of axonal degeneration and loss at T12 and at cord segments cranial and caudal to T12. Severity of axonal loss in individual dogs positively correlated with the duration of clinical signs. The distribution of axonal degeneration resembled that reported in German Shepherd Dog degenerative myelopathy but differed with respect to the transverse and longitudinal extent of the lesions within more clearly defined funicular areas. Although these lesion differences might reflect disease longevity, they could also indicate a form of degenerative myelopathy unique to the Pembroke Welsh Corgi dog.

Task-dependent compensation after pyramidal tract and dorsolateral spinal lesions in rats

The purpose of this research was to investigate whether pathways in the dorsal part of the lateral spinal funiculus (DLF) can compensate for loss of corticospinal input (CST) to the spinal cord. The CST is known to control skilled limb movements in rats. The DLF contains several different pathways, including the rubrospinal tract (RST) which is also thought to influence limb movements. After lesions of either the corticospinal or the rubrospinal system, it is unclear how much of the remaining forelimb function is due to the presence of the alternate pathway. To begin to address this issue, the present study investigates the compensatory role of pathways in the DLF, including the rubrospinal tract, after bilateral lesions of the pyramidal tract (PT). We initially performed bilateral PT lesions in rats, which effectively removed the CST input to the spinal cord. We tested these rats during overground locomotion, skilled locomotion and skilled forelimb usage. After a 6 week recovery period, we then performed bilateral DLF lesions and compared the behavioural abilities of these rats to those of animals which underwent simultaneous PT and DLF lesions. If DLF pathways do compensate for PT lesions, then animals with PT lesions would rely more on DLF pathways than animals without PT lesions. Thus we hypothesized that animals with DLF lesions which were performed 6 weeks after PT lesions would exhibit more deficits on several behavioural tasks compared to animals which received PT and DLF lesions simultaneously. Our hypothesis was supported only for skilled pellet retrieval. Hence some DLF pathways, including the RST, were able to compensate for loss of CST input during skilled reaching but not during overground or skilled locomotion in PT-lesioned rats. These differential responses suggest that behavioural tasks vary in their reliance on specific pathways after injury, and, furthermore, that compensation for loss of specific connections can arise from numerous sources.

Local injection of BDNF producing mesenchymal stem cells increases neuronal survival and synaptic stability following ventral root avulsion

The present study proposed to graft mesenchymal stem cells (MSCs), which continuously produce BDNF, into the spinal cord ventral horn, after ventral root avulsion. Neurotrophin expression was naturally achieved by culturing MSCs in an undifferentiated state for at least 10 weeks. Lewis rats were subjected to unilateral avulsion of lumbar ventral roots, receiving 3 × 10 5 cells injected through the lateral funiculus. Two weeks after surgery, the animals were sacrificed and neuronal survival, astroglial reaction and synaptic inputs within the motor nucleus analyzed. The results indicated that the MSCs treatment significantly rescued avulsed motoneurons. Such neuronal survival was related to in vivo mRNA up regulation as well as expression of BDNF and GDNF. Such increase was correlated to the preservation of synaptophysin- positive nerve terminals. Thus it was proposed that when maintained undifferentiated for a period of 10 weeks, MSCs may be used as a continuous source of BDNF, positively influencing neuronal survival and synaptic plasticity.

A Molecular Program for Contralateral Trajectory: Rig-1 Control by LIM Homeodomain Transcription Factors

Despite increasing evidence for transcriptional control of neural connectivity, how transcription factors regulate discrete steps in axon guidance remains obscure. Projection neurons in the dorsal spinal cord relay sensory signals to higher brain centers. Some projection neurons send their axons ipsilaterally, whereas others, commissural neurons, send axons contralaterally. We show that two closely related LIM homeodomain proteins, Lhx2 and Lhx9, are expressed by a set of commissural relay neurons (dI1c neurons) and are required for the dI1c axon projection. Midline crossing by dI1c axons is lost in Lhx2/9 double mutants, a defect that results from loss of expression of Rig-1 from dI1c axons. Lhx2 binds to a conserved motif in the Rig-1 gene, suggesting that Lhx2/9 regulate directly the expression of Rig-1. Our findings reveal a link between the transcriptional programs that define neuronal subtype identity and the expression of receptors that guide distinctive aspects of their trajectory.

Secondary pathology following contusion, dislocation, and distraction spinal cord injuries

Preclinical studies for spinal cord injury (SCI) have utilized transection and contusion injury paradigms even though human SCIs occur by a spectrum of primary injury mechanisms such as spinal cord contusion from vertebral burst fracture, shearing from fracture-dislocation, and stretching from distraction injuries. We contrasted the neuropathology in animal models mimicking these clinically relevant injuries at an early 3-hour time-point in order to relate patterns of secondary pathology to the primary injury mechanism. Axolemma compromise, detected by the intracellular penetration of dextran-conjugated fluorophores, was localized to the contusion epicentre but extended rostrally following dislocation and distraction injuries. Dextran infused post-trauma revealed extensive axolemma resealing whereas only modest membrane recovery was detected in neuronal somata. Fracture-dislocations produced greater axonal degeneration than either contusion or distraction injuries as evidenced by reduced neurofilament immunostaining in ventral tracts, increased β-amyloid precursor protein accumulation in lateral funiculi, and a longer lesion in the dorsal corticospinal tract. In the gray matter, cytochrome c release from neuronal mitochondria, indicative of early apoptosis, was detected within the penumbrae of the contusion and dislocation injuries only. Neurons positive for the oxidative stress marker 3-nitrotyrosine were most numerous rostral to the dislocation epicentre. Microglial activation was localized to the contusion epicentre, extended rostro-caudally following dislocation, but was similar to surgical controls after distraction injuries. Reactive astrocytes extended rostro-caudally only following dislocation injuries. Hence, the primary injury mechanism alters the pattern of secondary degeneration indicating that different neuroprotective strategies may ultimately be required for treating distinct clinically relevant SCIs.

Nogo-66 Receptor Antagonist Peptide (NEP1-40) Administration Promotes Functional Recovery and Axonal Growth After Lateral Funiculus Injury in the Adult Rat

Objective. The myelin protein Nogo inhibits axon regeneration by binding to its receptor (NgR) on axons. Intrathecal delivery of an NgR antagonist (NEP1-40) promotes growth of injured corticospinal axons and recovery of motor function following a dorsal hemisection. The authors used a similar design to examine recovery and repair after a lesion that interrupts the rubrospinal tract (RST). Methods. Rats received a lateral funiculotomy at C4 and NEP1-40 or vehicle was delivered to the cervical spinal cord for 4 weeks. Outcome measures included motor and sensory tests and immunohistochemistry. Results. Gait analysis showed recovery in the NEP1-40-treated group compared to operated controls, and a test of forelimb usage also showed a beneficial effect. The density of labeled RST axons increased ipsilaterally in the NEP1-40 group in the lateral funiculus rostral to the lesion and contralaterally in both gray and white matter. Thus, rubrospinal axons exhibited diminished dieback and/or growth up to the lesion site. This was accompanied by greater density of 5HT and calcitonin gene-related peptide axons adjacent to and into the lesion/matrix site in the NEP1-40 group. Conclusions. NgR blockade after RST injury is associated with axonal growth and/or diminished dieback of severed RST axons up to but not into or beyond the lesion/matrix site, and growth of serotonergic and dorsal root axons adjacent to and into the lesion/matrix site. NgR blockade also supported partial recovery of function. The authors' results indicate that severed rubrospinal axons respond to NEP1-40 treatment but less robustly than corticospinal, raphe-spinal, or dorsal root axons.

Biomechanical study of cervical flexion myelopathy using a three-dimensional finite element method

The goal of this study was to perform a biomechanical study of cervical flexion myelopathy (CFM) using a finite element method. A 3D finite element model of the spinal cord was established consisting of gray matter, white matter, and pia mater. After the application of semi-static compression, the model underwent anterior flexion to simulate CFM. The flexion angles used were 5 degrees and 10 degrees , and stress distributions inside the spinal cord were then evaluated. Stresses on the spinal cord were very low under semi-static compression but increased after 5 degrees of flexion was applied. Stresses were concentrated in the gray matter, especially the anterior and posterior horns. The stresses became much higher after application of 10 degrees of flexion and were observed in the gray matter, posterior funiculus, and a portion of the lateral funiculus. The 5 degrees model was considered to represent the mild type of CFM. This type corresponds to the cases described in the original report by Hirayama and colleagues. The main symptom of this type of CFM is muscle atrophy and weakness caused by the lesion of the anterior horn. The 10 degrees model was considered to represent a severe type of CFM and was associated with lesions in the posterior fand lateral funiculi. This type of CFM corresponds to the more recently reported clinical cases with combined long tract signs and sensory disturbance.