Publisher Summary Regeneration appears to depend on an interaction between the injured axon's intrinsic capacity to regrow and the environment in which the regrowth must occur. This chapter describes and shows that regeneration occurs... more
Publisher Summary Regeneration appears to depend on an interaction between the injured axon's intrinsic capacity to regrow and the environment in which the regrowth must occur. This chapter describes and shows that regeneration occurs and that calcitonin gene-related peptide (CGRP)-containing axons are among those that regenerate. Exposed to the same type of graft, populations of neurons differ in their regenerative capacity, suggesting that some central neurons may be extremely limited in their ability to regrow or that the conditions necessary to elicit their growth are not provided by the usual grafts. The dorsal root ganglion (DRG) neurons are classified into subgroups based on criteria, such as size and immunocytochemical staining characteristics, and may differ in their capacity to regenerate, or in the vigor of their response to the conducive environment, or the stimulation provided by a transplant. The chapter shows using a marker specific for a population of small- and medium-sized DRG neurons that dorsal root cells immunoreactive for CGRP are among those, which regenerate into transplants.
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Publisher Summary This chapter highlights some basic facts pertaining to glial intermediate filaments with emphasis on the chemistry and metabolism of their major constituent protein, glial fibrillary acidic protein (GFAP). Gliosis is... more
Publisher Summary This chapter highlights some basic facts pertaining to glial intermediate filaments with emphasis on the chemistry and metabolism of their major constituent protein, glial fibrillary acidic protein (GFAP). Gliosis is usually characterized by extensive astroglial proliferation and hypertrophy. In addition, reactive astrocytes undergo numerous cytological and histochemical features, including increases in nuclear diameter, elevated DNA levels, an accumulation of intermediate filaments, heightened oxidoreductive enzyme activity, and increased synthesis of GFAP, vimentin, glutamine synthetase, and glycogen. In principle, fibrous gliosis can be considered as a part of an important healing response to a central nervous system (CNS) injury because astrocytes are thought to actively monitor and control the contents of the extracellular space of the CNS, including the amounts of ions, transmitters, trophic factors, nutrients, and waste materials. They also play a role in the removal of myelin and neuronal debris and encapsulate the regions of the CNS that are exposed to non-CNS tissue environments following trauma. The most prominent characteristic of fibrous gliosis is an extensive synthesis of intermediate filaments.
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The cytotoxic effects of N-ethyl-N-nitrosourea (ENU) and the potential for recovery from this damage in the developing rat spinal cord was investigated. Emphasis was placed on determining the severity and location of initial cell necrosis... more
The cytotoxic effects of N-ethyl-N-nitrosourea (ENU) and the potential for recovery from this damage in the developing rat spinal cord was investigated. Emphasis was placed on determining the severity and location of initial cell necrosis and the subsequent reorganizational changes in the damaged tissues. Pregnant rats were injected i.v. with a single dose of ENU (60 mg/kg) on one of days 12-16 of gestation. At 6, 12, 24 and 48 h post-injection one pregnant rat from each gestational stage was anesthetized, the embryos were removed, fixed and processed for embedding in paraplast or epon-araldite. Transverse sections from embryos killed at 6 h revealed extensive necrosis throughout the neuroepithelium in accordance with the temporal-spatial patterns of neurogenesis. At this dose level the post-mitotic neuroblasts appeared unaffected. Regeneration of the damaged neural tissue as defined by the restoration of the neuroepithelial cell layer and removal of necrotic debris proceeded quickl...
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To test whether known growth factors could promote the regenerative reponse of chronically injured neurons, we exposed the injured adult rat spinal cord to insulin-like growth factor 1 (IGF-1), basic fibroblast growth factor (bFGF) or... more
To test whether known growth factors could promote the regenerative reponse of chronically injured neurons, we exposed the injured adult rat spinal cord to insulin-like growth factor 1 (IGF-1), basic fibroblast growth factor (bFGF) or transforming growth factor beta 1 + 2 (TGFβs) 1 month after creation of a hemisection lesion. At 1 week later an autologous peripheral nerve graft was apposed to the rostral cavity wall and 1 month later Nuclear Yellow (NY) was used to retrogradely label neurons that had grown an axon into the graft. Neurons capable of axonal regeneration after a long term (5 weeks) injury were double labeled with True Blue (TB, provided at the time of hemisection lesion) and NY. Exposure to any of the three growth factors, compared to a PBS-treated control, resulted in a significant increase in the total number of regenerating supraspinal neurons, with the greatest increase after treatment with TGFβs. Treatment with TGFβs or bFGF led to a significant increase in the n...
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The relationship between astrocytes forming in the presence of dibutyryl cyclic AMP (dBcAMP) in culture and reactive astrocytes responding to a cerebral cortex stab wound was investigated using computerized image analysis (Zeiss IBAS 1)... more
The relationship between astrocytes forming in the presence of dibutyryl cyclic AMP (dBcAMP) in culture and reactive astrocytes responding to a cerebral cortex stab wound was investigated using computerized image analysis (Zeiss IBAS 1) and immunocytochemical staining. The diameters of the nuclei of astrocytes in primary cultures of newborn mouse neopallial cells were compared to those of the nuclei of normal and reactive astrocytes in histological sections of mouse cerebral cortex. We found that the nuclei of astrocytes that formed in the presence of dBcAMP in cultures are significantly larger than those of spontaneously occurring small stellate astrocytes in culture and of normal astrocytes of the cerebral cortex in vivo but corresponded more closely to the nuclei of reactive astrocytes in the area surrounding a stab wound in the cerebral cortex. Large stellate cells formed in the presence of dBcAMP had vimentin and an increase in GFP-containing intermediate filaments. Formation of reactive astrocytes in vivo is also associated with an increase in both vimentin and GFP-containing intermediate filaments. These observations indicate a closer relationship of astrocytes formed in the presence of dBcAMP in cultures to the reactive astrocytes in the cerebral cortex than to normal astrocytes. We propose, therefore, that the large stellate astrocytes that form in the presence of dBcAMP be referred to as reactive astrocytes in culture.
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The potential for fetal spinal cord (FSC) tissue transplants to modify an established glial scar or to restrict the reformation of a scar following surgical manipulation of a chronic lesion site was studied in the injured rat spinal cord.... more
The potential for fetal spinal cord (FSC) tissue transplants to modify an established glial scar or to restrict the reformation of a scar following surgical manipulation of a chronic lesion site was studied in the injured rat spinal cord. Six to eight weeks after preparation of a hemisection lesion cavity, glial scar tissue was left intact in one group, whereas in a second group it was excised prior to transplantation of a suspension of FSC tissue. From the first group, examination of serial sections through the graft‐host interface that had been immunoreacted for glial fibrillary acidic protein (GFAP) demonstrated that in many cases the glial scar no longer was a continuous wall separating the two tissues. Quantitation of the area occupied by these discrete gaps in the scar provided an Index of Fusion, indicating the extent of direct contact between the transplant and host spinal cord. In some animals this constituted as much as 60% of the interface, while in others there were no b...
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Cut dorsal root axons regenerate into transplants of embryonic spinal cord and form synapses that resemble those found in the dorsal horn of normal spinal cord. One aim of the present study was to determine whether these axons also... more
Cut dorsal root axons regenerate into transplants of embryonic spinal cord and form synapses that resemble those found in the dorsal horn of normal spinal cord. One aim of the present study was to determine whether these axons also regenerate into and establish synapses within transplants of embryonic brain. A second aim was to compare the patterns of growth in embryonic brain and spinal cord transplants.Embryonic spinal cord or brain was transplanted into the lumbar enlargement of adult Sprague‐Dawley rats, the L4 or L5 dorsal root was cut, and the cut root was juxtaposed to the transplant. The transplants included whole pieces or dissociated cell suspensions of embryonic day 14 (E14) spinal cord, or whole pieces of E14 neocortex, E18 occipital cortex, E15 cerebellum, or E18 hippocampus. One month later the regenerated dorsal root axons were labeled by immunocytochemical methods to demonstrate calcitonin gene‐related peptide (CGRP).CGRP‐immunoreactive axons regenerated into all the...
Research Interests: Electron Microscopy, Biology, Immunohistochemistry, Medicine, Immunocytochemistry, and 15 moreAnatomy, Hippocampus, Cerebellum, Cerebral Cortex, Female, Animals, Embryonic Stem Cell, Male, Medical Physiology, Clinical Sciences, Embryonic Development, Neocortex, Fetus, Comparative Neurology, and Axons
Axonal regeneration has been demonstrated by supraspinal neurons long after a spinal cord injury, although this potential seems limited to a few neurons in specific nuclear groups. Whether the regenerative response could be enhanced by... more
Axonal regeneration has been demonstrated by supraspinal neurons long after a spinal cord injury, although this potential seems limited to a few neurons in specific nuclear groups. Whether the regenerative response could be enhanced by exposure to neurotrophic factors was examined in this study. Neurons injured during a cervical spinal cord hemisection lesion were labeled with true blue (TB). Four weeks after spinal cord injury, gel foam saturated with brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), ciliary neurotrophic factor (CNTF), or saline as a control was placed into the lesion cavity. The gel foam was replaced with fresh factor after 3 days, and 4 days later a peripheral nerve (PN) graft was apposed to the rostral cavity wall. Four weeks later neurons that grew an axon into the PN graft were labeled with nuclear yellow (NY). Cells that were double labeled (TB and NY) represented chronically injured neurons capable of axon regeneration. Cells labeled with NY only were either acutely injured neurons capable of axonal regrowth or uninjured neurons that had sprouted into the PN graft. The total number of TB/NY-labeled neurons was significantly increased following exposure to BDNF, NT-3, or CNTF. Specific regions most influenced by NT-3 and BDNF were the reticular formation and red nucleus. Treatment with CNTF resulted in a significant increase in most brain regions with a major contribution to descending pathways in the spinal cord, the motor cortex being the exception, with no evidence of axonal regeneration by neurons forming the corticospinal tract. The total number of NY-only labeled neurons also was significantly greater after treatment with BDNF or CNTF. These results demonstrate the potential to increase the regenerative response of specific chronically injured supraspinal neurons by application of neurotrophic factors to the injury site.
Research Interests: Medicine, In Situ Hybridization, Axon, Chronic Disease, Female, and 15 moreAnimals, Motor Cortex, Neurons, Corticospinal Tract, Nerve Regeneration, Clinical Sciences, Lesion, GDNF, Experimental Neurology, Axons, Gene Expression Regulation, Ciliary Neurotrophic Factor, Cell Size, Cell count, and axon regeneration
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Neocortical tissue obtained from rat embryos was frozen and stored at - 70 degrees C for 6 h prior to transplantation into the cerebellum of neonatal rats. Growth, differentiation, and integration of this tissue within the host brain was... more
Neocortical tissue obtained from rat embryos was frozen and stored at - 70 degrees C for 6 h prior to transplantation into the cerebellum of neonatal rats. Growth, differentiation, and integration of this tissue within the host brain was comparable to that obtained from freshly dissected and transplanted tissue. It is suggested that freezing to low temperatures does not adversely effect the viability or transplantability of the neural tissue.
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Although initially argued to be a feature of immature neurons with incomplete polarization, there is clear evidence that neurons in the peripheral nervous system retain the capacity for intra-axonal protein synthesis well into adulthood.... more
Although initially argued to be a feature of immature neurons with incomplete polarization, there is clear evidence that neurons in the peripheral nervous system retain the capacity for intra-axonal protein synthesis well into adulthood. This localized protein synthesis has been shown to contribute to injury signaling and axon regeneration in peripheral nerves. Recent works point to potential for protein synthesis in axons of the vertebrate central nervous system. mRNAs and protein synthesis machinery have now been documented in lamprey, mouse, and rat spinal cord axons. Intra-axonal protein synthesis appears to be activated in adult vertebrate spinal cord axons when they are regeneration-competent. Rat spinal cord axons regenerating into a peripheral nerve graft contain mRNAs and markers of activated translational machinery. Indeed, levels of some growth-associated mRNAs in these spinal cord axons are comparable to the regenerating sciatic nerve. Markers of active translation tend ...
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The potential of two interventions, alone or in combination, to restore chronic spinal cord transection-induced changes in skeletal muscles of adult Sprague-Dawley rats was studied. Hind limb skeletal muscles were examined in the... more
The potential of two interventions, alone or in combination, to restore chronic spinal cord transection-induced changes in skeletal muscles of adult Sprague-Dawley rats was studied. Hind limb skeletal muscles were examined in the following groups of animals: rats with a complete spinal cord transection (Tx) for 8 weeks; Tx with a 4-week delay before initiation of a 4-week motor-assisted cycling exercise (Ex) program; Tx with a 4-week delay before transplantation (Tp) of fetal spinal cord tissue into the lesion cavity; Tx with a 4-week delay before Tp and Ex; and uninjured control animals. Muscle mass, muscle to body mass ratios, and mean myofiber cross-sectional areas were significantly reduced 8 weeks after transection. Whereas transplantation of fetal spinal cord tissue did not reverse this atrophy and exercise alone had only a modest effect in restoring lost muscle mass, the combination of exercise and transplantation significantly increased muscle mass, muscle to body mass ratio...
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Research Interests: Neuroscience, Psychology, Medicine, Female, Animals, and 15 moreNeurons, Fibroblast Growth Factor, Nerve Regeneration, Rats, Peripheral Nerve, Lesion, Neurotrophic Factors, Cell Survival, Neurosciences, Ciliary Neurotrophic Factor, Phosphate Buffer Saline, Brain stem, cross sectional area, Basic Fibroblast Growth Factor, and axon regeneration
Large animal and primate models of spinal cord injury (SCI) are being increasingly utilized for the testing of novel therapies. While these represent intermediary animal species between rodents and humans and offer the opportunity to pose... more
Large animal and primate models of spinal cord injury (SCI) are being increasingly utilized for the testing of novel therapies. While these represent intermediary animal species between rodents and humans and offer the opportunity to pose unique research questions prior to clinical trials, the role that such large animal and primate models should play in the translational pipeline is unclear. In this initiative we engaged members of the SCI research community in a questionnaire and round-table focus group discussion around the use of such models. Forty-one SCI researchers from academia, industry, and granting agencies were asked to complete a questionnaire about their opinion regarding the use of large animal and primate models in the context of testing novel therapeutics. The questions centered around how large animal and primate models of SCI would be best utilized in the spectrum of preclinical testing, and how much testing in rodent models was warranted before employing these mo...
Research Interests: Psychology, Neurology, Focus Groups, Developmental neuroscience, Translational Research, and 15 moreMedicine, Translation, Primates, Humans, Questionnaire, Animals, Clinical Sciences, Questionnaires, Cellular Therapies, Experimental Neurology, Preclinical Testing, Spinal Cord Injuries, Neurosciences, Translational Medical Research, and Drug Therapies
This study tested whether adult rat brain stem neurons could respond to growth or trophic factors provided after an extended post-injury period. The number of neurons that regenerated their axon into a peripheral nerve graft following... more
This study tested whether adult rat brain stem neurons could respond to growth or trophic factors provided after an extended post-injury period. The number of neurons that regenerated their axon into a peripheral nerve graft following exposure to ciliary neurotrophic factor (CNTF) 8 weeks after a cervical lesion was comparable to the number regenerating after exposure to CNTF 4 weeks after injury. In contrast, there was a significant decrease of 50% in the number of regenerating neurons following exposure to basic fibroblast growth factor (bFGF) 8 weeks after injury compared with the number regenerating after treatment with bFGF 4 weeks after injury. These results indicate that some factors are effective promoters of regeneration only if provided within a defined post-injury period.
Research Interests: Cognitive Science, Biology, Medicine, Peripheral Nerve Injury, Axon, and 15 moreFemale, Animals, Neurons, Fibroblast Growth Factor, Nerve Regeneration, Lesion, Nerve Growth Factor, Neurotrophic Factors, Axons, Neurosciences, Ciliary Neurotrophic Factor, Brain stem, Brain injuries, Basic Fibroblast Growth Factor, and axon regeneration
Studies were carried out to determine if an intraspinal transplant (Trpl) of fetal spinal cord tissue or hind limb exercise (Ex) affected the changes in myosin heavy chain (MyHC) composition or myofiber size that occur following a... more
Studies were carried out to determine if an intraspinal transplant (Trpl) of fetal spinal cord tissue or hind limb exercise (Ex) affected the changes in myosin heavy chain (MyHC) composition or myofiber size that occur following a complete transection (Tx) of the lower thoracic spinal cord of the adult rat. In one group of animals, transplants were made acutely, whereas in a second group, daily cycling exercise was initiated 5 days after injury, with animals in both groups being sacrificed 90 days after injury. The soleus muscle is normally composed of myofibers expressing either type I (90%) or type IIa (10%) MyHC. Following a spinal transection, expression of type I MyHC isoform decreased (18% of myofibers), type IIa MyHC expression increased (65% of myofibers), and the majority of myofibers (80%) expressed type IIx MyHC. Most myofibers coexpressed multiple MyHC isoforms. Compared with Tx only, with Ex or with Trpl, there was a decrease in the number of myofibers expressing type I or IIa isoforms but little change in expression of IIx MyHC. Myofibers expressing the IIb isoform appeared in several transplant recipients but not after exercise. Transection resulted in atrophy of type I myofibers to approximately 50% of normal size, whereas myofibers were significantly larger after exercise (74% of control) and in Trpl recipients (77% of control). Type IIa myofibers also were significantly larger in Trpl recipients compared with the Tx only group. Overall, the mean myofiber size was significantly greater after exercise and in Trpl recipients compared with myofibers in Tx only animals. Thus, although neither strategy shifted the MyHC profile towards the control, both interventions influenced the extent of atrophy observed after spinalization. These data suggest that palliative strategies can be developed to modulate some of the changes in hind limb muscles that occur following a spinal cord injury.
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Exogenous neurotrophic factors provided at a spinal cord injury site promote regeneration of chronically injured rubrospinal tract (RST) neurons into a peripheral nerve graft. The present study tested whether the response to neurotrophins... more
Exogenous neurotrophic factors provided at a spinal cord injury site promote regeneration of chronically injured rubrospinal tract (RST) neurons into a peripheral nerve graft. The present study tested whether the response to neurotrophins is associated with changes in the expression of two regeneration-associated genes, betaII-tubulin and growth-associated protein (GAP)-43. Adult female rats were subjected to a right full hemisection lesion via aspiration of the C3 spinal cord. A second aspiration lesion was made 4 weeks later and gel foam saturated in brain-derived neurotrophic factor (BDNF), glial cell-line derived neurotrophic factor (GDNF), or phosphate-buffered saline (PBS) was applied to the lesion site for 60 min. Using in situ hybridization, RST neurons were examined for changes in mRNA levels of betaII-tubulin and GAP-43 at 1, 3, and 7 days after treatment. Based on analysis of gene expression in single cells, there was no effect of BDNF treatment on either betaII-tubulin or GAP-43 mRNA expression at any time point. betaII-Tubulin mRNA levels were enhanced significantly at 1 and 3 days in animals treated with GDNF relative to levels in animals treated with PBS. Treatment with GDNF did not affect GAP-43 mRNA levels at 1 and 3 days, but at 7 days there was a significant increase in mRNA expression. Interestingly, 7 days after GDNF treatment, the mean cell size of chronically injured RST neurons was increased significantly. Although GDNF and BDNF both promote axonal regeneration by chronically injured neurons, only GDNF treatment is associated with upregulation of betaII-tubulin or GAP-43 mRNA. It is not clear from the present study how exogenous BDNF stimulates regrowth of injured axons.
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Embryonic neocortical and brainstem tissues were frozen, stored for variable periods, thawed and transplanted into the cerebellum of neonatal host rats. Various conditions related to freezing, media for freezing, DMSO as the... more
Embryonic neocortical and brainstem tissues were frozen, stored for variable periods, thawed and transplanted into the cerebellum of neonatal host rats. Various conditions related to freezing, media for freezing, DMSO as the cryoprotectant, and thawing were analyzed. The findings indicated that the following conditions yielded best results for neocortical transplantation: freezing at a rate of 1 degrees C/min, using rat amniotic fluid as the medium for freezing, using 10% DMSO as the cryoprotectant, storing the frozen tissues at -90 degrees C, thawing the tissues fast just prior to transplantation, and transplanting them in the host brain with little or no delay. Other conditions having adverse effects on the neural tissues were considered. Issues pertaining to transplantability and retainability of the neural tissues inside the host brain, and effects of freezing and thawing on the long-term viability of the neural tissues and their growth are discussed.
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Research Interests: Neuroscience, Cognitive Science, Biology, Medicine, Cell Culture, and 15 moreIn Vitro, Mice, Female, Animals, Embryonic Stem Cell, Neurons, In Vitro Studies, Culture Media, Hippophae, Cell Survival, Neurosciences, Hippocampal formation, Neuroscience Methods, Electric stimulation, and Cell culture techniques
Rubrospinal motoneurons (RSMN) represent a population of androgen receptor‐containing central motoneurons in rodents. In this study, the ability of testosterone propionate (TP), alone or in conjunction with a peripheral nerve graft (PNG),... more
Rubrospinal motoneurons (RSMN) represent a population of androgen receptor‐containing central motoneurons in rodents. In this study, the ability of testosterone propionate (TP), alone or in conjunction with a peripheral nerve graft (PNG), to alter the molecular program of injured RSMN was accomplished using βII‐tubulin cDNA probes and quantitative in situ hybridization (ISH). Initial fluoro‐gold labeling experiments following a T1 hemisection established that, as in the rat, the hamster rubrospinal system is essentially crossed and that injured RSMN concentrate in the ventrolateral region of the red nucleus. In the second experimental series, adult gonadectomized male hamsters were subjected to a right T1 hemisection, with half of the operated animals immediately subcutaneously implanted with 1 10 mm TP Silastic capsule and the other half sham implanted. In a third experimental series, animals were subjected to T1 hemisection, followed by transplantation of a predegenerated autologo...
Research Interests: Biology, Medicine, Gene expression, In Situ Hybridization, Cell and Tissue Transplantation, and 15 moreAnimals, Male, Medical Physiology, Hamster, Peripheral nerves, Peripheral Nerve, Protein isoforms, Comparative Neurology, Neurosciences, Axotomy, Peroneal nerve, Motor Neurons, Red nucleus, Cricetinae, and mRNA expression
Regeneration by chronically injured supraspinal neurons is enhanced by treatment of a spinal cord lesion site with a variety of neurotrophic and growth factors. The removal of scar tissue, with subsequent reinjury of the spinal cord, is... more
Regeneration by chronically injured supraspinal neurons is enhanced by treatment of a spinal cord lesion site with a variety of neurotrophic and growth factors. The removal of scar tissue, with subsequent reinjury of the spinal cord, is necessary for injured axons to access tissue transplants placed into the lesion to support axon regrowth. The present study examined chronically injured and reinjured rubrospinal tract (RST) neurons to determine if changes in gene expression could explain the failure of these neurons to regenerate without exogenous trophic factor support. Adult female rats were subjected to a right full hemisection lesion via aspiration of the cervical level 3 spinal cord. Using radioactive cDNA probes and in situ hybridization, RST neurons in the contralateral red nucleus were examined for changes in mRNA levels of βII-tubulin and GAP 43 in an acute injury period (6 h–3 days), a chronic injury period (28 days after spinal cord injury (SCI)) and following a second lesion of the chronic injury site (6 h–7 days). Based upon the analysis of gene expression in single cells, GAP-43 mRNA levels were increased as early as 1 day following the initial SCI, but were no different than uninjured control levels at 28 days postoperative (dpo). The response to relesion was more rapid and higher than that detected after the initial injury with a significant increase in GAP 43 mRNA at 6 h that was maintained for at least 7 days. βII-tubulin mRNA levels remained unchanged until 3 days after an acute injury followed by a decrease in expression to 30% below uninjured control values at 28 dpo. The expression of βII-tubulin mRNA was significantly higher within 6 h after a second injury, where it remained stable for 5 days before a second increase occurred at 7 days after reinjury of the spinal cord. Thus, neurons in a chronic injury state retain the ability to respond to a traumatic injury and, in fact, neurons subjected to a second injury exhibit a significantly heightened expression of regeneration-associated genes.
Research Interests: Psychology, Regeneration, Spinal Cord Injury, Medicine, Gene expression, and 15 moreIn Situ Hybridization, Axon, Spinal Cord, Corticospinal Tract, Single Cell, Clinical Sciences, mRna expression levels, Lesion, Experimental Neurology, Trophic Factors, Growth Factor, Neurosciences, Axotomy, Red nucleus, and mRNA expression
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Research Interests: Biology, Medicine, Gene expression, Chronic Disease, Female, and 15 moreAnimals, Fibroblast Growth Factor, Nerve Regeneration, Clinical Sciences, Lesion, Experimental Neurology, Growth Factor, Cell Survival, Axons, Neurosciences, Ciliary Neurotrophic Factor, Axotomy, Phosphate Buffer Saline, Basic Fibroblast Growth Factor, and axon regeneration
Research Interests: Psychology, Chronic Pain, Medicine, Axon, Humans, and 15 moreChronic Disease, Animals, Central Nervous System, Life Expectancy, Neurons, Nerve Regeneration, Clinical Sciences, Disease Progression, Experimental Neurology, Environment, Neurosciences, Long Distance, Acute Disease, axon growth, and axon regeneration
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Mesenchymal stem cells (MSC) derived from bone marrow are ideal transplants for a variety of CNS disorders and appear to support recovery after injury by secreting therapeutic factors. There is considerable variability in the secretion... more
Mesenchymal stem cells (MSC) derived from bone marrow are ideal transplants for a variety of CNS disorders and appear to support recovery after injury by secreting therapeutic factors. There is considerable variability in the secretion profile of MSC derived from different donors and it is known that MSC secretion changes in response to inflammatory stimuli, but no comprehensive analysis has been performed to address these issues. Here we show that MSC from seven donors secrete chemokines and cytokines in variable ranges, with some factors showing high variability. Treatment of cultured MSC with pro-inflammatory cytokines or tissue extracts from injured spinal cord resulted in up-regulation of selected cytokines, whereas treatment with an anti-inflammatory cytokine had little effect, indicating that the secretion profile is tightly regulated by environmental challenges. Patterns of up-regulated cytokines were similar in MSC from different donors suggesting a comparable response to inflammatory stimuli.
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Previously injured dorsal roots were electrically stimulated to determine if regenerating sensory axons can form physiologically active synaptic contacts with neurons within fetal spinal cord tissue transplants. Dorsal rootlets, sectioned... more
Previously injured dorsal roots were electrically stimulated to determine if regenerating sensory axons can form physiologically active synaptic contacts with neurons within fetal spinal cord tissue transplants. Dorsal rootlets, sectioned at their spinal cord entry zone, were apposed to intraspinal transplants of fetal spinal cord tissue grafted along each side of a nerve growth factor treated nitrocellulose implant. Two to six months later, the rootlets were transected between the spinal cord and their respective ganglia and electrically stimulated. Evoked potentials were recorded from the dorsal surface of the transplant, but were absent from adjacent ipsilateral and contralateral spinal cord regions. A glass micropipette was advanced through the transplant and used to record intramedullary field potentials evoked by dorsal root stimulation. Maximal negative potentials occurred 400-700 micron below the dorsal surface of the transplant, shifting to positive potentials deeper into the transplant. Additionally, both spontaneous and electrically evoked single neuronal action potentials were observed along the microelectrode track. Evoked potentials were abolished following transaction of the rootlets between the stimulation site and the transplant. Immunocytochemical evidence of the production of fos protein following electrical stimulation of the regenerated dorsal rootlets was demonstrated within transplant neurons and some ventrally located host neurons, providing an anatomical correlate to the electrophysiological recordings of synaptic activation. These results provide evidence of the structural and functional integration of regenerated sensory axons with both transplant and host neurons.
Research Interests: Neuroscience, Psychology, Biology, Medicine, Protein Structure and Function, and 14 moreAnatomy, Evoked Potentials, Animals, Spinal Cord, Nerve Regeneration, Clinical Sciences, Rats, Stimulation, Experimental Neurology, Action potential, Nerve Growth Factor, Axons, Neurosciences, and Electric stimulation
Adult central nervous system (CNS) neurons do not regenerate severed axons unaided but may regenerate axons into apposed predegenerated peripheral nerve grafts (PNGs). We examined gene expression by using microarray technology in... more
Adult central nervous system (CNS) neurons do not regenerate severed axons unaided but may regenerate axons into apposed predegenerated peripheral nerve grafts (PNGs). We examined gene expression by using microarray technology in laser-dissected lateral vestibular (LV) neurons whose axons were severed by a lateral hemisection at C3 (HX) and in lateral vestibular nucleus (LVN) neurons that were hemisected at C3 and that received immunosuppression with cyclosporine A (CsA) and a predegenerated PNG (termed I-PNG) into the lesion site. The results provide an expression analysis of temporal changes that occur in LVN neurons in nonregenerative and potentially regenerative states and over a period of 42 days. Axotomy alone resulted in a prolonged change in regulation of probe sets, with more being upregulated than downregulated. Apposition of a PNG with immunosuppression muted gene expression overall. Axotomized neurons (HX) upregulated genes commonly associated with axonal growth, whereas axotomized neurons whose axons were apposed to the PNG showed diminished expression of many of these genes but greater expression of genes related to energy production. The results suggest that axotomized LVN neurons express many genes thought to be associated with regeneration to a greater extent than LVN neurons that are apposed to a PNG. Thus the LVN neurons remain in a regenerative state following axotomy but the conditions provided by the I-PNG appear to be neuroprotective, preserving or enhancing mitochondrial activity, which may provide required energy for regeneration. We speculate that the graft also enables sufficient axonal synthesis of cytoskeletal components to allow axonal growth without marked increase in expression of genes normally associated with regeneration.
Research Interests: Neuroscience, Biology, Medicine, Gene expression, Neuroprotection, and 15 moreFemale, Animals, Central Nervous System, Medical Physiology, Neurons, Gene Regulatory Networks, Nerve Regeneration, Rats, Microarray Analysis, Peripheral nerves, Immune Tolerance, Comparative Neurology, Neurosciences, Gene Expression Regulation, and Axotomy
In this study, possible mechanisms underlying soleus muscle atrophy after spinal cord transection and attenuation of atrophy with cycling exercise were studied. Adult female Sprague-Dawley rats were divided into three groups; in two... more
In this study, possible mechanisms underlying soleus muscle atrophy after spinal cord transection and attenuation of atrophy with cycling exercise were studied. Adult female Sprague-Dawley rats were divided into three groups; in two groups the spinal cord was transected by a lesion at T10. One group was transected and killed 10 days later, and another group was transected and exercised for 5 days starting 5 days after transection. The third group served as an uninjured control. All animals received a continuous-release 5′-bromo-2′-deoxyuridine pellet 10 days before they were killed. Transection alone and transection with exercise lead to activation of satellite cells, but only the exercise group showed a trend toward an increase in the number of proliferating satellite cells. In all cases the number of activated satellite cells was significantly higher than the number that divided. Although the number of cells undergoing proliferation increased with exercise, no increase in fusion o...
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Intra-axonal localization of mRNAs and protein synthesis machinery (PSM) endows neurons with the capacity to generate proteins locally, allowing precise spatiotemporal regulation of the axonal response to extracellular stimuli. A number... more
Intra-axonal localization of mRNAs and protein synthesis machinery (PSM) endows neurons with the capacity to generate proteins locally, allowing precise spatiotemporal regulation of the axonal response to extracellular stimuli. A number of studies suggest that this local translation is a promising target to enhance the regenerative capacity of damaged axons. Using a model of central nervous system (CNS) axons regenerating into intraspinal peripheral nerve grafts (PNGs) we established that adult regenerating CNS axons contain several different mRNAs and protein synthetic machinery (PSM) components in vivo. After lower thoracic level spinal cord transection, ascending sensory axons regenerate into intraspinal PNGs but axon growth is stalled when they reach the distal end of the PNG (3 versus 7 weeks after grafting, resp.). By immunofluorescence with optical sectioning of axons by confocal microscopy, the total and phosphorylated forms of PSMs are significantly lower in stalled compare...
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Cells genetically modified to release a variety of growth and/or neurotrophic factors have been used for transplantation into the injured spinal cord as a means to deliver therapeutic products. Axon growth into and through such... more
Cells genetically modified to release a variety of growth and/or neurotrophic factors have been used for transplantation into the injured spinal cord as a means to deliver therapeutic products. Axon growth into and through such transplants has been demonstrated after intervention after an acute injury. The present study examined their potential to support regeneration in a chronic injury condition. Five weeks after a cervical hemisection in adult rats, the lesion site was debrided of scar tissue and expanded in both rostral and caudal directions. Animals received a transplant of cultured normal fibroblasts (control) or fibroblasts genetically modified to produce brain-derived neurotrophic factor (BDNF). Six weeks later, animals were killed to determine the extent of growth of serotonergic axons into the transplant. Axons immunoreactive for serotonin (5-HT-ir) were found to cross the rostral interface of host spinal cord readily with either type of fibroblast cell transplant, but the...
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Dopamine (DA) neurons in the mammalian central nervous system are thought to be restricted to the brain. DA-mediated regulation of urinary activity is considered to occur through an interaction between midbrain DA neurons and the pontine... more
Dopamine (DA) neurons in the mammalian central nervous system are thought to be restricted to the brain. DA-mediated regulation of urinary activity is considered to occur through an interaction between midbrain DA neurons and the pontine micturition center. Here we show that DA is produced in the rat spinal cord and modulates the bladder reflex. We observed numerous tyrosine hydroxylase (TH)(+) neurons in the autonomic nuclei and superficial dorsal horn in L6-S3 spinal segments. These neurons are dopamine-β-hydroxylase (DBH)(-) and some contain detectable dopamine decarboxylase (DDC), suggesting their capacity to produce DA. Interestingly, following a complete thoracic spinal cord injury (SCI) to interrupt supraspinal projections, more TH(+) neurons emerged in the lumbosacral spinal cord, coincident with a sustained, low level of DA expression there and a partially recovered micturition reflex. Non-selective blockade of spinal DA receptors reduced bladder activity whereas activation...