Persistent postsurgical pain is a major clinical concern,especially in the aging population,who represent a growing proportion of surgical patients.Although age is a known pain risk factor,the mechanisms driving age-r...Persistent postsurgical pain is a major clinical concern,especially in the aging population,who represent a growing proportion of surgical patients.Although age is a known pain risk factor,the mechanisms driving age-related vulnerability to chronic postoperative pain remain poorly understood.This study aims to investigate how aging influences the resolution of postoperative pain and to elucidate the roles of microglial activation and synaptic remodeling in the spinal dorsal horn.A plantar incision model in young(3-month-old)and aged(18-month-old)male and female mice was used to mimic postoperative pain conditions.Mechanical and thermal hypersensitivity at various postoperative intervals were assessed by von Frey and Hargreaves tests.Microglial activation and inhibitory/excitatory synaptic densities in the spinal dorsal horn were evaluated using immunofluorescence and 3D reconstruction with Imaris software.On postoperative day(POD)3,both age groups exhibited reduced pain thresholds on the ipsilateral side,along with microglial activation in the dorsal horn.On POD 7,pain thresholds in young mice had returned to baseline with no significant microglial activation,while aged mice showed sustained reduction in pain thresholds,continuous microglial activation,and significant loss of inhibitory synapses without detectable changes in excitatory synapse density.These findings are consistent across both sexes,with no sex-related differences.Collectively,these results suggest that aging is associated with persistent postoperative pain,which correlates with microglial activation and inhibitory synapse loss.These insights advance our understanding of age-related pain vulnerability and may inform the development of more effective,targeted,and age-specific therapeutic strategies to prevent or alleviate persistent postoperative pain in elderly patients.展开更多
Pseudounipolar neurons in the dorsal root ganglia(DRG),as the central nodes of primary sensory afferents,possess a distinctive T-junction that is not merely a morphological peculiarity but also performs complex roles ...Pseudounipolar neurons in the dorsal root ganglia(DRG),as the central nodes of primary sensory afferents,possess a distinctive T-junction that is not merely a morphological peculiarity but also performs complex roles in rapid,multiplexed shunting and regulation of sensory signals.This specialized geometry enables separation,filtering,and feedback regulation of neuronal signals,thereby coordinating peripheral and central responses at multiple levels.Recent advances,including spatial transcriptomics,single-cell sequencing,super-resolution microscopy,organoid models,and novel electrophysiological methods,have permitted more precise dissection of the T-junction's molecular composition,ion-channel distribution,and electrophysiological properties.Here,we review current knowledge of the T-junction's developmental regulation and multilayered molecular networks,and we detail its functional alterations in both physiological signaling and pathological pain states,with particular emphasis on ion-channel modulation,signal attenuation,and selective transmission mechanisms.Finally,we discuss contemporary pain-intervention approaches and prospects for precision-targeted therapies,aiming to provide a theoretical foundation for future studies in pain physiology and clinical translation.展开更多
To perform various functions in the body,skeletal muscle is controlled and coordinated as a whole by nerves.However,there has been little research into whether the nerve control characteristics of different muscles ar...To perform various functions in the body,skeletal muscle is controlled and coordinated as a whole by nerves.However,there has been little research into whether the nerve control characteristics of different muscles are different,and the importance of these potential differences.In the present study,we used a three-dimensional imaging of solvent-cleared organ-compatible multi-tracer technique to explore the spatial distribution patterns of sensory and sympathetic neurons that innervate limb muscles.We integrated transcriptome sequencing datasets from mouse limb muscles in public databases and performed correlation analysis with neuronal spatial distribution data to reveal the unique effects of different types of neurons on muscle functional pathways.In terms of spatial distribution patterns,sympathetic neurons exhibited a more concentrated distribution than sensory and motor neurons.In addition,the neuronal innervation of limb muscles exhibited four different characteristics:sympathetic neuron-rich muscle,sensory neuron-rich muscle,neuron-sparse muscle,and motor neuron-rich muscle.Sensory neuron density was mainly associated with muscle contractile structure and cell pH,whereas sympathetic neuron density was associated with protein kinase activity,muscle vasculature,muscle calcium-dependent protein kinase activity,lipid transport,and vesicle release.Motor neuron density was mainly associated with protein kinase activity,cell adhesion,oxidoreductase activity,and exocytosis.These findings may contribute to a deeper understanding of how nerves cooperate to endow muscles with diverse physiological functions,thereby providing new insights and experimental evidence for the treatment of various neuromuscular diseases.展开更多
Few studies have investigated alterations in the immune cell microenvironment of the dorsal root ganglia following spinal cord injury and whether these modifications facilitate axonal regeneration.In this study,we use...Few studies have investigated alterations in the immune cell microenvironment of the dorsal root ganglia following spinal cord injury and whether these modifications facilitate axonal regeneration.In this study,we used a single-cell RNA sequencing dataset to create a comprehensive profile of the diverse cell types in the dorsal root ganglia and spinal cord of a mid-thoracic contusion injury model in cynomolgus monkeys.Cell communication analysis indicated that specific signaling events among various dorsal root ganglia cell types occur in response to spinal cord injury.Single-cell analysis using dimensionality reduction clustering identified distinct molecular signatures for nine cell types,including macrophage subpopulations,and differential gene expression profiles between dorsal root ganglia cells and spinal cord cells following spinal cord injury.The macrophage subpopulations were categorized into 11 clusters(MC0-MC10)based on differentially expressed genes,with the top 10 genes being ABCA6,RBMS3,EBF1,LAMA4,ANTXR2,LAMA2,SOX5,FOXP2,GHR,and APOD.MC0,MC1,and MC2 constituted the predominant macrophage populations.MC4,MC6,and MC9 were nearly absent in the spinal cord,but exhibited significant increases in the dorsal root ganglia post-spinal cord injury.Notably,these subpopulations possess a strong capacity for regulating axonal regeneration.The developmental progression of dorsal root ganglia macrophages after spinal cord injury was elucidated using cell trajectory and pseudo-time analyses.Genes such as EBF1(MC6 and MC9 marker),RBMS3(MC6 and MC9 marker),and ABCA6(MC6 marker)showed high expression levels in the critical pathways of macrophage function.Through ligand-receptor pair analysis,we determined that the effects of macrophages on microglia are predominantly mediated through interaction pairs(e.g.,SPP1-CD44,LAMC1-CD44,and FN1-CD44),potentially facilitating specific cellular communications within the immune microenvironment.The single-cell RNA sequencing dataset used in this study represents the first comprehensive transcriptional analysis of the dorsal root ganglia after spinal cord injury in cynomolgus monkeys,encompassing nearly all cell types within the dorsal root ganglia region.Using this dataset,we evaluated diverse subtypes of macrophages in the post-spinal cord injury dorsal root ganglia area and examined the signaling pathways that facilitate interactions among immune response-related macrophages in the dorsal root ganglia.Findings from this study provide a theoretical basis for understanding how the immune microenvironment influences the regenerative capacity of dorsal root ganglia neurons after spinal cord injury and offer novel insights into the complex processes underlying the pathobiology of spinal cord injury.展开更多
Dorsal root ganglia neurons gradually lose their axonal regeneration ability during development and aging.To explore molecules that enhance axonal regeneration,we screened growth factors with differential gene express...Dorsal root ganglia neurons gradually lose their axonal regeneration ability during development and aging.To explore molecules that enhance axonal regeneration,we screened growth factors with differential gene expression patterns in the dorsal root ganglias of young adult and aged animals following sciatic nerve injury.In young adult animals,two transforming growth factor beta-related factors,activin A and angiopoietin 2,were found to be upregulated post nerve injury.Treatment of isolated dorsal root ganglia explants and cultured dorsal root ganglia neurons of neonatal and young adult rats with recombinant activin A or angiopoietin 2 protein stimulated neurite outgrowth and axonal elongation.The administration of recombinant activin A or angiopoietin 2 protein to sciatic nerve crush-injured dorsal root ganglias also supported the growth of sensory neurons and facilitated nerve regeneration in both young adult and aged rats.Using RNA sequencing,we characterized genetic changes in dorsal root ganglia neurons following recombinant activin A or angiopoietin 2 treatment,revealing the unique mechanisms of these transforming growth factor beta-related factors.Recombinant activin A elicited changes in the gene expression of cytoskeleton-related Gper1 and activated extracellular signal-regulated kinase signaling,while angiopoietin 2 increased the expression of the transcription factor gene E2f2.Our identification of activin A and angiopoietin 2 as crucial promotional factors of axonal regeneration may guide future therapeutic strategies for the treatment of nerve injury.展开更多
Dear Editor,Dorsal pontine lesions may cause a variety of complex neuro-ophthalmic deficits,including horizontal gaze palsy(HGP),internuclear ophthalmoplegia,one-and-ahalf syndrome,abducens nerve palsy,skew deviation,...Dear Editor,Dorsal pontine lesions may cause a variety of complex neuro-ophthalmic deficits,including horizontal gaze palsy(HGP),internuclear ophthalmoplegia,one-and-ahalf syndrome,abducens nerve palsy,skew deviation,or any combination of these.Here we present a rare case of an adult patient who developed multiple complicated clinical manifestations after surgical removal of a pontine cavernous hemangioma(PCH).Our case highlights a single pontine lesion may involve complicated neural pathways and result in complicated symptoms and signs,in which abducens nerve palsy or skew deviation is easily missed when combined with HGP.展开更多
Traumatic brain injury is a prevalent disorder of the central nervous system.In addition to primary brain parenchymal damage,the enduring biological consequences of traumatic brain injury pose long-term risks for pati...Traumatic brain injury is a prevalent disorder of the central nervous system.In addition to primary brain parenchymal damage,the enduring biological consequences of traumatic brain injury pose long-term risks for patients with traumatic brain injury;however,the underlying pathogenesis remains unclear,and effective intervention methods are lacking.Intestinal dysfunction is a significant consequence of traumatic brain injury.Being the most densely innervated peripheral tissue in the body,the gut possesses multiple pathways for the establishment of a bidirectional“brain-gut axis”with the central nervous system.The gut harbors a vast microbial community,and alterations of the gut niche contribute to the progression of traumatic brain injury and its unfavorable prognosis through neuronal,hormonal,and immune pathways.A comprehensive understanding of microbiota-mediated peripheral neuroimmunomodulation mechanisms is needed to enhance treatment strategies for traumatic brain injury and its associated complications.We comprehensively reviewed alterations in the gut microecological environment following traumatic brain injury,with a specific focus on the complex biological processes of peripheral nerves,immunity,and microbes triggered by traumatic brain injury,encompassing autonomic dysfunction,neuroendocrine disturbances,peripheral immunosuppression,increased intestinal barrier permeability,compromised responses of sensory nerves to microorganisms,and potential effector nuclei in the central nervous system influenced by gut microbiota.Additionally,we reviewed the mechanisms underlying secondary biological injury and the dynamic pathological responses that occur following injury to enhance our current understanding of how peripheral pathways impact the outcome of patients with traumatic brain injury.This review aimed to propose a conceptual model for future risk assessment of central nervous system-related diseases while elucidating novel insights into the bidirectional effects of the“brain-gut-microbiota axis.”展开更多
Peripheral nerve injuries result in the rapid degeneration of distal nerve segments and immediate loss of motor and sensory functions;behavioral recovery is typically poor.We used a plasmalemmal fusogen,polyethylene g...Peripheral nerve injuries result in the rapid degeneration of distal nerve segments and immediate loss of motor and sensory functions;behavioral recovery is typically poor.We used a plasmalemmal fusogen,polyethylene glycol(PEG),to immediately fuse closely apposed open ends of severed proximal and distal axons in rat sciatic nerves.We have previously reported that sciatic nerve axons repaired by PEG-fusion do not undergo Wallerian degeneration,and PEG-fused animals exhibit rapid(within 2–6 weeks)and extensive locomotor recovery.Furthermore,our previous report showed that PEG-fusion of severed sciatic motor axons was non-specific,i.e.,spinal motoneurons in PEG-fused animals were found to project to appropriate as well as inappropriate target muscles.In this study,we examined the consequences of PEG-fusion for sensory axons of the sciatic nerve.Young adult male and female rats(Sprague–Dawley)received either a unilateral single cut or ablation injury to the sciatic nerve and subsequent repair with or without(Negative Control)the application of PEG.Compound action potentials recorded immediately after PEG-fusion repair confirmed conduction across the injury site.The success of PEG-fusion was confirmed through Sciatic Functional Index testing with PEG-fused animals showing improvement in locomotor function beginning at 35 days postoperatively.At 2–42 days postoperatively,we anterogradely labeled sensory afferents from the dorsal aspect of the hindpaw following bilateral intradermal injection of wheat germ agglutinin conjugated horseradish peroxidase.PEG-fusion repair reestablished axonal continuity.Compared to unoperated animals,labeled sensory afferents ipsilateral to the injury in PEG-fused animals were found in the appropriate area of the dorsal horn,as well as inappropriate mediolateral and rostrocaudal areas.Unexpectedly,despite having intact peripheral nerves,similar reorganizations of labeled sensory afferents were also observed contralateral to the injury and repair.This central reorganization may contribute to the improved behavioral recovery seen after PEG-fusion repair,supporting the use of this novel repair methodology over currently available treatments.展开更多
Protein arginine methyltransferase-6 participates in a range of biological functions,particularly RNA processing,transcription,chromatin remodeling,and endosomal trafficking.However,it remains unclear whether protein ...Protein arginine methyltransferase-6 participates in a range of biological functions,particularly RNA processing,transcription,chromatin remodeling,and endosomal trafficking.However,it remains unclear whether protein arginine methyl transferase-6 modifies neuropathic pain and,if so,what the mechanisms of this effect.In this study,protein arginine methyltransferase-6 expression levels and its effect on neuropathic pain were investigated in the spared nerve injury model,chronic constriction injury model and bone cancer pain model,using immunohistochemistry,western blotting,immunoprecipitation,and label-free proteomic analysis.The results showed that protein arginine methyltransferase-6 mostly co-localized withβ-tubulinⅢin the dorsal root ganglion,and that its expression decreased following spared nerve injury,chronic constriction injury and bone cancer pain.In addition,PRMT6 knockout(Prmt6~(-/-))mice exhibited pain hypersensitivity.Furthermore,the development of spared nerve injury-induced hypersensitivity to mechanical pain was attenuated by blocking the decrease in protein arginine methyltransferase-6 expression.Moreover,when protein arginine methyltransferase-6 expression was downregulated in the dorsal root ganglion in mice without spared nerve injury,increased levels of phosphorylated extracellular signal-regulated kinases were observed in the ipsilateral dorsal horn,and the response to mechanical stimuli was enhanced.Mechanistically,protein arginine methyltransferase-6 appeared to contribute to spared nerve injury-induced neuropathic pain by regulating the expression of heterogeneous nuclear ribonucleoprotein-F.Additionally,protein arginine methyltransfe rase-6-mediated modulation of hete rogeneous nuclear ribonucleoprotein-F expression required amino atids 319 to 388,but not classical H3R2 methylation.These findings indicated that protein arginine methyltransferase-6 is a potential therapeutic target fo r the treatment of peripheral neuro pathic pain.展开更多
Objective:Neuropathic pain(NP)is one of the most common forms of chronic pain,yet current treatment options are limited in effectiveness.Peripheral nerve injury activates spinal microglia,altering their inflammatory r...Objective:Neuropathic pain(NP)is one of the most common forms of chronic pain,yet current treatment options are limited in effectiveness.Peripheral nerve injury activates spinal microglia,altering their inflammatory response and phagocytic functions,which contributes to the progression of NP.Most current research on NP focuses on microglial inflammation,with relatively little attention to their phagocytic function.Early growth response factor 2(EGR2)has been shown to regulate microglial phagocytosis,but its specific role in NP remains unclear.This study aims to investigate how EGR2 modulates microglial phagocytosis and its involvement in NP,with the goal of identifying potential therapeutic targets.Methods:Adult male Sprague-Dawley(SD)rats were used to establish a chronic constriction injury(CCI)model of the sciatic nerve.Pain behaviors were assessed on days 1,3,7,10,and 14 post-surgery to confirm successful model induction.The temporal and spatial expression of EGR2 in the spinal cord was examined using real-time quantitative PCR(RT-qPCR),Western blotting,and immunofluorescence staining.Adeno-associated virus(AAV)was used to overexpress EGR2 in the spinal cord,and behavioral assessments were performed to evaluate the effects of EGR2 modulation of NP.CCI and lipopolysaccharide(LPS)models were established in animals and microglial cell lines,respectively,and changes in phagocytic activity were measured using RT-qPCR and fluorescent latex bead uptake assays.After confirming the involvement of microglial phagocytosis in NP,AAV was used to overexpress EGR2 in both in vivo and in vitro models,and phagocytic activity was further evaluated.Finally,eukaryotic transcriptome sequencing was conducted to screen differentially expressed mRNAs,followed by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses to identify potential downstream effectors of EGR2.Results:The CCI model successfully induced NP.Following CCI,EGR2 expression in the spinal cord was upregulated in parallel with NP development.Overexpression of EGR2 via spinal AAV injection enhanced microglial phagocytic activity and increased pain hypersensitivity in rats.Both animal and cellular models showed that CCI or LPS stimulation enhanced microglial phagocytosis,which was further amplified by EGR2 overexpression.Transcriptomic analysis of spinal cord tissues from CCI rats overexpressing EGR2 revealed upregulation of numerous genes associated with microglial phagocytosis and pain regulation.Among them,Lag3 emerged as a potential downstream target of EGR2.Conclusion:EGR2 contributes to the maintenance of NP by enhancing microglial phagocytosis in the spinal dorsal horn.展开更多
Background:Neuropathic pain(NP)has a long course and is difficult to treat,causing great physical suffering and psychological burden to patients.Unfortunately,the pathogenesis of NP is still poorly understood.The occu...Background:Neuropathic pain(NP)has a long course and is difficult to treat,causing great physical suffering and psychological burden to patients.Unfortunately,the pathogenesis of NP is still poorly understood.The occurrence and progression of NP are influenced by microRNA(miRNA).It has been reported that Tuina may effectively alleviate NP,however,the mechanisms related to miRNA-mediated Tuina for NP are still unexplored.Methods:To generate NP,a rat model of chronic constriction injury(CCI)was developed.Rats’pain thresholds are studied through pain behaviour tests.The effect of Tuina on the structure and morphology of neurones in the spinal dorsal horn(SDH)of rats with neuropathological pain was examined using HE staining.The levels of miRNA in the SDH of rats with a CCI model were studied using RNA sequencing(RNA-seq)and bioinformatics analysis.The top three miRNAs with the highest fold changes were chosen for qRT-PCR detection to confirm the validity of the RNA-seq results.Results:On the 4th day after CCI surgery,the paw withdrawal threshold(PWT)of the CCI+Tuina group was considerably higher than that of the CCI group(P<0.001).Furthermore,there was a significant increase in the paw withdrawal latency(PWL)of the CCI+Tuina group from day 4 to day 17 after the CCI surgery(P<0.001).Differentially expressed miRNAs in the SDH of three groups of rats were examined using RNA-seq technology.Seven miRNAs were found to intersect in total.The Kyoto Encyclopaedia of Genes and Genomes(KEGG)and Gene Ontology(GO)both anticipated the possible roles of the miRNAs.The RNA-seq results matched the changes in the levels of miR-383-3p(P<0.01),miR-183-3p(P<0.01),and miR-184(P<0.01).Conclusion:CCI-induced NP in rats leads to changes in miRNA expression in the SDH,and Tuina may alleviate NP by modulating the expression pattern of miRNAs and their underlying mechanisms.These findings may provide new targets for future NP treatment.展开更多
Background:Dorsal approach is the potentially effective strategy for minimally invasive liver resection.This study aimed to compare the outcomes between robot-assisted and laparoscopic hemihepatectomy through dorsal a...Background:Dorsal approach is the potentially effective strategy for minimally invasive liver resection.This study aimed to compare the outcomes between robot-assisted and laparoscopic hemihepatectomy through dorsal approach.Methods:We compared the patients who underwent robot-assisted hemihepatectomy(Rob-HH)and who had laparoscopic hemihepatectomy(Lap-HH)through dorsal approach between January 2020 and December 2022.A 1:1 propensity score-matching(PSM)analysis was performed to minimize bias and confounding factors.Results:Ninety-six patients were included,41 with Rob-HH and 55 with Lap-HH.Among them,58 underwent left hemihepatectomy(LHH)and 38 underwent right hemihepatectomy(RHH).Compared with LapHH group,patients with Rob-HH had less estimated blood loss(median:100.0 vs.300.0 m L,P=0.016),lower blood transfusion rates(4.9%vs.29.1%,P=0.003)and postoperative complication rates(26.8%vs.54.5%,P=0.016).These significant differences consistently existed after PSM and in the LHH subgroups.Furthermore,robot-assisted LHH was associated with decreased Pringle duration(45 vs.60 min,P=0.047).RHH subgroup analysis showed that compared with Lap-RHH,Rob-RHH was associated with less estimated blood loss(200.0 vs.400.0 m L,P=0.013).No significant differences were found in other perioperative outcomes among pre-and post-PSM cohorts,such as Pringle duration,operative time,and hospital stay.Conclusions:The dorsal approach was a safe and feasible strategy for hemi-hepatectomy with favorable outcomes under robot-assisted system in reducing intraoperative blood loss,transfusion,and postoperative complications.展开更多
Social hierarchies are central to the organizational structure of group-living species,shaping individual physiology,behavior,and social interactions.Dopaminergic(DA)systems,particularly within the ventral tegmental a...Social hierarchies are central to the organizational structure of group-living species,shaping individual physiology,behavior,and social interactions.Dopaminergic(DA)systems,particularly within the ventral tegmental area(VTA)and dorsal raphe nucleus(DR),have been linked to motivation and competitive behaviors,yet their region-specific contributions to social dominance remain insufficiently defined.This study investigated the role of VTA and DR DA neurons in regulating social dominance in sexually naïve male C57BL/6J mice.Stable hierarchies were established using the tube test,after which both dominant and subordinate mice exhibited elevated c-Fos expression within the VTA and DR.Notably,dominant mice displayed significantly greater c-Fos activation in DR DA neurons compared to subordinates.Fiber photometry revealed that DA neurons in both regions were activated during proactive push behaviors and inhibited during passive retreats,with DR neurons showing stronger activation during dominance-related actions.Chemogenetic inhibition of DR DA neurons in dominant mice reduced their social rank,whereas activation in subordinates elevated their rank.In contrast,chemogenetic modulation of VTA DA neurons had no significant effect on social dominance.Manipulation of DA neurons in both regions produced rank-dependent changes in specific anxiety-like behavioral phenotypes.These findings highlight the distinct roles of DR and VTA DA neurons in social hierarchy regulation,identifying DR DA neurons as a critical component in the modulation of social dominance.展开更多
Patients suffering from nerve injury often experience exacerbated pain responses and complain of memory deficits.The dorsal hippocampus(dHPC),a well-defined region responsible for learning and memory,displays maladapt...Patients suffering from nerve injury often experience exacerbated pain responses and complain of memory deficits.The dorsal hippocampus(dHPC),a well-defined region responsible for learning and memory,displays maladaptive plasticity upon injury,which is assumed to underlie pain hypersensitivity and cognitive deficits.However,much attention has thus far been paid to intracellular mechanisms of plasticity rather than extracellular alterations that might trigger and facilitate intracellular changes.Emerging evidence has shown that nerve injury alters the microarchitecture of the extracellular matrix(ECM)and decreases ECM rigidity in the dHPC.Despite this,it remains elusive which element of the ECM in the dHPC is affected and how it contributes to neuropathic pain and comorbid cognitive deficits.Laminin,a key element of the ECM,consists ofα-,β-,andγ-chains and has been implicated in several pathophysiological processes.Here,we showed that peripheral nerve injury downregulates lamininβ1(LAMB1)in the dHPC.Silencing of hippocampal LAMB1 exacerbates pain sensitivity and induces cognitive dysfunction.Further mechanistic analysis revealed that loss of hippocampal LAMB1 causes dysregulated Src/NR2A signaling cascades via interaction with integrinβ1,leading to decreased Ca2+levels in pyramidal neurons,which in turn orchestrates structural and functional plasticity and eventually results in exaggerated pain responses and cognitive deficits.In this study,we shed new light on the functional capability of hippocampal ECM LAMB1 in the modulation of neuropathic pain and comorbid cognitive deficits,and reveal a mechanism that conveys extracellular alterations to intracellular plasticity.Moreover,we identified hippocampal LAMB1/integrinβ1 signaling as a potential therapeutic target for the treatment of neuropathic pain and related memory loss.展开更多
Erratum to:Current Medical Science 44(5):987–1000,2024 https://doi.org/10.1007/s11596-024-2908-9 In the originally published article,there was an error in the funding information.Instead of“Shenzhen Science and Tech...Erratum to:Current Medical Science 44(5):987–1000,2024 https://doi.org/10.1007/s11596-024-2908-9 In the originally published article,there was an error in the funding information.Instead of“Shenzhen Science and Technology Program(No.2021-22154)”,it should be corrected to“Shenzhen Science and Technology Program(No.JCYJ20210324111609024)”.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.展开更多
Reach-to-grasp movements require integrating information on both object location and grip type,but how these elements are planned and to what extent they interact remains unclear.We designed a new experimental paradig...Reach-to-grasp movements require integrating information on both object location and grip type,but how these elements are planned and to what extent they interact remains unclear.We designed a new experimental paradigm in which monkeys sequentially received reach and grasp cues with delays,requiring them to retain and integrate both cues to grasp the goal object with appropriate hand gestures.Neural activity in the dorsal premotor cortex(PMd)revealed that reach and grasp were similarly represented yet not independent.Upon receiving the second cue,the PMd continued encoding the first,but over half of the neurons displayed incongruent modulations:enhanced,attenuated,or even reversed.Population-level analysis showed significant changes in encoding structure,forming distinct neural patterns.Leveraging canonical correlation analysis,we identified a shared subspace preserving the initial cue’s encoding,contributed by both congruent and incongruent neurons.Together,these findings reveal a novel perspective on the interactive planning of reach and grasp within the PMd,providing insights into potential applications for brain–machine interfaces.展开更多
Astrocytes in the spinal dorsal horn(SDH)exhibit diverse reactive phenotypes under neuropathic conditions,yet the mechanisms driving this diversity and its implications in chronic pain remain unclear.Here,we report th...Astrocytes in the spinal dorsal horn(SDH)exhibit diverse reactive phenotypes under neuropathic conditions,yet the mechanisms driving this diversity and its implications in chronic pain remain unclear.Here,we report that spared nerve injury(SNI)induces marked upregulation of both complement component 3(C3⁺,A1-like)and S100 calcium-binding protein A10(S100A10⁺,A2-like)astrocyte subpopulations in the SDH,with elevated microglial cytokines including interleukin-1α,tumor necrosis factor-α,and complement component 1q.Transcriptomic,immunohistochemical,and Western blot analyses reveal co-activation of multiple reactive astrocyte states over a unidirectional shift toward an A1-like phenotype.Fibroblast growth factor 8(FGF8),a neuroprotective factor via FGFR3,mitigated microglia-induced C3⁺astrocyte reactivity in vitro and suppressed spinal C3 expression and mechanical allodynia following intrathecal administration in SNI mice.These findings reveal a microglia–astrocyte signaling axis that promotes A1 reactivity and position FGF8 as a promising therapeutic candidate for neuropathic pain by modulating astrocyte heterogeneity.展开更多
Dear Editor,Herpes zoster(HZ),which is characterized by a unilateral painful dermatomal rash,is caused by reactivation of the latent varicella-zoster virus(VZV)in the dorsal root ganglia following primary infection du...Dear Editor,Herpes zoster(HZ),which is characterized by a unilateral painful dermatomal rash,is caused by reactivation of the latent varicella-zoster virus(VZV)in the dorsal root ganglia following primary infection during childhood[1].HZ tends to occur more frequently in older adults,in whom cellmediated immunity often declines.The incidence of HZ among immunocompetent unvaccinated individuals aged>50y is 9.92/1000 person-years[2].HZ ophthalmicus(HZO)occurs when HZ involves the first division of the trigeminal nerve,i.e.,the ophthalmic nerve[3].展开更多
Background:The channel-forming protein Pannexin1(Panx1)has been implicated in both human studies and animal models of chronic pain,but the underlying mechanisms remain incompletely understood.Methods:Wild-type(WT,n=24...Background:The channel-forming protein Pannexin1(Panx1)has been implicated in both human studies and animal models of chronic pain,but the underlying mechanisms remain incompletely understood.Methods:Wild-type(WT,n=24),global Panx1 KO(n=24),neuron-specific Panx1 KO(n=20),and glia-specific Panx1 KO(n=20)mice were used in this study at Albert Einstein College of Medicine.The von Frey test was used to quantify pain sensitivity in these mice following complete Freund’s adjuvant(CFA)injection(7,14,and 21 d).The qRT-PCR was employed to measure mRNA levels of Panx1,Panx2,Panx3,Cx43,Calhm1,andβ-catenin.Laser scanning confocal microscopy imaging,Sholl analysis,and electrophysiology were utilized to evaluate the impact of Panx1 on neuronal excitability and morphology in Neuro2a and dorsal root ganglion neurons(DRGNs)in which Panx1 expression or function was manipulated.Ethidium bromide(EtBr)dye uptake assay and calcium imaging were employed to investigate the role of Panx1 in adenosine triphosphate(ATP)sensitivity.β-galactosidase(β-gal)staining was applied to determine the relative cellular expression levels of Panx1 in trigeminal ganglia(TG)and DRG of transgenic mice.Results:Global or neuron-specific Panx1 deletion markedly decreased pain thresholds after CFA stimuli(7,14,and 21 d;P<0.01 vs.WT group),indicating that Panx1 was positively correlated with pain sensitivity.In Neuro2a,global Panx1 deletion dramatically reduced neurite extension and inward currents compared to the WT group(P<0.05),revealing that Panx1 enhanced neurogenesis and excitability.Similarly,global Panx1 deletion significantly suppressed Wnt/β-catenin dependent DRG neurogenesis following 5 d of nerve growth factor(NGF)treatment(P<0.01 vs.WT group).Moreover,Panx1 channels enhanced DRG neuron response to ATP after CFA injection(P<0.01 vs.Panx1 KO group).Furthermore,ATP release increased Ca2+responses in DRGNs and satellite glial cells surrounding them following 7 d of CFA treatment(P<0.01 vs.Panx1 KO group),suggesting that Panx1 in glia also impacts exaggerated neuronal excitability.Interestingly,neuron-specific Panx1 deletion was found to markedly reduce differentiation in cultured DRGNs,as evidenced by stunted neurite outgrowth(P<0.05 vs.Panx1 KO group;P<0.01 vs.WT group or GFAP-Cre group),blunted activation of Wnt/β-catenin signaling(P<0.01 vs.WT,Panx1 KO and GFAP-Cre groups),and diminished cell excitability(P<0.01 vs.GFAP-Cre group)and response to ATP stimulation(P<0.01 vs.WT group).Analysis ofβ-gal staining showed that cellular expression levels of Panx1 in neurons are significantly higher(2.5-fold increase)in the DRG than in the TG.Conclusions:The present study revealed that neuronal Panx1 is a prominent driver of peripheral sensitivity in the setting of inflammatory pain through cell-autonomous effects on neuronal excitability.This hyperexcitability dependence on neuronal Panx1 contrasts with inflammatory orofacial pain,where similar studies revealed a prominent role for glial Panx1.The apparent differences in Panx1 expression in neuronal and non-neuronal TG and DRG cells are likely responsible for the distinct impact of these cell types in the two pain models.展开更多
BACKGROUND Group cognitive behavioral therapy(GCBT)is increasingly being used to treat obsessive-compulsive disorder(OCD)because of its high efficiency,economy,and interaction among group members.However,the changes i...BACKGROUND Group cognitive behavioral therapy(GCBT)is increasingly being used to treat obsessive-compulsive disorder(OCD)because of its high efficiency,economy,and interaction among group members.However,the changes in network functional connectivity(FC)in patients with OCD with GCBT remain unclear.AIM To investigate inter-and intra-network resting-state FC(rs-FC)abnormalities before and after GCBT in unmedicated patients with OCD and validate the efficacy of GCBT.METHODS Overall,33 individuals with OCD and 26 healthy controls underwent resting-state functional magnetic resonance imaging.The patients were rescanned 12 weeks after GCBT.Four cognition-related networks-default mode network(DMN),dorsal attention network(DAN),salience network(SAN),and frontoparietal network(FPN)-were selected to examine FC abnormalities within and between OCD networks before and after GCBT.Neuropsychological assessments including memory,executive function,speech,attention,and visuospatial ability were reassessed following GCBT.Pearson’s correlations were used to analyze the relationship between aberrant FC in cognition-related networks and altered neuropsychological assessments in patients.RESULTS Rs-FC within the DMN and DAN decreased significantly.Additionally,rs-FC between the DMN-DAN,DMNFPN,DMN-SAN,and DAN-SAN also decreased.Significant improvements were observed in cognitive functions,such as memory,executive function,attention,and visuospatial ability.Furthermore,reduced rs-FC within the DMN correlated with visuospatial ability and executive function;DAN positively correlated with Shape Trails Test(STT)-A test elapsed time;DMN-DAN negatively correlated with Rey-Osterrieth Complex Figure(Rey-O)mimicry time and the three elapsed times of the tower of Hanoi;DMN-SAN negatively correlated with Rey-O imitation time and positively correlated with STT-A test elapsed time;and DMN-FPN negatively correlated with Auditory Word Learning Test N1 and N4 scores.CONCLUSION Decreased rs-FC within the DMN and DAN,which correlated with executive function post-treatment,has potential as a neuroimaging marker to predict treatment response to GCBT in patients with OCD.展开更多
基金supported by the National Natural Science Foundation of China(No.82401445 and 82271249)the China Postdoctoral Science Foundation(No.2024M752251)+3 种基金the Postdoctoral Fellowship Program of CPSF(No.GZC20241141)the Sichuan Science and Technology Program(No.2024NSFSC1636 and 2025ZNSFSC1645)the Postdoctoral Research Fund of West China Hospital of Sichuan University(No.2024HXBH013)1-3-5 Project for Disciplines of Excellence of West China Hospital of Sichuan University(No.ZYYC23002)。
文摘Persistent postsurgical pain is a major clinical concern,especially in the aging population,who represent a growing proportion of surgical patients.Although age is a known pain risk factor,the mechanisms driving age-related vulnerability to chronic postoperative pain remain poorly understood.This study aims to investigate how aging influences the resolution of postoperative pain and to elucidate the roles of microglial activation and synaptic remodeling in the spinal dorsal horn.A plantar incision model in young(3-month-old)and aged(18-month-old)male and female mice was used to mimic postoperative pain conditions.Mechanical and thermal hypersensitivity at various postoperative intervals were assessed by von Frey and Hargreaves tests.Microglial activation and inhibitory/excitatory synaptic densities in the spinal dorsal horn were evaluated using immunofluorescence and 3D reconstruction with Imaris software.On postoperative day(POD)3,both age groups exhibited reduced pain thresholds on the ipsilateral side,along with microglial activation in the dorsal horn.On POD 7,pain thresholds in young mice had returned to baseline with no significant microglial activation,while aged mice showed sustained reduction in pain thresholds,continuous microglial activation,and significant loss of inhibitory synapses without detectable changes in excitatory synapse density.These findings are consistent across both sexes,with no sex-related differences.Collectively,these results suggest that aging is associated with persistent postoperative pain,which correlates with microglial activation and inhibitory synapse loss.These insights advance our understanding of age-related pain vulnerability and may inform the development of more effective,targeted,and age-specific therapeutic strategies to prevent or alleviate persistent postoperative pain in elderly patients.
基金supported by grant from the National Key Technology Support Program of the Ministry of Science and Technology of China(No.2021ZD0203204)。
文摘Pseudounipolar neurons in the dorsal root ganglia(DRG),as the central nodes of primary sensory afferents,possess a distinctive T-junction that is not merely a morphological peculiarity but also performs complex roles in rapid,multiplexed shunting and regulation of sensory signals.This specialized geometry enables separation,filtering,and feedback regulation of neuronal signals,thereby coordinating peripheral and central responses at multiple levels.Recent advances,including spatial transcriptomics,single-cell sequencing,super-resolution microscopy,organoid models,and novel electrophysiological methods,have permitted more precise dissection of the T-junction's molecular composition,ion-channel distribution,and electrophysiological properties.Here,we review current knowledge of the T-junction's developmental regulation and multilayered molecular networks,and we detail its functional alterations in both physiological signaling and pathological pain states,with particular emphasis on ion-channel modulation,signal attenuation,and selective transmission mechanisms.Finally,we discuss contemporary pain-intervention approaches and prospects for precision-targeted therapies,aiming to provide a theoretical foundation for future studies in pain physiology and clinical translation.
基金supported by the National Natural Science Foundation of China,No.82072162(to XY).
文摘To perform various functions in the body,skeletal muscle is controlled and coordinated as a whole by nerves.However,there has been little research into whether the nerve control characteristics of different muscles are different,and the importance of these potential differences.In the present study,we used a three-dimensional imaging of solvent-cleared organ-compatible multi-tracer technique to explore the spatial distribution patterns of sensory and sympathetic neurons that innervate limb muscles.We integrated transcriptome sequencing datasets from mouse limb muscles in public databases and performed correlation analysis with neuronal spatial distribution data to reveal the unique effects of different types of neurons on muscle functional pathways.In terms of spatial distribution patterns,sympathetic neurons exhibited a more concentrated distribution than sensory and motor neurons.In addition,the neuronal innervation of limb muscles exhibited four different characteristics:sympathetic neuron-rich muscle,sensory neuron-rich muscle,neuron-sparse muscle,and motor neuron-rich muscle.Sensory neuron density was mainly associated with muscle contractile structure and cell pH,whereas sympathetic neuron density was associated with protein kinase activity,muscle vasculature,muscle calcium-dependent protein kinase activity,lipid transport,and vesicle release.Motor neuron density was mainly associated with protein kinase activity,cell adhesion,oxidoreductase activity,and exocytosis.These findings may contribute to a deeper understanding of how nerves cooperate to endow muscles with diverse physiological functions,thereby providing new insights and experimental evidence for the treatment of various neuromuscular diseases.
基金supported by the Tianjin Key Medical Discipline(Specialty)Construct Project,No.TJYXZDXK-027A(to SF)the National Key Research andDevelopment Project of Stem Cell and Transformation Research,No.2019YFA0112100(to SF)+2 种基金Tianjin Natural Science Foundation’s Youth Project for DiverseInvestments,No.21JCQNJC01300(to BF)the National Natural Science Foundation of China(Youth Program),No.82102563(to BF)Tianjin Major Science andTechnology Special Projects and Engineering Projects,No.21ZXJBSY00080(to YR).
文摘Few studies have investigated alterations in the immune cell microenvironment of the dorsal root ganglia following spinal cord injury and whether these modifications facilitate axonal regeneration.In this study,we used a single-cell RNA sequencing dataset to create a comprehensive profile of the diverse cell types in the dorsal root ganglia and spinal cord of a mid-thoracic contusion injury model in cynomolgus monkeys.Cell communication analysis indicated that specific signaling events among various dorsal root ganglia cell types occur in response to spinal cord injury.Single-cell analysis using dimensionality reduction clustering identified distinct molecular signatures for nine cell types,including macrophage subpopulations,and differential gene expression profiles between dorsal root ganglia cells and spinal cord cells following spinal cord injury.The macrophage subpopulations were categorized into 11 clusters(MC0-MC10)based on differentially expressed genes,with the top 10 genes being ABCA6,RBMS3,EBF1,LAMA4,ANTXR2,LAMA2,SOX5,FOXP2,GHR,and APOD.MC0,MC1,and MC2 constituted the predominant macrophage populations.MC4,MC6,and MC9 were nearly absent in the spinal cord,but exhibited significant increases in the dorsal root ganglia post-spinal cord injury.Notably,these subpopulations possess a strong capacity for regulating axonal regeneration.The developmental progression of dorsal root ganglia macrophages after spinal cord injury was elucidated using cell trajectory and pseudo-time analyses.Genes such as EBF1(MC6 and MC9 marker),RBMS3(MC6 and MC9 marker),and ABCA6(MC6 marker)showed high expression levels in the critical pathways of macrophage function.Through ligand-receptor pair analysis,we determined that the effects of macrophages on microglia are predominantly mediated through interaction pairs(e.g.,SPP1-CD44,LAMC1-CD44,and FN1-CD44),potentially facilitating specific cellular communications within the immune microenvironment.The single-cell RNA sequencing dataset used in this study represents the first comprehensive transcriptional analysis of the dorsal root ganglia after spinal cord injury in cynomolgus monkeys,encompassing nearly all cell types within the dorsal root ganglia region.Using this dataset,we evaluated diverse subtypes of macrophages in the post-spinal cord injury dorsal root ganglia area and examined the signaling pathways that facilitate interactions among immune response-related macrophages in the dorsal root ganglia.Findings from this study provide a theoretical basis for understanding how the immune microenvironment influences the regenerative capacity of dorsal root ganglia neurons after spinal cord injury and offer novel insights into the complex processes underlying the pathobiology of spinal cord injury.
基金supported by Major Program of National Natural Science Foundation of China,No.92368207Frontier Leading Technology BasicResearch Major Project of Jiangsu Province,No.BK20232023(both to XG).
文摘Dorsal root ganglia neurons gradually lose their axonal regeneration ability during development and aging.To explore molecules that enhance axonal regeneration,we screened growth factors with differential gene expression patterns in the dorsal root ganglias of young adult and aged animals following sciatic nerve injury.In young adult animals,two transforming growth factor beta-related factors,activin A and angiopoietin 2,were found to be upregulated post nerve injury.Treatment of isolated dorsal root ganglia explants and cultured dorsal root ganglia neurons of neonatal and young adult rats with recombinant activin A or angiopoietin 2 protein stimulated neurite outgrowth and axonal elongation.The administration of recombinant activin A or angiopoietin 2 protein to sciatic nerve crush-injured dorsal root ganglias also supported the growth of sensory neurons and facilitated nerve regeneration in both young adult and aged rats.Using RNA sequencing,we characterized genetic changes in dorsal root ganglia neurons following recombinant activin A or angiopoietin 2 treatment,revealing the unique mechanisms of these transforming growth factor beta-related factors.Recombinant activin A elicited changes in the gene expression of cytoskeleton-related Gper1 and activated extracellular signal-regulated kinase signaling,while angiopoietin 2 increased the expression of the transcription factor gene E2f2.Our identification of activin A and angiopoietin 2 as crucial promotional factors of axonal regeneration may guide future therapeutic strategies for the treatment of nerve injury.
文摘Dear Editor,Dorsal pontine lesions may cause a variety of complex neuro-ophthalmic deficits,including horizontal gaze palsy(HGP),internuclear ophthalmoplegia,one-and-ahalf syndrome,abducens nerve palsy,skew deviation,or any combination of these.Here we present a rare case of an adult patient who developed multiple complicated clinical manifestations after surgical removal of a pontine cavernous hemangioma(PCH).Our case highlights a single pontine lesion may involve complicated neural pathways and result in complicated symptoms and signs,in which abducens nerve palsy or skew deviation is easily missed when combined with HGP.
基金supported by the National Natural Science Foundation of China,No.82174112(to PZ)Science and Technology Project of Haihe Laboratory of Modern Chinese Medicine,No.22HHZYSS00015(to PZ)State-Sponsored Postdoctoral Researcher Program,No.GZC20231925(to LN)。
文摘Traumatic brain injury is a prevalent disorder of the central nervous system.In addition to primary brain parenchymal damage,the enduring biological consequences of traumatic brain injury pose long-term risks for patients with traumatic brain injury;however,the underlying pathogenesis remains unclear,and effective intervention methods are lacking.Intestinal dysfunction is a significant consequence of traumatic brain injury.Being the most densely innervated peripheral tissue in the body,the gut possesses multiple pathways for the establishment of a bidirectional“brain-gut axis”with the central nervous system.The gut harbors a vast microbial community,and alterations of the gut niche contribute to the progression of traumatic brain injury and its unfavorable prognosis through neuronal,hormonal,and immune pathways.A comprehensive understanding of microbiota-mediated peripheral neuroimmunomodulation mechanisms is needed to enhance treatment strategies for traumatic brain injury and its associated complications.We comprehensively reviewed alterations in the gut microecological environment following traumatic brain injury,with a specific focus on the complex biological processes of peripheral nerves,immunity,and microbes triggered by traumatic brain injury,encompassing autonomic dysfunction,neuroendocrine disturbances,peripheral immunosuppression,increased intestinal barrier permeability,compromised responses of sensory nerves to microorganisms,and potential effector nuclei in the central nervous system influenced by gut microbiota.Additionally,we reviewed the mechanisms underlying secondary biological injury and the dynamic pathological responses that occur following injury to enhance our current understanding of how peripheral pathways impact the outcome of patients with traumatic brain injury.This review aimed to propose a conceptual model for future risk assessment of central nervous system-related diseases while elucidating novel insights into the bidirectional effects of the“brain-gut-microbiota axis.”
基金supported by the Department of Defense AFIRMⅢW81XWH-20-2-0029 grant subcontractLone Star Paralysis gift,UT POC19-1774-13 grant+1 种基金Neuraptive Therapeutics Inc.26-7724-56 grantNational Institutes of Health R01-NS128086(all to GDB)。
文摘Peripheral nerve injuries result in the rapid degeneration of distal nerve segments and immediate loss of motor and sensory functions;behavioral recovery is typically poor.We used a plasmalemmal fusogen,polyethylene glycol(PEG),to immediately fuse closely apposed open ends of severed proximal and distal axons in rat sciatic nerves.We have previously reported that sciatic nerve axons repaired by PEG-fusion do not undergo Wallerian degeneration,and PEG-fused animals exhibit rapid(within 2–6 weeks)and extensive locomotor recovery.Furthermore,our previous report showed that PEG-fusion of severed sciatic motor axons was non-specific,i.e.,spinal motoneurons in PEG-fused animals were found to project to appropriate as well as inappropriate target muscles.In this study,we examined the consequences of PEG-fusion for sensory axons of the sciatic nerve.Young adult male and female rats(Sprague–Dawley)received either a unilateral single cut or ablation injury to the sciatic nerve and subsequent repair with or without(Negative Control)the application of PEG.Compound action potentials recorded immediately after PEG-fusion repair confirmed conduction across the injury site.The success of PEG-fusion was confirmed through Sciatic Functional Index testing with PEG-fused animals showing improvement in locomotor function beginning at 35 days postoperatively.At 2–42 days postoperatively,we anterogradely labeled sensory afferents from the dorsal aspect of the hindpaw following bilateral intradermal injection of wheat germ agglutinin conjugated horseradish peroxidase.PEG-fusion repair reestablished axonal continuity.Compared to unoperated animals,labeled sensory afferents ipsilateral to the injury in PEG-fused animals were found in the appropriate area of the dorsal horn,as well as inappropriate mediolateral and rostrocaudal areas.Unexpectedly,despite having intact peripheral nerves,similar reorganizations of labeled sensory afferents were also observed contralateral to the injury and repair.This central reorganization may contribute to the improved behavioral recovery seen after PEG-fusion repair,supporting the use of this novel repair methodology over currently available treatments.
基金supported by the National Natural Science Foundation of China,Nos.82001178(to LW),81901129(to LH),82001175(to FX)Shanghai Sailing Program,No.20YF1439200(to LW)+1 种基金the Natural Science Foundation of Shanghai,China,No.23ZR1450800(to LH)and the Fundamental Research Funds for the Central Universities,No.YG2023LC15(to ZX)。
文摘Protein arginine methyltransferase-6 participates in a range of biological functions,particularly RNA processing,transcription,chromatin remodeling,and endosomal trafficking.However,it remains unclear whether protein arginine methyl transferase-6 modifies neuropathic pain and,if so,what the mechanisms of this effect.In this study,protein arginine methyltransferase-6 expression levels and its effect on neuropathic pain were investigated in the spared nerve injury model,chronic constriction injury model and bone cancer pain model,using immunohistochemistry,western blotting,immunoprecipitation,and label-free proteomic analysis.The results showed that protein arginine methyltransferase-6 mostly co-localized withβ-tubulinⅢin the dorsal root ganglion,and that its expression decreased following spared nerve injury,chronic constriction injury and bone cancer pain.In addition,PRMT6 knockout(Prmt6~(-/-))mice exhibited pain hypersensitivity.Furthermore,the development of spared nerve injury-induced hypersensitivity to mechanical pain was attenuated by blocking the decrease in protein arginine methyltransferase-6 expression.Moreover,when protein arginine methyltransferase-6 expression was downregulated in the dorsal root ganglion in mice without spared nerve injury,increased levels of phosphorylated extracellular signal-regulated kinases were observed in the ipsilateral dorsal horn,and the response to mechanical stimuli was enhanced.Mechanistically,protein arginine methyltransferase-6 appeared to contribute to spared nerve injury-induced neuropathic pain by regulating the expression of heterogeneous nuclear ribonucleoprotein-F.Additionally,protein arginine methyltransfe rase-6-mediated modulation of hete rogeneous nuclear ribonucleoprotein-F expression required amino atids 319 to 388,but not classical H3R2 methylation.These findings indicated that protein arginine methyltransferase-6 is a potential therapeutic target fo r the treatment of peripheral neuro pathic pain.
基金supported by the National Natural Science Foundation of China(82071249 and 81771207).
文摘Objective:Neuropathic pain(NP)is one of the most common forms of chronic pain,yet current treatment options are limited in effectiveness.Peripheral nerve injury activates spinal microglia,altering their inflammatory response and phagocytic functions,which contributes to the progression of NP.Most current research on NP focuses on microglial inflammation,with relatively little attention to their phagocytic function.Early growth response factor 2(EGR2)has been shown to regulate microglial phagocytosis,but its specific role in NP remains unclear.This study aims to investigate how EGR2 modulates microglial phagocytosis and its involvement in NP,with the goal of identifying potential therapeutic targets.Methods:Adult male Sprague-Dawley(SD)rats were used to establish a chronic constriction injury(CCI)model of the sciatic nerve.Pain behaviors were assessed on days 1,3,7,10,and 14 post-surgery to confirm successful model induction.The temporal and spatial expression of EGR2 in the spinal cord was examined using real-time quantitative PCR(RT-qPCR),Western blotting,and immunofluorescence staining.Adeno-associated virus(AAV)was used to overexpress EGR2 in the spinal cord,and behavioral assessments were performed to evaluate the effects of EGR2 modulation of NP.CCI and lipopolysaccharide(LPS)models were established in animals and microglial cell lines,respectively,and changes in phagocytic activity were measured using RT-qPCR and fluorescent latex bead uptake assays.After confirming the involvement of microglial phagocytosis in NP,AAV was used to overexpress EGR2 in both in vivo and in vitro models,and phagocytic activity was further evaluated.Finally,eukaryotic transcriptome sequencing was conducted to screen differentially expressed mRNAs,followed by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses to identify potential downstream effectors of EGR2.Results:The CCI model successfully induced NP.Following CCI,EGR2 expression in the spinal cord was upregulated in parallel with NP development.Overexpression of EGR2 via spinal AAV injection enhanced microglial phagocytic activity and increased pain hypersensitivity in rats.Both animal and cellular models showed that CCI or LPS stimulation enhanced microglial phagocytosis,which was further amplified by EGR2 overexpression.Transcriptomic analysis of spinal cord tissues from CCI rats overexpressing EGR2 revealed upregulation of numerous genes associated with microglial phagocytosis and pain regulation.Among them,Lag3 emerged as a potential downstream target of EGR2.Conclusion:EGR2 contributes to the maintenance of NP by enhancing microglial phagocytosis in the spinal dorsal horn.
基金supported by the Project of National Natural Science Foundation of China(No.82174523,No.82205303)Fujian Provincial Health Commission Traditional Chinese Medicine Science and Technology Plan Project(No.2025YBB010)Natural Science Foundation of Fujian Province(No.2023J06037,No.2024J01141).
文摘Background:Neuropathic pain(NP)has a long course and is difficult to treat,causing great physical suffering and psychological burden to patients.Unfortunately,the pathogenesis of NP is still poorly understood.The occurrence and progression of NP are influenced by microRNA(miRNA).It has been reported that Tuina may effectively alleviate NP,however,the mechanisms related to miRNA-mediated Tuina for NP are still unexplored.Methods:To generate NP,a rat model of chronic constriction injury(CCI)was developed.Rats’pain thresholds are studied through pain behaviour tests.The effect of Tuina on the structure and morphology of neurones in the spinal dorsal horn(SDH)of rats with neuropathological pain was examined using HE staining.The levels of miRNA in the SDH of rats with a CCI model were studied using RNA sequencing(RNA-seq)and bioinformatics analysis.The top three miRNAs with the highest fold changes were chosen for qRT-PCR detection to confirm the validity of the RNA-seq results.Results:On the 4th day after CCI surgery,the paw withdrawal threshold(PWT)of the CCI+Tuina group was considerably higher than that of the CCI group(P<0.001).Furthermore,there was a significant increase in the paw withdrawal latency(PWL)of the CCI+Tuina group from day 4 to day 17 after the CCI surgery(P<0.001).Differentially expressed miRNAs in the SDH of three groups of rats were examined using RNA-seq technology.Seven miRNAs were found to intersect in total.The Kyoto Encyclopaedia of Genes and Genomes(KEGG)and Gene Ontology(GO)both anticipated the possible roles of the miRNAs.The RNA-seq results matched the changes in the levels of miR-383-3p(P<0.01),miR-183-3p(P<0.01),and miR-184(P<0.01).Conclusion:CCI-induced NP in rats leads to changes in miRNA expression in the SDH,and Tuina may alleviate NP by modulating the expression pattern of miRNAs and their underlying mechanisms.These findings may provide new targets for future NP treatment.
基金supported by grants from the National Nat-ural Science Foundation of China(82173129)the Innova-tive and Entrepreneurial Talent Doctor of Jiangsu Province,China(JSSCBS20221872)。
文摘Background:Dorsal approach is the potentially effective strategy for minimally invasive liver resection.This study aimed to compare the outcomes between robot-assisted and laparoscopic hemihepatectomy through dorsal approach.Methods:We compared the patients who underwent robot-assisted hemihepatectomy(Rob-HH)and who had laparoscopic hemihepatectomy(Lap-HH)through dorsal approach between January 2020 and December 2022.A 1:1 propensity score-matching(PSM)analysis was performed to minimize bias and confounding factors.Results:Ninety-six patients were included,41 with Rob-HH and 55 with Lap-HH.Among them,58 underwent left hemihepatectomy(LHH)and 38 underwent right hemihepatectomy(RHH).Compared with LapHH group,patients with Rob-HH had less estimated blood loss(median:100.0 vs.300.0 m L,P=0.016),lower blood transfusion rates(4.9%vs.29.1%,P=0.003)and postoperative complication rates(26.8%vs.54.5%,P=0.016).These significant differences consistently existed after PSM and in the LHH subgroups.Furthermore,robot-assisted LHH was associated with decreased Pringle duration(45 vs.60 min,P=0.047).RHH subgroup analysis showed that compared with Lap-RHH,Rob-RHH was associated with less estimated blood loss(200.0 vs.400.0 m L,P=0.013).No significant differences were found in other perioperative outcomes among pre-and post-PSM cohorts,such as Pringle duration,operative time,and hospital stay.Conclusions:The dorsal approach was a safe and feasible strategy for hemi-hepatectomy with favorable outcomes under robot-assisted system in reducing intraoperative blood loss,transfusion,and postoperative complications.
基金supported by the National Natural Science Foundation of China(32270529 to L.F.L.32270510 to F.D.T.)+2 种基金STI2030-Majior Projects(2022ZD0205101 to F.D.T.)Natural Science Foundation of Henan Province(252300420211 to Y.J.L.)Key Scientific Research Project of Higher Education Institutions in Henan Province(23A180001 to L.F.L.)#。
文摘Social hierarchies are central to the organizational structure of group-living species,shaping individual physiology,behavior,and social interactions.Dopaminergic(DA)systems,particularly within the ventral tegmental area(VTA)and dorsal raphe nucleus(DR),have been linked to motivation and competitive behaviors,yet their region-specific contributions to social dominance remain insufficiently defined.This study investigated the role of VTA and DR DA neurons in regulating social dominance in sexually naïve male C57BL/6J mice.Stable hierarchies were established using the tube test,after which both dominant and subordinate mice exhibited elevated c-Fos expression within the VTA and DR.Notably,dominant mice displayed significantly greater c-Fos activation in DR DA neurons compared to subordinates.Fiber photometry revealed that DA neurons in both regions were activated during proactive push behaviors and inhibited during passive retreats,with DR neurons showing stronger activation during dominance-related actions.Chemogenetic inhibition of DR DA neurons in dominant mice reduced their social rank,whereas activation in subordinates elevated their rank.In contrast,chemogenetic modulation of VTA DA neurons had no significant effect on social dominance.Manipulation of DA neurons in both regions produced rank-dependent changes in specific anxiety-like behavioral phenotypes.These findings highlight the distinct roles of DR and VTA DA neurons in social hierarchy regulation,identifying DR DA neurons as a critical component in the modulation of social dominance.
基金supported by the National Key Research and Development Program of China(2024YFC2510102)the National Natural Science Foundation of China(NSFC)grants(82330036 and 82221001)+9 种基金STI2030-Major Projects(2021ZD0203100(2021ZD0203104))the Innovation Teams in Priority Areas Accredited by Shaanxi Science and Technology(2022TD-49)to C.L.NSFC grant(82201370)China Postdoctoral Science Foundation grant(2021MD703955)to F.W.NSFC grants(82101293,82221001)to W.J.H.and S.X.W.NSFC grant(82201368)China Postdoctoral Science Foundation grant(2022M713847)to Z.Z.L.STI2030-Major Projects(2021ZD0203205)NSFC grants(82171212,82371225)to R.G.X.grant from Joint Founding Project of Innovation Research Institute,Xijing Hospital(LHJJ24JH08)Shaanxi Province Sanqin Talent Program to C.L.
文摘Patients suffering from nerve injury often experience exacerbated pain responses and complain of memory deficits.The dorsal hippocampus(dHPC),a well-defined region responsible for learning and memory,displays maladaptive plasticity upon injury,which is assumed to underlie pain hypersensitivity and cognitive deficits.However,much attention has thus far been paid to intracellular mechanisms of plasticity rather than extracellular alterations that might trigger and facilitate intracellular changes.Emerging evidence has shown that nerve injury alters the microarchitecture of the extracellular matrix(ECM)and decreases ECM rigidity in the dHPC.Despite this,it remains elusive which element of the ECM in the dHPC is affected and how it contributes to neuropathic pain and comorbid cognitive deficits.Laminin,a key element of the ECM,consists ofα-,β-,andγ-chains and has been implicated in several pathophysiological processes.Here,we showed that peripheral nerve injury downregulates lamininβ1(LAMB1)in the dHPC.Silencing of hippocampal LAMB1 exacerbates pain sensitivity and induces cognitive dysfunction.Further mechanistic analysis revealed that loss of hippocampal LAMB1 causes dysregulated Src/NR2A signaling cascades via interaction with integrinβ1,leading to decreased Ca2+levels in pyramidal neurons,which in turn orchestrates structural and functional plasticity and eventually results in exaggerated pain responses and cognitive deficits.In this study,we shed new light on the functional capability of hippocampal ECM LAMB1 in the modulation of neuropathic pain and comorbid cognitive deficits,and reveal a mechanism that conveys extracellular alterations to intracellular plasticity.Moreover,we identified hippocampal LAMB1/integrinβ1 signaling as a potential therapeutic target for the treatment of neuropathic pain and related memory loss.
文摘Erratum to:Current Medical Science 44(5):987–1000,2024 https://doi.org/10.1007/s11596-024-2908-9 In the originally published article,there was an error in the funding information.Instead of“Shenzhen Science and Technology Program(No.2021-22154)”,it should be corrected to“Shenzhen Science and Technology Program(No.JCYJ20210324111609024)”.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.
基金supported by STI 2030-Major Projects(2022ZD0208903)the National Natural Science Foundation of China(62336007)+3 种基金the Natural Science Foundation of Shandong Province(ZR2024QH582)the Pioneer R&D Program of Zhejiang Province(2024C03001)the Starry Night Science Fund of Zhejiang University Shanghai Institute for Advanced Study(SN-ZJU-SIAS-002)the Fundamental Research Funds for the Central Universities(2024ZFJH01-01).
文摘Reach-to-grasp movements require integrating information on both object location and grip type,but how these elements are planned and to what extent they interact remains unclear.We designed a new experimental paradigm in which monkeys sequentially received reach and grasp cues with delays,requiring them to retain and integrate both cues to grasp the goal object with appropriate hand gestures.Neural activity in the dorsal premotor cortex(PMd)revealed that reach and grasp were similarly represented yet not independent.Upon receiving the second cue,the PMd continued encoding the first,but over half of the neurons displayed incongruent modulations:enhanced,attenuated,or even reversed.Population-level analysis showed significant changes in encoding structure,forming distinct neural patterns.Leveraging canonical correlation analysis,we identified a shared subspace preserving the initial cue’s encoding,contributed by both congruent and incongruent neurons.Together,these findings reveal a novel perspective on the interactive planning of reach and grasp within the PMd,providing insights into potential applications for brain–machine interfaces.
基金supported by the Science and Technology Innovation(STI)2030-Major Projects(2025ZD0214900-02 and 2021ZD0203200-05)the National Natural Science Foundation of China(82130032)+1 种基金the Natural Science Foundation of Shanghai(24ZR1413900 and 25ZR1402460)and the China Postdoctoral Science Foundation(2021M690685).
文摘Astrocytes in the spinal dorsal horn(SDH)exhibit diverse reactive phenotypes under neuropathic conditions,yet the mechanisms driving this diversity and its implications in chronic pain remain unclear.Here,we report that spared nerve injury(SNI)induces marked upregulation of both complement component 3(C3⁺,A1-like)and S100 calcium-binding protein A10(S100A10⁺,A2-like)astrocyte subpopulations in the SDH,with elevated microglial cytokines including interleukin-1α,tumor necrosis factor-α,and complement component 1q.Transcriptomic,immunohistochemical,and Western blot analyses reveal co-activation of multiple reactive astrocyte states over a unidirectional shift toward an A1-like phenotype.Fibroblast growth factor 8(FGF8),a neuroprotective factor via FGFR3,mitigated microglia-induced C3⁺astrocyte reactivity in vitro and suppressed spinal C3 expression and mechanical allodynia following intrathecal administration in SNI mice.These findings reveal a microglia–astrocyte signaling axis that promotes A1 reactivity and position FGF8 as a promising therapeutic candidate for neuropathic pain by modulating astrocyte heterogeneity.
文摘Dear Editor,Herpes zoster(HZ),which is characterized by a unilateral painful dermatomal rash,is caused by reactivation of the latent varicella-zoster virus(VZV)in the dorsal root ganglia following primary infection during childhood[1].HZ tends to occur more frequently in older adults,in whom cellmediated immunity often declines.The incidence of HZ among immunocompetent unvaccinated individuals aged>50y is 9.92/1000 person-years[2].HZ ophthalmicus(HZO)occurs when HZ involves the first division of the trigeminal nerve,i.e.,the ophthalmic nerve[3].
基金This work was NIH(R01NS092466),NSFC(U2004201)Central Plains Thousand People Plan of Henan Province(204200510013)+1 种基金Henan Overseas Expertise Introduction Center for Discipline Innovation(CXJD2021002)Key Special Project of Zhengzhou University Disciplinary Construction(XKZDJC202001)。
文摘Background:The channel-forming protein Pannexin1(Panx1)has been implicated in both human studies and animal models of chronic pain,but the underlying mechanisms remain incompletely understood.Methods:Wild-type(WT,n=24),global Panx1 KO(n=24),neuron-specific Panx1 KO(n=20),and glia-specific Panx1 KO(n=20)mice were used in this study at Albert Einstein College of Medicine.The von Frey test was used to quantify pain sensitivity in these mice following complete Freund’s adjuvant(CFA)injection(7,14,and 21 d).The qRT-PCR was employed to measure mRNA levels of Panx1,Panx2,Panx3,Cx43,Calhm1,andβ-catenin.Laser scanning confocal microscopy imaging,Sholl analysis,and electrophysiology were utilized to evaluate the impact of Panx1 on neuronal excitability and morphology in Neuro2a and dorsal root ganglion neurons(DRGNs)in which Panx1 expression or function was manipulated.Ethidium bromide(EtBr)dye uptake assay and calcium imaging were employed to investigate the role of Panx1 in adenosine triphosphate(ATP)sensitivity.β-galactosidase(β-gal)staining was applied to determine the relative cellular expression levels of Panx1 in trigeminal ganglia(TG)and DRG of transgenic mice.Results:Global or neuron-specific Panx1 deletion markedly decreased pain thresholds after CFA stimuli(7,14,and 21 d;P<0.01 vs.WT group),indicating that Panx1 was positively correlated with pain sensitivity.In Neuro2a,global Panx1 deletion dramatically reduced neurite extension and inward currents compared to the WT group(P<0.05),revealing that Panx1 enhanced neurogenesis and excitability.Similarly,global Panx1 deletion significantly suppressed Wnt/β-catenin dependent DRG neurogenesis following 5 d of nerve growth factor(NGF)treatment(P<0.01 vs.WT group).Moreover,Panx1 channels enhanced DRG neuron response to ATP after CFA injection(P<0.01 vs.Panx1 KO group).Furthermore,ATP release increased Ca2+responses in DRGNs and satellite glial cells surrounding them following 7 d of CFA treatment(P<0.01 vs.Panx1 KO group),suggesting that Panx1 in glia also impacts exaggerated neuronal excitability.Interestingly,neuron-specific Panx1 deletion was found to markedly reduce differentiation in cultured DRGNs,as evidenced by stunted neurite outgrowth(P<0.05 vs.Panx1 KO group;P<0.01 vs.WT group or GFAP-Cre group),blunted activation of Wnt/β-catenin signaling(P<0.01 vs.WT,Panx1 KO and GFAP-Cre groups),and diminished cell excitability(P<0.01 vs.GFAP-Cre group)and response to ATP stimulation(P<0.01 vs.WT group).Analysis ofβ-gal staining showed that cellular expression levels of Panx1 in neurons are significantly higher(2.5-fold increase)in the DRG than in the TG.Conclusions:The present study revealed that neuronal Panx1 is a prominent driver of peripheral sensitivity in the setting of inflammatory pain through cell-autonomous effects on neuronal excitability.This hyperexcitability dependence on neuronal Panx1 contrasts with inflammatory orofacial pain,where similar studies revealed a prominent role for glial Panx1.The apparent differences in Panx1 expression in neuronal and non-neuronal TG and DRG cells are likely responsible for the distinct impact of these cell types in the two pain models.
基金Supported by the Pharmaceutical Science and Technology Project of Zhejiang Province,No.2023RC266the Natural Science Foundation of Ningbo,No.202003N4266.
文摘BACKGROUND Group cognitive behavioral therapy(GCBT)is increasingly being used to treat obsessive-compulsive disorder(OCD)because of its high efficiency,economy,and interaction among group members.However,the changes in network functional connectivity(FC)in patients with OCD with GCBT remain unclear.AIM To investigate inter-and intra-network resting-state FC(rs-FC)abnormalities before and after GCBT in unmedicated patients with OCD and validate the efficacy of GCBT.METHODS Overall,33 individuals with OCD and 26 healthy controls underwent resting-state functional magnetic resonance imaging.The patients were rescanned 12 weeks after GCBT.Four cognition-related networks-default mode network(DMN),dorsal attention network(DAN),salience network(SAN),and frontoparietal network(FPN)-were selected to examine FC abnormalities within and between OCD networks before and after GCBT.Neuropsychological assessments including memory,executive function,speech,attention,and visuospatial ability were reassessed following GCBT.Pearson’s correlations were used to analyze the relationship between aberrant FC in cognition-related networks and altered neuropsychological assessments in patients.RESULTS Rs-FC within the DMN and DAN decreased significantly.Additionally,rs-FC between the DMN-DAN,DMNFPN,DMN-SAN,and DAN-SAN also decreased.Significant improvements were observed in cognitive functions,such as memory,executive function,attention,and visuospatial ability.Furthermore,reduced rs-FC within the DMN correlated with visuospatial ability and executive function;DAN positively correlated with Shape Trails Test(STT)-A test elapsed time;DMN-DAN negatively correlated with Rey-Osterrieth Complex Figure(Rey-O)mimicry time and the three elapsed times of the tower of Hanoi;DMN-SAN negatively correlated with Rey-O imitation time and positively correlated with STT-A test elapsed time;and DMN-FPN negatively correlated with Auditory Word Learning Test N1 and N4 scores.CONCLUSION Decreased rs-FC within the DMN and DAN,which correlated with executive function post-treatment,has potential as a neuroimaging marker to predict treatment response to GCBT in patients with OCD.
