A debilitating consequence of complete spinal cord injury (SCI) is the loss of motor control. Although the goal of most SCI treatments is to re-establish neural connections, a potential complication in restoring motor function is that SCI may result in anatomical and functional changes in brain areas controlling motor output. Some animal investigations show cell death in the primary motor cortex following SCI, but similar anatomical changes in humans are not yet established. The aim of this investigation was to use voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) to determine if SCI in humans results in anatomical changes within motor cortices and descending motor pathways. Using VBM, we found significantly lower gray matter volume in complete SCI subjects compared with controls in the primary motor cortex, the medial prefrontal, and adjacent anterior cingulate cortices. DTI analysis revealed structural abnormalities in the same areas with reduced gray matter volume and in the superior cerebellar cortex. In addition, tractography revealed structural abnormalities in the corticospinal and corticopontine tracts of the SCI subjects. In conclusion, human subjects with complete SCI show structural changes in cortical motor regions and descending motor tracts, and these brain anatomical changes may limit motor recovery following SCI.

Traumatic spinal cord injuries (SCIs) lead to axonal damage at the trauma site, as well as disconnections within the central nervous system. While the exact mechanisms of the long-term pathophysiological consequences of SCIs are not fully understood, it is known that neuronal damage and degeneration are not limited to the direct proximity of the trauma. Instead, the effects can be detected even in the cerebrum. We examined SCI-induced chronic brain changes with a case-control design using 32 patients and 70 control subjects. Whole-brain white matter (WM) tracts were assessed with diffusion tensor imaging (DTI). In addition, we analysed associations between DTI metrics and several clinical SCI variables. Whole-brain analyses were executed by tract-based spatial statistics (TBSS), with an additional complementary atlas-based analysis (ABA). We observed widespread, statistically significant (P ≤ 0.01) changes similar to neural degeneration in SCI patients, both in the corticospinal tract (CST) and beyond. In addition, associations between DTI metrics and time since injury were found with TBSS and ABA, implying possible long-term post-injury neural regeneration. Using the ABA approach, we observed a correlation between SCI severity and DTI metrics, indicating a decrease in WM integrity along with patient sensory or motor scores. Our results suggest a widespread neurodegenerative effect of SCI within the cerebrum that is not limited to the motor pathways. Furthermore, DTI-measured WM integrity of chronic SCI patients seemed to improve as time elapsed since injury. Hum Brain Mapp 38:3637-3647, 2017. © 2017 Wiley Periodicals, Inc.© 2017 Wiley Periodicals, Inc.

Plasticity constitutes the basis of behavioral changes as a result of experience. It refers to neural network shaping and re-shaping at the global level and to synaptic contacts remodeling at the local level, either during learning or memory encoding, or as a result of acute or chronic pathological conditions. 'Plastic' brain reorganization after central nervous system lesions has a pivotal role in the recovery and rehabilitation of sensory and motor dysfunction, but can also be "maladaptive". Moreover, it is clear that brain reorganization is not a "static" phenomenon but rather a very dynamic process. Spinal cord injury immediately initiates a change in brain state and starts cortical reorganization. In the long term, the impact of injury - with or without accompanying therapy - on the brain is a complex balance between supraspinal reorganization and spinal recovery. The degree of cortical reorganization after spinal cord injury is highly variable, and can range from no reorganization (i.e. "silencing") to massive cortical remapping. This variability critically depends on the species, the age of the animal when the injury occurs, the time after the injury has occurred, and the behavioral activity and possible therapy regimes after the injury. We will briefly discuss these dependencies, trying to highlight their translational value. Overall, it is not only necessary to better understand how the brain can reorganize after injury with or without therapy, it is also necessary to clarify when and why brain reorganization can be either "good" or "bad" in terms of its clinical consequences. This information is critical in order to develop and optimize cost-effective therapies to maximize functional recovery while minimizing maladaptive states after spinal cord injury. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Background. Although the consequences of spinal cord injury (SCI) within the spinal cord and peripheral nervous system have been studied extensively, the influence of SCI on supraspinal structures during recovery remains largely unexplored. Objective. To assess temporal changes in cortical sensorimotor representations beginning in the subacute phase following SCI and determine if an association exists between the plastic changes within cortical sensorimotor areas and recovery of movement postinjury. Methods. Functional magnetic resonance imaging (fMRI) was used to study 6 SCI patients for 1 year, beginning shortly postinjury, and 10 healthy control individuals. During fMRI, individuals performed a simple self-paced wrist extension motor task. Recovery of movement was assessed using the American Spinal Injury Association (ASIA) Standard Neurological Classification of SCI. Results. In the subacute period post-SCI, during impaired movement, little task-related activation within the primary motor cortex (M1) was present, whereas activation in associated cortical sensorimotor areas was more extensive than in controls. During motor recovery, a progressive enlargement in the volume of movement-related M1 activation and decreased activation in associated cortical sensorimotor areas was seen. When movement was performed with little to no impairment, the overall pattern of cortical activation was similar to that observed in control individuals. Conclusions. This study provides the first report of the temporal progression of cortical sensorimotor representational plasticity during recovery following traumatic SCI in humans and suggests an association between movement-related fMRI activation and motor recovery postinjury. These findings have implications on current and future rehabilitative interventions for patients with SCI.

Central nervous system injury often causes lifelong impairment of neural function, because the regenerative ability of axons is limited, making a sharp contrast to the successful regeneration that is seen in the peripheral nervous system. Nevertheless, partial functional recovery is observed, because axonal branches of damaged or undamaged neurons sprout and form novel relaying circuits. Using a lot of animal models such as the spinal cord injury model or the optic nerve injury model, previous studies have identified many factors that promote or inhibit axonal regeneration or sprouting. Molecules in the myelin such as myelin-associated glycoprotein, Nogo-A or oligodendrocyte-myelin glycoprotein, or molecules found in the glial scar such as chondroitin sulfate proteoglycans, activate Ras homolog A (RhoA) signaling, which leads to the collapse of the growth cone and inhibit axonal regeneration. By contrast, axonal regeneration programs can be activated by many molecules such as regeneration-associated transcription factors, cyclic AMP, neurotrophic factors, growth factors, mechanistic target of rapamycin or immune-related molecules. Axonal sprouting and axonal regeneration largely share these mechanisms. For functional recovery, appropriate pruning or suppressing of aberrant sprouting are also important. In contrast to adults, neonates show much higher sprouting ability. Specific cell types, various mouse strains and different species show higher regenerative ability. Studies focusing on these models also identified a lot of molecules that affect the regenerative ability. A deeper understanding of the mechanisms of neural circuit repair will lead to the development of better therapeutic approaches for central nervous system injury.© The Japanese Society for Immunology. 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Plasticity changes of uninjured nerves can result in a novel neural circuit after spinal cord injury, which can restore sensory and motor functions to different degrees. Although processes of neural plasticity have been studied, the mechanism and treatment to effectively improve neural plasticity changes remain controversial. The present study reviewed studies regarding plasticity of the central nervous system and methods for promoting plasticity to improve repair of injured central nerves. The results showed that synaptic reorganization, axonal sprouting, and neurogenesis are critical factors for neural circuit reconstruction. Directed functional exercise, neurotrophic factor and transplantation of nerve-derived and non-nerve-derived tissues and cells can effectively ameliorate functional disturbances caused by spinal cord injury and improve quality of life for patients.

This study examined sustained co-delivery of vascular endothelial growth factor (VEGF), angiopoietin-1 and basic fibroblast growth factor (bFGF) encapsulated in angiogenic microspheres. These spheres were delivered to sites of spinal cord contusion injury in rats, and their ability to induce vessel formation, neural regeneration and improve hindlimb motor function was assessed. At 2-8 weeks after spinal cord injury, ELISA-determined levels of VEGF, angiopoietin-1, and bFGF were significantly higher in spinal cord tissues in rats that received angiogenic microspheres than in those that received empty microspheres. Sites of injury in animals that received angiogenic microspheres also contained greater numbers of isolectin B4-binding vessels and cells positive for nestin or beta III-tubulin (P < 0.01), significantly more NF-positive and serotonergic fibers, and more MBP-positive mature oligodendrocytes. Animals receiving angiogenic microspheres also suffered significantly less loss of white matter volume. At 10 weeks after injury, open field tests showed that animals that received angiogenic microspheres scored significantly higher on the Basso-Beattie-Bresnahan scale than control animals (P < 0.01). Our results suggest that biodegradable, biocompatible PLGA microspheres can release angiogenic factors in a sustained fashion into sites of spinal cord injury and markedly stimulate angiogenesis and neurogenesis, accelerating recovery of neurologic function.

Blood vessels form extensive networks that nurture all tissues in the body. Abnormal vessel growth and function are hallmarks of cancer and ischemic and inflammatory diseases, and they contribute to disease progression. Therapeutic approaches to block vascular supply have reached the clinic, but limited efficacy and resistance pose unresolved challenges. Recent insights establish how endothelial cells communicate with each other and with their environment to form a branched vascular network. The emerging principles of vascular growth provide exciting new perspectives, the translation of which might overcome the current limitations of pro- and antiangiogenic medicine.Copyright © 2011 Elsevier Inc. All rights reserved.

Since hepatocyte growth factor (HGF) plays a pivotal role in the development of the central nervous system and pathological conditions, we examined the long-term changes in the mRNA and protein expression of HGF and its receptor c-Met after spinal cord injury (SCI) in rats. HGF mRNA was significantly increased from 7 days after SCI in the injured segment, and the peak was at 7 days after SCI as assessed by real-time RT-PCR. Importantly, c-met mRNA expression was up-regulated from 1 day after SCI, and reached a peak at 14 days after SCI. Although up-regulation of HGF and c-met mRNA expression in the injured segment gradually decreased, the increased expression level persisted until 56 days after SCI. Consistent with HGF mRNA expression, HGF protein level was significantly increased mainly in the injured region, which persisted until 56 days after SCI. Immunohistochemistry showed that most of GFAP-positive reactive astrocytes expressed HGF and c-Met both on 14 days and 56 days after SCI. Staining with the mitotic indicator, bromodeoxyuridine (BrdU), revealed that a small number of BrdU-incorporated cells were co-localized with HGF/GFAP-positive or c-Met/GFAP-positive cells both on 14 and 56 days. These data suggest that HGF and c-Met were up-regulated mainly in the reactive astrocytes around the injured region in the subacute to chronic stage of spinal cord injury. Since HGF plays a critical role in neurotrophic activity, activation of the HGF/c-Met signaling system might be involved in the process of post-traumatic regeneration.

Many therapeutic interventions using neurotrophic factors or pharmacological agents have focused on secondary degeneration after spinal cord injury (SCI) to reduce damaged areas and promote axonal regeneration and functional recovery. Hepatocyte growth factor (HGF), which was identified as a potent mitogen for mature hepatocytes and a mediator of inflammatory responses to tissue injury, has recently been highlighted as a potent neurotrophic and angiogenic factor in the central nervous system (CNS). In the present study, we revealed that the extent of endogenous HGF up-regulation was less than that of c-Met, an HGF receptor, during the acute phase of SCI and administered exogenous HGF into injured spinal cord using a replication-incompetent herpes simplex virous-1 (HSV-1) vector to determine whether HGF exerts beneficial effects and promotes functional recovery after SCI. This treatment resulted in the significant promotion of neuron and oligodendrocyte survival, angiogenesis, axonal regrowth, and functional recovery after SCI. These results suggest that HGF gene delivery to the injured spinal cord exerts multiple beneficial effects and enhances endogenous repair after SCI. This is the first study to demonstrate the efficacy of HGF for SCI.Copyright 2007 Wiley-Liss, Inc.

This study assessed whether ultra-small particles of iron oxide (USPIO) intravascular contrast agent could enhance visualization of tumor microvascularity in F98 glioma bearing rats by means of ultra high field (UHF) high-resolution gradient echo (GRE) magnetic resonance imaging (MRI). In an effort to explain differences in visualization of microvascularity before and after USPIO administration, hypoxia and vessel diameters were assessed on corresponding histopathologic sections.F98 glioma cells were implanted stereotactically into the brains of syngeneic Fischer rats. Based on clinical criteria, rats were imaged 1 to 2 days before their death with and without USPIO contrast on an 8 Tesla MRI. To identify hypoxic regions of the brain tumor by immunohistochemical staining, a subset of animals also received a nitroimidazole-based hypoxia marker, EF5, before euthanasia. These sections then were compared with noncontrast enhanced MR images. The relative caliber of tumor microvasculature, compared with that of normal brain, was analyzed in a third group of animals.After USPIO administration, UHF high-resolution GRE MRI consistently predicted increased microvascular density relative to normal gray matter when correlated with histopathology. The in-plane visibility of glioma microvascularity in 22 rats increased by an average of 115% and signal intensity within the tumor decreased by 13% relative to normal brain. Tumor microvascularity identified on noncontrast MR images matched hypoxic regions identified by immunohistochemical staining with a sensitivity of 83% and specificity of 89%. UHF GRE MRI was able to resolve microvessels less than 20 micro in diameter, although differences in tumor vessel size did not consistently account for differences in visualization of microvascularity.USPIO administration significantly enhanced visualization of tumor microvascularity on gradient echo 8 T MRI and significantly improved visualization of tumor microvascularity. Microvascularity identified on precontrast images is suspected to be partly associated with hypoxia.

The aim of this study was to test the feasibility of vessel size imaging with precise evaluation of apparent diffusion coefficient and cerebral blood volume and to apply this novel technique in acute stroke patients within a pilot group to observe the microvascular responses in acute ischemic tissue. Microvessel density-related quantity Q and mean vessel size index ( VSI) were assessed in 9 healthy volunteers and 13 acute stroke patients with vessel occlusion within 6hours after symptom onset. Our results in healthy volunteers matched with general anatomical observations. Given the limitation of a small patient cohort, the median VSI in the ischemic area was higher than that in the mirrored region in the contralateral hemisphere ( P &lt; 0.05). Decreased Q was observed in the ischemic region in 2 patients, whereas no obvious changes of Q were found in the remaining 11 patients. In a patient without recanalization, the VSI hyperintensity in the subcortical area matched well with the final infarct. These data reveal that different observations of microvascular response in the acute ischemic tissue seem to emerge and vessel size imaging may provide useful information for the definition of ischemic penumbra and have an impact on future therapeutic approaches.

Aterations indensity and morphology of the cerebral microvasculature have been reported to occur in Alzheimer's disease patients and animal models of the disease. In this study we compared magnetic resonance imaging (MRI) techniques for the irutility to detectage-dependent changes of the cerebralvasculature in the arc Ab mouse model of cerebralamyloidosis. Dynamic susceptibility contrast (DSC)-MRI was performed by tracking the passage of a super paramagnetic iron oxide nanoparticle in the brain with dynamic gradientechoplanarimaging(EPI). From this measurements relative cerebral blood volume rCBV(DSC) and relative cerebral blood flow (rCBF) were estimated. For the same animal maps of the relaxation shift index Q were computed from high resolution gradientecho and spine chodata that were acquired before and after superparamagnetic iron oxide(SPIO )nanoparticle injection. Q-values were used to derive estimates of microves seldensity. The change in the relaxation rates Delta R*(2) obtained from pre- and Delta*(2) post-contrast gradientecho data was used for the alternative determination of rCBV rCBV(Delta R*(2)). L near mixed effects modeling found no significant association between rCBV(DSC),rCBV(Delta R*(2)),rCBF,and Q with genotype in 1-montholdmicecompared to age-matchednon-transgenic litter mates(NTLs) for any of the evaluated brain regions. In 24-month old mice there was a significant association for rCBV(DSC) with genotype in the cerebralcortex, and for rCBV(Delta R*(2)) in the cerebralcortex and cerebellum. For rCBF there was a significant association in the cerebellum but not in other brain regions. Q-values in the olfactory bulb, cerebral cortex, striatum, hippocampus, and cerebellumin 24-month old mice were significantly associated with genotype. In those regions Q-values were reduced between 11 and 26% in arc Ab mice comparedtoage-matched NTLs. Vessel staining with CD31 immunohistochemistry confirmed are duction of microvessel density in the old arc Ab mice. We further demonstrated a region-specific association between parenchymaland vascularde position of beta-amyloidand decreased vasculardensity, without a correlation with the amount of Abde position.We found that Q mapping was more suitable than the he modynamicread-outs to detectamyloid-related de generation of the cerebral microvasculature.

The aim of this study was to compare magnetic resonance imaging (MRI) and histological estimates of the mean vessel diameter (mVD), the vessel density (Density), and the vessel size index (VSI) obtained in the same tumor-bearing animals. Twenty-seven rats bearing intracranial glioma (C6 or RG2) were imaged by MRI. Changes in transverse relaxations (ΔR 2* and R(2)) were induced by the injection of an iron-based contrast agent and were mapped using a multi gradient-echo spin-echo sequence. Then, brain vascular network was studied ex vivo by histology. Three regions of interest were drawn in apparently normal tissue (neocortex and striatum) and in the tumor. In vivo mVD(MRI), Density(MRI), and VSI(MRI) were measured; ex vivo, mVD(histo), Density(histo), and VSI(histo) were quantified on the same animals. MRI and histology measurements differed by -15 to 26%. A positive correlation was found between MRI and histology for mVD, Density, and VSI counterparts (R(2) = 0.62, 0.50, 0.73, respectively; P < 0.001 in all cases). This study indicates that MRI and histology yields well correlated the estimates of mVD, Density, and VSI. VSI is the closest MRI estimate to histology. As Density and mVD or VSI provide complementary information, it is worth computing them to characterize angiogenesis beyond blood volume fraction.Copyright © 2012 Wiley Periodicals, Inc.

Glial fibrillary acidic protein (GFAP) is the hallmark intermediate filament (IF; also known as nanofilament) protein in astrocytes, a main type of glial cells in the central nervous system (CNS). Astrocytes have a range of control and homeostatic functions in health and disease. Astrocytes assume a reactive phenotype in acute CNS trauma, ischemia, and in neurodegenerative diseases. This coincides with an upregulation and rearrangement of the IFs, which form a highly complex system composed of GFAP (10 isoforms), vimentin, synemin, and nestin. We begin to unravel the function of the IF system of astrocytes and in this review we discuss its role as an important crisis-command center coordinating cell responses in situations connected to cellular stress, which is a central component of many neurological diseases. Copyright © 2015 Elsevier Ltd. All rights reserved.

Functional MRI (fMRI) on spinal cord-injured rodents at 4 and 8 weeks post injury (PI) is described. The paradigm for fMRI, based on electrical stimulation of rat paws, was automated using an in-house designed microprocessor-based controller that was interfaced to a stimulator. The MR images were spatially normalized to the Paxinos and Watson atlas using publicly available digital images of the cryosections. In normal uninjured animals, the activation was confined to the contralateral somatosensory cortex. In contrast, in injured animals, extensive activation, which included structures such as ipsilateral cortex, thalamus, hippocampus, and the caudate putamen, was observed at 4 and 8 weeks PI. Quantitative cluster analysis was carried out to calculate the volumes and centers of activation in individual brain structures. Based on this analysis, significant increase in activation between 4 and 8 weeks was observed only in the ipsilateral caudate putamen and thalamus. These studies suggest extensive and ongoing brain reorganization in spinal cord-injured animals.Copyright 2006 Wiley-Liss, Inc.

The purpose of this study was to determine whether DTI changes in the brain induced by a thoracic spinal cord injury are sensitive to varying severity of spinal contusion in rats.A control, mild, moderate, or severe contusion injury was administered over the eighth thoracic vertebral level in 32 Sprague-Dawley rats. At 11 weeks postinjury, ex vivo DTI of the brain was performed on a 9.4T Bruker scanner using a pulsed gradient spin-echo sequence.Mean water diffusion in the internal capsule regions of the brain and pyramid locations of the brainstem were correlated with motor function (r(2)  = 0.55). Additionally, there were significant differences between injury severity groups for mean diffusivity and fractional anisotropy at regions associated with the corticospinal tract (P = 0.05).These results indicate that DTI is sensitive to changes in brain tissue as a consequence of thoracic SCI.© 2015 Wiley Periodicals, Inc.

Astrocytes constitute approximately 30% of the cells in the mammalian central nervous system (CNS). They are integral to brain and spinal-cord physiology and perform many functions important for normal neuronal development, synapse formation, and proper propagation of action potentials. We still know very little, however, about how these functions change in response to immune attack, chronic neurodegenerative disease, or acute trauma. In this review, we summarize recent studies that demonstrate that different initiating CNS injuries can elicit at least two types of "reactive" astrocytes with strikingly different properties, one type being helpful and the other harmful. We will also discuss new methods for purifying and investigating reactive-astrocyte functions and provide an overview of new markers for delineating these different states of reactive astrocytes. The discovery that astrocytes have different types of reactive states has important implications for the development of new therapies for CNS injury and diseases.Copyright © 2017 Elsevier Inc. All rights reserved.

Reactive astrocytosis occurs prominently in response to all forms of CNS injury or disease. The functions of reactive astrocytes are not well understood, and both harmful and beneficial activities have been attributed to these cells. The basic process of reactive astrocytosis is conserved in vertebrate evolution, suggesting fitness-enhancing benefits, but scar-forming reactive astrocytes are often regarded as uniformly detrimental to clinical outcome, in particular, when implicated as inhibitors of axon regeneration. Transgenic mouse models are providing new means to study the activities of reactive astrocytes after CNS insults in vivo. Recent studies point toward roles for reactive astrocytes in restricting inflammation and protecting neurons and oligodendrocytes, thereby helping to limit tissue degeneration and preserve function after CNS injury.

After traumatic injuries of the central nervous system (CNS), including spinal cord injury (SCI), astrocytes surrounding the lesion become reactive and typically undergo hypertrophy and process extension. These reactive astrocytes migrate centripetally to the lesion epicenter and aid in the tissue repair process, however, they eventually become scar-forming astrocytes and form a glial scar which produces axonal growth inhibitors and prevents axonal regeneration. This sequential phenotypic change has long been considered to be unidirectional and irreversible; thus glial scarring is one of the main causes of the limited regenerative capability of the CNS. We recently demonstrated that the process of glial scar formation is regulated by environmental cues, such as fibrotic extracellular matrix material. In this review, we discuss the role and mechanism underlying glial scar formation after SCI as well as plasticity of astrogliosis, which helps to foster axonal regeneration and functional recovery after CNS injury.Copyright © 2017 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

Traumatic spinal cord injury produces long-term neurological damage, and presents a significant public health problem with nearly 18,000 new cases per year in the U.S. The injury results in both acute and chronic changes in the spinal cord, ultimately resulting in the production of a glial scar, consisting of multiple cells including fibroblasts, macrophages, microglia, and reactive astrocytes. Within the scar, there is an accumulation of extracellular matrix (ECM) molecules-primarily tenascins and chondroitin sulfate proteoglycans (CSPGs)-which are considered to be inhibitory to axonal regeneration. In this review article, we discuss the role of CSPGs in the injury response, especially how sulfated glycosaminoglycan (GAG) chains act to inhibit plasticity and regeneration. This includes how sulfation of GAG chains influences their biological activity and interactions with potential receptors. Comprehending the role of CSPGs in the inhibitory properties of the glial scar provides critical knowledge in the much-needed production of new therapies.Copyright © 2020 Hussein, Mencio, Katagiri, Brake and Geller.

Promotion of remyelination is an important therapeutic strategy to facilitate functional recovery after traumatic spinal cord injury (SCI). Transplantation of neural stem cells (NSCs) or oligodendrocyte precursor cells (OPCs) has been used to enhance remyelination after SCI. However, the microenvironment in the injured spinal cord is inhibitory for oligodendrocyte (OL) differentiation of NSCs or OPCs. Identifying the signaling pathways that inhibit OL differentiation in the injured spinal cord could lead to new therapeutic strategies to enhance remyelination and functional recovery after SCI. In the present study, we show that reactive astrocytes from the injured rat spinal cord or their conditioned media inhibit OL differentiation of adult OPCs with concurrent promotion of astrocyte differentiation. The expression of bone morphogenetic proteins (BMP) is dramatically increased in the reactive astrocytes and their conditioned media. Importantly, blocking BMP activity by BMP receptor antagonist, noggin, reverse the effects of active astrocytes on OPC differentiation by increasing the differentiation of OL from OPCs while decreasing the generation of astrocytes. These data indicate that the upregulated bone morphogenetic proteins in the reactive astrocytes are major factors to inhibit OL differentiation of OPCs and to promote its astrocyte differentiation. These data suggest that manipulation of BMP signaling in the endogenous or grafted NSCs or OPCs may be a useful therapeutic strategy to increase their OL differentiation and remyelination and enhance functional recovery after SCI.

Damage to the adult CNS often leads to persistent deficits due to the inability of mature axons to regenerate after injury. Mounting evidence suggests that the glial environment of the adult CNS, which includes inhibitory molecules in CNS myelin as well as proteoglycans associated with astroglial scarring, might present a major hurdle for successful axon regeneration. Here, we evaluate the molecular basis of these inhibitory influences and their contributions to the limitation of long-distance axon repair and other types of structural plasticity. Greater insight into glial inhibition is crucial for developing therapies to promote functional recovery after neural injury.

Recovery from spinal cord injury (SCI) remains an unsolved problem. As a major component of the SCI lesion, the glial scar is primarily composed of scar-forming astrocytes and plays a crucial role in spinal cord regeneration. In recent years, it has become increasingly accepted that the glial scar plays a dual role in SCI recovery. However, the underlying mechanisms of this dual role are complex and need further clarification. This dual role also makes it difficult to manipulate the glial scar for therapeutic purposes. Here, we briefly discuss glial scar formation and some representative components associated with scar-forming astrocytes. Then, we analyze the dual role of the glial scar in a dynamic perspective with special attention to scar-forming astrocytes to explore the underlying mechanisms of this dual role. Finally, taking the dual role of the glial scar into account, we provide several pieces of advice on novel therapeutic strategies targeting the glial scar and scar-forming astrocytes.Copyright © 2020 Yang, Dai, Chen and Cui.

In the injured central nervous system (CNS), reactive astrocytes form a glial scar and are considered to be detrimental for axonal regeneration, but their function remains elusive. Here we show that reactive astrocytes have a crucial role in wound healing and functional recovery by using mice with a selective deletion of the protein signal transducer and activator of transcription 3 (Stat3) or the protein suppressor of cytokine signaling 3 (Socs3) under the control of the Nes promoter-enhancer (Nes-Stat3(-/-), Nes-Socs3(-/-)). Reactive astrocytes in Nes-Stat3(-/-) mice showed limited migration and resulted in markedly widespread infiltration of inflammatory cells, neural disruption and demyelination with severe motor deficits after contusive spinal cord injury (SCI). On the contrary, we observed rapid migration of reactive astrocytes to seclude inflammatory cells, enhanced contraction of lesion area and notable improvement in functional recovery in Nes-Socs3(-/-) mice. These results suggest that Stat3 is a key regulator of reactive astrocytes in the healing process after SCI, providing a potential target for intervention in the treatment of CNS injury.

Astrocytes form borders (glia limitans) that separate neural from non-neural tissue along perivascular spaces, meninges and tissue lesions in the CNS. Transgenic loss-of-function studies reveal that astrocyte borders and scars serve as functional barriers that restrict the entry of inflammatory cells into CNS parenchyma in health and disease. Astrocytes also have powerful pro-inflammatory potential. Thus, astrocytes are emerging as pivotal regulators of CNS inflammatory responses. This Review discusses evidence that astrocytes have crucial roles in attracting and restricting CNS inflammation, with important implications for diverse CNS disorders.

Damage caused by administering glutamate into the spinal cord was characterized histologically. Glutamate destroyed neurons for several hundred micrometers around the administering microdialysis fiber. At 24 h after treatment, significant (P = 0.036) loss of neurons was observed (75%) relative to control (47%) near the fiber when glutamate was administered for 1 h at a concentration outside the fiber approximating the maximum glutamate released upon spinal cord injury. Significant loss of neurons (P = 0.006, 0.022) was also caused by administering a combination of glutamate at about its average concentration released upon injury over the 1 h period of administration in combination with the maximum aspartate concentration released upon injury. This work provides a direct demonstration that the concentrations of excitatory amino acids released upon spinal cord injury are neurotoxic. The destruction of neurons by exposure to excitatory amino acids when there is also substantial loss of neurons simply from the presence of the microdialysis fiber may reflect sensitization of neurons to excitotoxicity by stress.

Functional studies suggest that up to 95% of all glutamate transport is handled by the glutamate transporter EAAT2. Amino and C-terminal antibodies demonstrate that under normal conditions EAAT2 is specific to astrocytes. A truncated splice variant of EAAT2, known as EAAT2b, also has been identified in astrocytes and some neurons. In vitro studies suggest EAAT2b transports glutamate similar to EAAT2, although the contribution of EAAT2b to normal clearance of extracellular glutamate is unknown. To investigate EAAT2b biology in pathological conditions, we examined the cellular and regional distribution of EAAT2b in amyotrophic lateral sclerosis. Using epitope-specific, affinity purified antibodies, we found that EAAT2b tissue levels were increased by more than twofold in amyotrophic lateral sclerosis motor cortex, whereas EAAT2 levels were decreased by up to 95%. EAAT2b distribution in normal human cortex was largely confined to the neuropil-like EAAT2, with occasional faint neuronal expression. In contrast, amyotrophic lateral sclerosis motor cortex had an obvious qualitative increase in neuropil EAAT2b staining and a drastic increase in neuronal soma and dendritic EAAT2b immunostaining. Despite these increases in EAAT2b immunostaining, functional transporter studies demonstrated a large loss of EAAT2 function. These studies clearly document altered regulation and splicing of the dominant glutamate transporter EAAT2 under conditions of neurological stress.

Blood vessels identified by laminin staining were studied in uninjured spinal cord and at 2, 4, 7, and 14 days following a moderate contusion (weight drop) injury. At 2 days after injury most blood vessels had been destroyed in the lesion epicenter; neurons and astrocytes were also absent, and few ED1+ cells were seen infiltrating the lesion center. By 4 days, laminin associated with vessel staining was increased and ED1+ cells appeared to be more numerous in the lesion. By 7 days after injury, the new vessels formed a continuous cordon oriented longitudinally through the lesion center. ED1+ cells were abundant at this time point and were found in the same area as the newly formed vessels. Astrocyte migration from the margins of the lesion into the new cordon was apparent. By 14 days, a decrease in the number of vessels in the lesion center was observed; in contrast, astrocytes were more prominent in those areas. In addition to providing a blood supply to the lesion site, protecting the demise of the newly formed vascular bridge might provide an early scaffold to hasten axonal regeneration across the injury site.(c) 2002 Elsevier Science.

Spinal cord injury (SCI) results in neural tissue loss and so far untreatable functional impairment. In addition, at the initial injury site, inflammation induces secondary damage, and glial scar formation occurs to limit inflammation-mediated tissue damage. Consequently, it obstructs neural regeneration. Many studies have been conducted in the field of SCI; however, no satisfactory treatment has been established to date. Hepatocyte growth factor (HGF) is one of the neurotrophic growth factors and has been listed as a candidate medicine for SCI treatment. The highlighted effects of HGF on neural regeneration are associated with its anti-inflammatory and anti-fibrotic activities. Moreover, HGF exerts positive effects on transplanted stem cell differentiation into neurons. This paper reviews the mechanisms underlying the therapeutic effects of HGF in SCI recovery, and introduces recent advances in the clinical applications of HGF therapy.

The prevailing view of the astrocytic response to injury is that reactive astrocytes impede the regenerative process by forming scar tissue. As the levels of many cytokines dramatically increase following CNS insult and as this increase in cytokine expression precedes the production of the glial scar, a long-standing view has been that cytokines diminish neuronal survival and regeneration by stimulating the formation of astrogliotic scar tissue. However, there is a wealth of data indicating that cytokines "activate" astrocytes, and that cytokine-stimulated astrocytes can promote the recovery of CNS function. Supporting evidence demonstrates that cytokine-activated astrocytes produce energy substrates and trophic factors for neurons and oligodendrocytes, act as free radical and excess glutamate scavengers, actively restore the blood-brain barrier, promote neovascularization, restore CNS ionic homeostasis, promote remyelination and also stimulate neurogenesis from neural stem cells. Accordingly, a re-assessment of cytokine-activated astrocytes is necessary. Here, we review studies that promote the thesis that cytokines elicit potent neuroprotective and regenerative responses from astrocytes.

The blood-spinal cord barrier (BSCB) is the functional equivalent of the blood-brain barrier (BBB) in the sense of providing a specialized microenvironment for the cellular constituents of the spinal cord. Even if intuitively the BSCB could be considered as the morphological extension of the BBB into the spinal cord, evidence suggests that this is not so. The BSCB shares the same principal building blocks with the BBB; nevertheless, it seems that morphological and functional differences may exist between them. Dysfunction of the BSCB plays a fundamental role in the etiology or progression of several pathological conditions of the spinal cord, such as spinal cord injury, amyotrophic lateral sclerosis, and radiation-induced myelopathy. This review summarizes current knowledge of the morphology of the BSCB, the methodology of studying the BSCB, and the potential role of BSCB dysfunction in selected disorders of the spinal cord, and finally summarizes therapeutic approaches to the BSCB.Copyright © 2011 American Neurological Association.

Spinal cord injury produces prominent disruption of the blood-spinal cord barrier. We have defined the blood-spinal cord barrier breakdown to the protein luciferase (61 kDa) in the acutely injured murine spinal cord and during revascularization. We show that newly formed and regenerating blood vessels that have abnormal permeability exhibit differential expression of the glucose-1 transporter (Glut-1), and that its expression is dependent on astrocytes. There was overt extravasation of luciferase within the first hour after injury, a period that coincided with marked tissue disruption within the epicenter of the lesion. Although there was a significant reduction in the number of blood vessels relative to controls by 24 hr after injury, abnormal barrier permeability remained significantly elevated. A second peak of abnormal barrier permeability at 3-7 days postinjury coincided with prominent revascularization of the epicenter. The barrier to luciferase was restored by 21 days postinjury and vascularity was similar to that of controls. During wound-healing process, the cord was reorganized into distinct domains. Between 14 and 21 days postinjury, each domain consisted primarily of nonneuronal cells, including macrophages. Astrocytes were limited characteristically to the perimeter of each domain. Only blood vessels affiliated closely with astrocytes in the perimeter expressed Glut-1, whereas blood vessels within each domain of the repairing cord did not express it. Together, these data demonstrate that both injured and regenerating vessels exhibit abnormal permeability and suggest that Glut-1 expression during revascularization is dependent on the presence of astrocytes.Copyright 2003 Wiley-Liss, Inc.

Plasticity is a fundamental property of neuronal circuits, allowing them to adapt to alterations in activation. Generally speaking, plasticity has been viewed from a 'neuron-centric' perspective, with changes in circuit function attributed to alterations in neuronal excitability, synaptic strength or neuronal connectivity. However, it is now clear that glial cells, in particular astrocytes, are key regulators of neuronal plasticity. This article reviews recent progress made in understanding astrocyte function and attempts to summarize these functions into a coherent framework that positions astrocytes as central players in the plasticity process.Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.