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High-intensity swimming alleviates nociception and neuroinflammation in a mouse model of chronic postischemia pain by activating the resolvin E1-chemerin receptor 23 axis in the Spinal cord

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Neural Regeneration Research 2023年第11期18卷 2535-2544页

作者： Xin Jia Ziyang Li Xiafeng Shen Yu Zhang Li Zhang Ling Zhang Department of Neurology and Neurological Rehabilitation Shanghai Yangzhi Rehabilitation Hospital(Shanghai Sunshine Rehabilitation Center)School of MedicineTongji UniversityShanghaiChina Department of Rehabilitation Shanghai Pudong HospitalFudan University Pudong Medical CenterShanghaiChina Key Laboratory of Cellular Physiology(Shanxi Medical University) Ministry of Educationand the Department of PhysiologyShanxi Medical UniversityTaiyuanShanxi ProvinceChina Key Laboratory of Central CNS Regeneration(Ministry of Education) Guangdong-Hong Kong-Macao Institute of CNS RegenerationJinan UniversityGuangzhouGuangdong ProvinceChina

Physical exe rcise effectively alleviates chronic pain associated with complex regional pain syndrome type-Ⅰ.However,the mechanism of exe rcise-induced analgesia has not been clarified.Recent studies have shown that the specialized pro-resolving lipid mediator resolvin E1 promotes relief of pathologic pain by binding to chemerin receptor 23 in the nervous system.However,whether the resolvin E1-chemerin receptor 23 axis is involved in exercise-induced analgesia in complex regional pain syndrome type-Ⅰ has not been demonstrated.In the present study,a mouse model of chronic post-ischemia pain was established to mimic complex regional pain syndrome type-Ⅰ and subjected to an intervention involving swimming at different intensities.Chronic pain was reduced only in mice that engaged in high-intensity swimming.The resolvin E1-chemerin receptor 23 axis was clearly downregulated in the Spinal cord of mice with chronic pain,while high-intensity swimming restored expression of resolvin E1 and chemerin receptor 23.Finally,shRNA-mediated silencing of chemerin receptor 23in the Spinal cord reve rsed the analgesic effect of high-intensity swimming exercise on chronic post-ischemic pain and the anti-inflammato ry pola rization of microglia in the dorsal horn of the Spinal cord.These findings suggest that high-intensity swimming can decrease chronic pain via the endogenous resolvin E1-chemerin receptor 23 axis in the Spinal cord.

关键词： central sensitization chemerin receptor 23 chronic post-ischemia pain complex regional pain syndrome exercise-induced analgesia microglia neuroinflammation resolvin E1 Spinal cord swimming

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Gradient descent decomposition of force-field motor primitives optogenetically elicited for motor mapping of the murine lumbosacral Spinal cord

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Zoological Research 2023年第3期44卷 604-619页

作者： Paola Salmas Vincent C.K Cheung School of Biomedical Sciences and Gerald Choa Neuroscience InstituteThe Chinese University of Hong KongHong Kong SARChina Kunming Institute of Zoology-The Chinese University of Hong Kong(KIZ-CUHK)Joint Laboratory of Bioresources and Molecular Research of Common Diseases Hong Kong SARChina

Generating diverse motor behaviors critical for survival is a challenge that confronts the central nervous system(CNS)of all animals.During movement execution,the CNS performs complex calculations to control a large number of neuromusculoskeletal elements.The theory of modular motor control proposes that spinal interneurons are organized in discrete modules that can be linearly combined to generate a variety of behavioral patterns.These modules have been previously represented as stimulus-evoked force fields(FFs)comprising isometric limb-endpoint forces across workspace locations.Here,we ask whether FFs elicited by different stimulations indeed represent the most elementary units of motor control or are themselves the combination of a limited number of even more fundamental motor modules.To probe for potentially more elementary modules,we optogenetically stimulated the lumbosacral Spinal cord of intact and spinalized Thy1-ChR2 transgenic mice(n=21),eliciting FFs from as many single stimulation loci as possible(20-70 loci per mouse)at minimally necessary power.We found that the resulting varieties of FFs defied simple categorization with just a few clusters.We used gradient descent to further decompose the FFs into their underlying basic force fields(BFFs),whose linear combination explained FF variability.Across mice,we identified 4-5 BFFs with partially localizable but overlapping representations along the Spinal cord.The BFFs were structured and topographically distributed in such a way that a rostral-to-caudal traveling wave of activity across the lumbosacral Spinal cord may generate a swing-to-stance gait cycle.These BFFs may represent more rudimentary submodules that can be flexibly merged to produce a library of motor modules for building different motor behaviors.

关键词： Motor mapping Optogenetics Spinal cord Motor primitives Traveling wave

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Heat shock factor 1 promotes neurite outgrowth and suppresses inflammation in the severed Spinal cord of geckos

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Neural Regeneration Research 2023年第9期18卷 2011-2018页

作者： Bing-Qiang He Ai-Cheng Li Yu-Xuan Hou Hui Li Xing-Yuan Zhang Hui-Fei Hao Hong-Hua Song Ri-Xin Cai Ying-Jie Wang Yue Zhou Yong-Jun Wang Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Co-innovation Center of NeuroregenerationMedical School of Nantong UniversityNantongJiangsu ProvinceChina Department of Rehabilitation Medicine Affiliated Hospital of Nantong UniversityNantongJiangsu ProvinceChina

The low intrinsic growth capacity of neurons and an injury-induced inhibitory milieu are major contributo rs to the failure of sensory and motor functional recovery following Spinal cord injury.Heat shock transcription factor 1(HSF1),a master regulator of the heat shock response,plays neurogenetic and neuroprotective roles in the damaged or diseased central nervous system.However,the underlying mechanism has not been fully elucidated.In the present study,we used a gecko model of spontaneous nerve regeneration to investigate the potential roles of gecko HSF1(gHSF1) in the regulation of neurite outgrowth and inflammatory inhibition of macrophages following Spinal cord injury.gHSF1 expression in neurons and microglia at the lesion site increased dramatically immediately after tail amputation.gHSF1 ove rexpression in gecko primary neuro ns significantly promoted axonal growth by suppressing the expression of suppressor of cytokine signaling-3,and fa cilitated neuro nal survival via activation of the mitogen-activated extracellular signal-regulated kinase/extracellular regulated protein kinases and phosphatidylinositol 3-kinase/protein kinase B pathways.Furthermore,gHSF1 efficiently inhibited the macrophagemediated inflammatory response by inactivating 1kappa B-alpha/NF-kappaB signaling.Our findings show that HSF1 plays dual roles in promoting axonal regrowth and inhibiting leukocyte inflammation,and provide new avenues of investigation for promoting spinal co rd injury repair in mammals.

关键词： apoptosis gecko heat shock factor 1 inflammation neuron regeneration Spinal cord suppressor of cytokine signaling-3

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Serum response factor promotes axon regeneration following Spinal cord transection injury

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Neural Regeneration Research 2023年第9期18卷 1956-1960页

作者： Guo-Ying Feng Nai-Li Zhang Xiao-Wei Liu Ling-Xi Tong Chun-Lei Zhang Shuai Zhou Lu-Ping Zhang Fei Huang Institute of Neurobiology Binzhou Medical UniversityLaishanShandong ProvinceChina School of Health and Life Sciences University of Health and Rehabilitation SciencesQingdaoShandong ProvinceChina

Studies have snown that serum response factor is beneficaial for axonar regeneration of peripheral herves.However,Its role after central nervous system injury remains unclear. In this study,we established a rat model of T9-T10 Spinal cord transection injury.We found that the expression of serum response factor in injured Spinal cord gray matter neurons gradually increased with time,reached its peak on the 7^(th) day,and then gradually decreased.To investigate the role of serum response factor,we used lentivirus vecto rs to ove rexpress and silence serum response factor in Spinal cord tissue.We found that overexpression of serum response factor promoted motor function recovery in rats with Spinal cord injury.Qualitative observation of biotinylated dextran amine anterograde tra cing showed that ove rexpression of serum response factor increased nerve fibers in the injured spinal co rd.Additionally,transmission electron microscopy showed that axon and myelin sheath morphology was restored.Silencing serum response factor had the opposite effects of ove rexpression.These findings suggest that serum response factor plays a role in the recovery of motor function after Spinal cord injury.The underlying mechanism may be related to the regulation of axonal regeneration.

关键词： axon growth associated protein 43 motor function myelin sheath neuron regeneration serum response factor Spinal cord Spinal cord transection

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Evolution of the ErbB gene family and analysis of regulators of Egfr expression during development of the rat Spinal cord

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Neural Regeneration Research 2022年第11期17卷 2484-2490页

作者： Yu Zhang Tao Zhang Lian Xu Ye Zhu Li-Li Zhao Xiao-Di Li Wei-Wei Yang Jing Chen Miao Gu Xiao-Song Gu Jian Yang School of Medicine&Holistic Integrative Medicine Nanjing University of Chinese MedicineNanjingJiangsu ProvinceChina Key Laboratory of Neuroregeneration of Jiangsu Province and Ministry of Education Co-innovation Center of NeuroregenerationNMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology ProductsNantong UniversityNantongJiangsu ProvinceChina

Egfr,a member of the ErbB gene family,plays a critical role in tissue development and homeostasis,wound healing,and disease.However,expression and regulators of Egfr during Spinal cord development remain poorly understood.In this study,we investigated ErbB evolution and analyzed co-expression modules,miRNAs,and transcription factors that may regulate Egfr expression in rats.We found that ErbB family members formed via Egfr duplication in the ancient ve rtebrates but dive rged after speciation of gnathostomes.We identified a module that was co-expressed with Egfr,which involved cell proliferation and blood vessel development.We predicted 25 miRNAs and nine transcription factors that may regulate Egfr expression.Dual-luciferase reporter assays showed six out of nine transcription factors significantly affected Egfr promoter reporter activity.Two of these transcription factors(KLF1 and STAT3)inhibited the Egfr promoter repo rter,whereas four transcription factors(including FOXA2)activated the Egfr promoter reporter.Real-time PCR and immunofluorescence expe riments showed high expression of FOXA2 during the embryonic period and FOXA2 was expressed in the floor plate of the Spinal cord,suggesting the importance of FOXA2 during embryonic Spinal cord development.Considering the importance of Egfr in embryonic Spinal cord development,wound healing,and disease(specifically in cancer),regulatory elements identified in this study may provide candidate targets for nerve regeneration and disease treatment in the future.

关键词： co-expression Egfr evolution FOXA2 gene expression miRNA Spinal cord transcription factor

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Effects of targeted muscle reinnervation on Spinal cord motor neurons in rats following tibial nerve transection

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Neural Regeneration Research 2022年第8期17卷 1827-1832页

作者： Wei Lu Jian-Ping Li Zhen-Dong Jiang Lin Yang Xue-Zheng Liu Department of Human Anatomy School of Basic Medical ScinencesGuangxi Medical UniversityNanningGuangxi Zhuang Autonomous RegionChina Department of Human Anatomy Zhuhai Campus of Zunyi Medical UniversityZhuhaiGuangdong ProvinceChina

Targeted muscle reinnervation(TMR)is a surgical procedure used to transfer residual peripheral nerves from amputated limbs to targeted muscles,which allows the target muscles to become sources of motor control information for function reconstruction.However,the effect of TMR on injured motor neurons is still unclear.In this study,we aimed to explore the effect of hind limb TMR surgery on injured motor neurons in the Spinal cord of rats after tibial nerve transection.We found that the reduction in hind limb motor function and atrophy in mice caused by tibial nerve transection improved after TMR.TMR enhanced nerve regeneration by increasing the number of axons and myelin sheath thickness in the tibial nerve,increasing the number of anterior horn motor neurons,and increasing the number of choline acetyltransferase-positive cells and immunofluorescence intensity of synaptophysin in rat Spinal cord.Our findings suggest that TMR may enable the reconnection of residual nerve fibers to target muscles,thus restoring hind limb motor function on the injured side.

关键词： function reconstruction motor neuron nerve injury nerve implant Nissl staining Spinal cord synaptophysin targeted muscle reinnervation tibial nerve transection

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Growth associated protein 43 and neurofilament immunolabeling in the transected lumbar Spinal cord of lizard indicates limited axonal regeneration

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Neural Regeneration Research 2022年第5期17卷 1034-1041页

作者： Lorenzo Alibardi Comparative Histolab Padova and Department of Biology University of BolognaBolognaItaly

Previous cytological studies on the transected lumbar Spinal cord of lizards have shown the presence of differentiating glial cells,few neurons and axons in the bridge region between the proximal and distal stumps of the Spinal cord in some cases.A limited number of axons(20-50)can cross the bridge and re-connect the caudal stump of the Spinal cord with small neurons located in the rostral stump of the Spinal cord.This axonal regeneration appears to be related to the recovery of hind-limb movements after initial paralysis.The present study extends previous studies and shows that after transection of the lumbar Spinal cord in lizards,a glial-connective tissue bridge that reconnects the rostral and caudal stumps of the interrupted Spinal cord is formed at 11-34 days post-injury.Following an initial paralysis some recovery of hindlimb movements occurs within 1-3 months post-injury.Immunohistochemical and ultrastructural analysis for a growth associated protein 43(GAP-43)of 48-50 k Da shows that sparse GAP-43 positive axons are present in the proximal stump of the Spinal cord but their number decreased in the bridge at 11-34 days post-transection.Few immunolabeled axons with a neurofilament protein of 200-220 k Da were seen in the bridge at 11-22 days post-transection but their number increased at 34 days and 3 months post-amputation in lizards that have recovered some hindlimb movements.Numerous neurons in the rostral and caudal stumps of the Spinal cord were also labeled for GAP43,a cytoplasmic protein that is trans-located into their axonal growth cones.This indicates that GAP-43 biosynthesis is related to axonal regeneration and sprouting from neurons that were damaged by the transection.Taken together,previous studies that utilized tract-tracing technique to label the present observations confirm that a limited axonal re-connection of the transected Spinal cord occurs 1-3 months post-injury in lizards.The few regenerating-sprouting axons within the bridge reconnect the caudal with the rostral stumps of the spina

关键词： GAP-43 immunocytochemistry lizard neurofilaments regeneration Spinal cord

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The functional properties of synapses made by regenerated axons across Spinal cord lesion sites in lamprey

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Neural Regeneration Research 2022年第10期17卷 2272-2277页

作者： David Parker Department of Physiology Developmentand NeuroscienceUniversity of CambridgeCambridgeUK

While the anatomical properties of regenerated axons across Spinal cord lesion sites have been studied extensively,little is known of how the functional properties of regenerated synapses compared to those in unlesioned animals.This study aims to compare the properties of synapses made by regenerated axons with unlesioned axons using the lamprey,a model system for spinal injury research,in which functional locomotor recovery after Spinal cord lesions is associated with axonal regeneration across the lesion site.Regenerated synapses below the lesion site did not differ from synapses from unlesioned axons with respect to the amplitude and duration of single excitatory postsynaptic potentials.They also showed the same activity-dependent depression over spike trains.However,regenerated synapses did differ from unlesioned synapses as the estimated number of synaptic vesicles was greater and there was evidence for increased postsynaptic quantal amplitude.For axons above the lesion site,the amplitude and duration of single synaptic inputs also did not differ significantly from unlesioned animals.However,in this case,there was evidence of a reduction in release probability and inputs facilitated rather than depressed over spike trains.Synaptic inputs from single regenerated axons below the lesion site thus do not increase in amplitude to compensate for the reduced number of descending axons after functional recovery.However,the postsynaptic input was maintained at the unlesioned level using different synaptic properties.Conversely,the facilitation from the same initial amplitude above the lesion site made the synaptic input over spike trains functionally stronger.This may help to increase propriospinal activity across the lesion site to compensate for the lesion-induced reduction in supraspinal inputs.The animal experiments were approved by the Animal Ethics Committee of Cambridge University.

关键词： electrophysiology lamprey plasticity regeneration reticulospinal axon Spinal cord spinal injury synapse

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Peripheral nerve regeneration through nerve conduits evokes differential expression of growth-associated protein-43 in the Spinal cord

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Neural Regeneration Research 2023年第8期18卷 1852-1856页

作者： Jesús Chato-Astrain Olga Roda David Sánchez-Porras Esther Miralles Miguel Alaminos Fernando Campos Óscar Darío García-García Víctor Carriel Department of Histology(Tissue Engineering Group) University of GranadaInstituto de Investigación Biosanitaria ibs.GRANADAGranadaSpain Department of Human Anatomy and Embryology University of GranadaGranadaSpain Unit of Clinical Neurophysiology University Hospital San CecilioGranadaSpain

Growth-associated protein 43 plays a key role in neurite outgrowth through cytoskeleton remodeling.We have previously demonstrated that structural damage of peripheral nerves induces growth-associated protein 43 upregulation to promote growth cone formation.Conversely,the limited regenerative capacity of the central nervous system due to an inhibitory environment prevents major changes in neurite outgrowth and should be presumably associated with low levels of growth-associated protein 43 expression.However,central alterations due to peripheral nerve damage have never been assessed using the growthassociated protein 43 marker.In this study,we used the tubulization technique to repair 1 cm-long nerve gaps in the rat nerve injury/repair model and detected growth-associated protein 43 expression in the peripheral and central nervous systems.First,histological analysis of the regeneration process confirmed an active regeneration process of the nerve gaps through the conduit from 10 days onwards.The growth-associated protein 43 expression profile varied across regions and follow-up times,from a localized expression to an abundant and consistent expression throughout the regeneration tissue,confirming the presence of an active nerve regeneration process.Second,Spinal cord changes were also histologically assessed,and no apparent changes in the structural and cellular organization were observed using routine staining methods.Surprisingly,remarkable differences and local changes appeared in growth-associated protein 43 expression at the Spinal cord level,in particular at 20 days post-repair and beyond.Growth-associated protein 43 protein was first localized in the gracile fasciculus and was homogeneously distributed in the left posterior cord.These findings differed from the growth-associated protein 43 pattern observed in the healthy control,which did not express growth-associated protein 43 at these levels.Our results revealed a differential expression in growth-associated protein 43 protein not only in the regeneratin

关键词： growth-associated protein 43(GAP-43) immunohistochemistry nerve guide nerve tissue regeneration peripheral nerve repair Spinal cord tissue engineering

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Simultaneous 3D Visualization of the Microvascular and Neural Network in Mouse Spinal cord Using Synchrotron Radiation Micro-Computed Tomography

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Neuroscience Bulletin 2021年第10期37卷 1469-1480页

作者： Liyuan Jiang Chengjun Li Miao Li Xianzhen Yin Handing Wu Chunyue Duan Yong Cao Hongbin Lu Jianzhong Hu Department of Spine Surgery Xiangya HospitalCentral South UniversityChangsha 410008China National Clinical Research Center for Geriatric Disorders Xiangya HospitalCentral South UniversityChangsha 410008China Key Laboratory of Organ Injury Aging and Regenerative Medicine of Hunan ProvinceChangsha 410008China Department of Sports Medicine Xiangya HospitalCentral South UniversityChangsha 410008China Xiangya Hospital-International Chinese Musculoskeletal Research Society Sports Medicine Research Centre Changsha 410008China Hunan Engineering Research Center of Sport and Health Changsha 410008China Center for Drug Delivery Systems Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China

Effective methods for visualizing neurovascular morphology are essential for understanding the normal Spinal cord and the morphological alterations associated with diseases.However,ideal techniques for simultaneously imaging neurovascular structure in a broad region of a specimen are still lacking.In this study,we combined Golgi staining with angiography and synchrotron radiation micro-computed tomography(SRμCT)to visualize the 3D neurovascular network in the mouse Spinal cord.Using our method,the 3D neurons,nerve fibers,and vasculature in a broad region could be visualized in the same image at cellular resolution without destructive sectioning.Besides,we found that the 3D morphology of neurons,nerve fiber tracts,and vasculature visualized by SRjiCT were highly consistent with that visualized using the histological method.Moreover,the 3D neurovascular structure could be quantitatively evaluated by the combined methodology.The method shown here will be useful in fundamental neuroscience studies.

关键词： Srμct 3D High-resolution Neurovascular Spinal cord

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