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
Background:The first web space not only plays an integral role in hand functionality,but also holds an important aesthetic function for patients with cicatricial contractures,which hinders the ability to move joints,t...Background:The first web space not only plays an integral role in hand functionality,but also holds an important aesthetic function for patients with cicatricial contractures,which hinders the ability to move joints,thereby restricting the performance of everyday activities.Therefore,a wide variety of reconstruction options are available.In this study,our main aim was to have a clear surgical plan prior to surgery according to preoperative findings and the degree of thumb abduction span.Methods:This study was conducted at Kasr Al-Ainy Hospital.This cohort study included 33 patients with cicatricial first web space contractures who underwent reconstructive procedures to restore the first web space.Patients were assessed preoperatively and categorized according to the degree of contracture,and the reconstruction procedure was chosen accordingly.They were assessed using both objective and subjective methods.Results:In this study,33 cases of cicatricial contracture of the first web space due to physical or thermal trauma were included.Measurements of the change in the span of abduction were performed for all patients included in the study preoperatively and postoperatively.Skin grafting and skin substitutes had an average change in abduction span of 32.5°(±14.4°),Z-plasty release had a mean of 30.59°(±8.82°)increase in abduction span,regional flaps had an increase of 40.71°(±12.39°),while distant flaps had an increase of 35°(±3.54°).Conclusion:No single reconstruction method can be used in all cases.When viewing a patient,one must consider that each individual has a unique representation.However,if we follow a systematic method for the initial evaluation,the most efficient flap can be chosen for each case,thus reducing the need for secondary procedures.Categorizing the cases according to the abduction span into mild,moderate,or severe forms is the first building block of this algorithm.Adjacent tissue condition,patient occupation,compliance,and the need to return to work are important factors.展开更多
The dorsal and ventral visual streams have been considered to play distinct roles in visual processing for action:the dorsal stream is assumed to support real-time actions,while the ventral stream facilitates memory-g...The dorsal and ventral visual streams have been considered to play distinct roles in visual processing for action:the dorsal stream is assumed to support real-time actions,while the ventral stream facilitates memory-guided actions.However,recent evidence suggests a more integrated function of these streams.We investigated the neural dynamics and functional connectivity between them during memory-guided actions using intracranial EEG.We tracked neural activity in the inferior parietal lobule in the dorsal stream,and the ventral temporal cortex in the ventral stream as well as the hippocampus during a delayed action task involving object identity and location memory.We found increased alpha power in both streams during the delay,indicating their role in maintaining spatial visual information.In addition,we recorded increased alpha power in the hippocampus during the delay,but only when both object identity and location needed to be remembered.We also recorded an increase in theta band phase synchronization between the inferior parietal lobule and ventral temporal cortex and between the inferior parietal lobule and hippocampus during the encoding and delay.Granger causality analysis indicated dynamic and frequency-specific directional interactions among the inferior parietal lobule,ventral temporal cortex,and hippocampus that varied across task phases.Our study provides unique electrophysiological evidence for close interactions between dorsal and ventral streams,supporting an integrated processing model in which both streams contribute to memory-guided actions.展开更多
The thalamic reticular nucleus(TRN)plays a crucial role in regulating sensory encoding,even at the earliest stages of visual processing,as evidenced by numerous studies.Orientation selectivity,a vital neural response,...The thalamic reticular nucleus(TRN)plays a crucial role in regulating sensory encoding,even at the earliest stages of visual processing,as evidenced by numerous studies.Orientation selectivity,a vital neural response,is essential for detecting objects through edge perception.Here,we demonstrate that somatostatin(SOM)-expressing and parvalbumin(PV)-expressing neurons in the TRN project to the dorsal lateral geniculate nucleus and modulate orientation selectivity and the capacity for visual information processing in the primary visual cortex(V1).These findings show that SOM-positive and PV-positive neurons in the TRN are powerful modulators of visual information encoding in V1,revealing a novel role for this thalamic nucleus in influencing visual processing.展开更多
Objective:Preventing the transition from acute to chronic pain(pain transition)is a new strategy for treating chronic pain.The present study aimed to investigate the role of K+-Cl−Cotransporter Isoform 2(KCC2)andγ-am...Objective:Preventing the transition from acute to chronic pain(pain transition)is a new strategy for treating chronic pain.The present study aimed to investigate the role of K+-Cl−Cotransporter Isoform 2(KCC2)andγ-aminobutyric acid receptor type A(GABAAR)in the spinal cord dorsal horn(SCDH)in pain transition and the intervention effect of electroacupuncture(EA),and to understand the mechanism of EA in preventing acute and chronic pain transition in the spinal center.Methods:A rat model of hyperalgesic priming(HP)was established by injecting carrageenan(Car)into the plantar area of rats,followed by the injection of prostaglandin E2(PGE2)into the dorsal foot 7 days later.The GABAAR agonist(muscimol)and KCC2 activator(CLP257)were intrathecally injected for three consecutive days after PGE2 injection.EA was applied at a frequency of 2/100 Hz to the bilateral foot Zusanli(ST36)and Kunlun(BL60).A von Frey filament was used to detect the pain threshold in each group of rats.Western blotting(WB)and immunofluorescence(IF)were used to detect GABAAR and KCC2 expression in each rats group.By combining EA intervention with a KCC2 inhibitor(VU0240551),we explored the mechanism of pain transition of EA regulation of GABAAR and KCC2 expression in SCDH.Results:The HP model was established by injecting mice with Car/PGE2.Compared to the normal saline(NS)+NS and NS+PGE2 groups,the pain threshold of the Car+PGE2 group decreased significantly 48 hours after PGE2 injection(P<0.01).The WB results indicated that intrathecal injection of a GABAAR agonist upregulated GABAAR expression in the SCDH of HP model rats(P<0.05).WB and IF results revealed that intrathecal injection of the KCC2 activator significantly increased GABAAR and KCC2 expression in the SCDH of HP model rats(P<0.01)and that GABAAR and KCC2 were co-expressed in the same SCDH cells.Compared to the Car+PGE2 group,EA intervention significantly increased MWTs from 48 to 72 hours after the first injection and 4,24,and 48 hours after the second injection(P<0.01).EA upregulated GABAAR and KCC2 expression in the SCDH of rats with HP(P<0.05).Intrathecal injection of the KCC2 inhibitor blocked the analgesic effect of EA in HP model rats(P<0.01).Conclusions:In SCDH,KCC2 expression was downregulated,causing downregulation of GABAAR expression and resulting in pain transition.EA upregulates KCC2 and GABAAR expression and prevents pain transition.展开更多
This research study focuses on addressing the limitations of current neuropathic pain(NP)treatments by developing a novel dual-target modulator,E0199,targeting both Na_(V)1.7,Na_(V)1.8,and Na_(V)1.9 and K_(V)7 channel...This research study focuses on addressing the limitations of current neuropathic pain(NP)treatments by developing a novel dual-target modulator,E0199,targeting both Na_(V)1.7,Na_(V)1.8,and Na_(V)1.9 and K_(V)7 channels,a crucial regulator in controlling NP symptoms.The objective of the study was to synthesize a compound capable of modulating these channels to alleviate NP.Through an experimental design involving both in vitro and in vivo methods,E0199 was tested for its efficacy on ion channels and its therapeutic potential in a chronic constriction injury(CCI)mouse model.The results demonstrated that E0199 significantly inhibited Na_(V)1.7,Na_(V)1.8,and Na_(V)1.9 channels with a particularly low half maximal inhibitory concentration(IC50)for Na_(V)1.9 by promoting sodium channel inactivation,and also effectively increased K_(V)7.2/7.3,K_(V)7.2,and K_(V)7.5 channels,excluding K_(V)7.1 by promoting potassium channel activation.This dual action significantly reduced the excitability of dorsal root ganglion neurons and alleviated pain hypersensitivity in mice at low doses,indicating a potent analgesic effect without affecting heart and skeletal muscle ion channels critically.The safety of E0199 was supported by neurobehavioral evaluations.Conclusively,E0199 represents a ground-breaking approach in NP treatment,showcasing the potential of dual-target small-molecule compounds in providing a more effective and safe therapeutic option for NP.This study introduces a promising direction for the future development of NP therapeutics.展开更多
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.
文摘Background:The first web space not only plays an integral role in hand functionality,but also holds an important aesthetic function for patients with cicatricial contractures,which hinders the ability to move joints,thereby restricting the performance of everyday activities.Therefore,a wide variety of reconstruction options are available.In this study,our main aim was to have a clear surgical plan prior to surgery according to preoperative findings and the degree of thumb abduction span.Methods:This study was conducted at Kasr Al-Ainy Hospital.This cohort study included 33 patients with cicatricial first web space contractures who underwent reconstructive procedures to restore the first web space.Patients were assessed preoperatively and categorized according to the degree of contracture,and the reconstruction procedure was chosen accordingly.They were assessed using both objective and subjective methods.Results:In this study,33 cases of cicatricial contracture of the first web space due to physical or thermal trauma were included.Measurements of the change in the span of abduction were performed for all patients included in the study preoperatively and postoperatively.Skin grafting and skin substitutes had an average change in abduction span of 32.5°(±14.4°),Z-plasty release had a mean of 30.59°(±8.82°)increase in abduction span,regional flaps had an increase of 40.71°(±12.39°),while distant flaps had an increase of 35°(±3.54°).Conclusion:No single reconstruction method can be used in all cases.When viewing a patient,one must consider that each individual has a unique representation.However,if we follow a systematic method for the initial evaluation,the most efficient flap can be chosen for each case,thus reducing the need for secondary procedures.Categorizing the cases according to the abduction span into mild,moderate,or severe forms is the first building block of this algorithm.Adjacent tissue condition,patient occupation,compliance,and the need to return to work are important factors.
基金supported by European Union–Next Generation EU(LX22NPO5107(MEYS))the Czech Science Foundation(20-21339S)+2 种基金the Grant Agency of Charles University(GAUK 248122 and 272221)ERDF-Project Brain Dynamics(CZ.02.01.01/00/22_008/0004643)the Ministry of Health of the Czech Republic Project NU21J-08-00081.
文摘The dorsal and ventral visual streams have been considered to play distinct roles in visual processing for action:the dorsal stream is assumed to support real-time actions,while the ventral stream facilitates memory-guided actions.However,recent evidence suggests a more integrated function of these streams.We investigated the neural dynamics and functional connectivity between them during memory-guided actions using intracranial EEG.We tracked neural activity in the inferior parietal lobule in the dorsal stream,and the ventral temporal cortex in the ventral stream as well as the hippocampus during a delayed action task involving object identity and location memory.We found increased alpha power in both streams during the delay,indicating their role in maintaining spatial visual information.In addition,we recorded increased alpha power in the hippocampus during the delay,but only when both object identity and location needed to be remembered.We also recorded an increase in theta band phase synchronization between the inferior parietal lobule and ventral temporal cortex and between the inferior parietal lobule and hippocampus during the encoding and delay.Granger causality analysis indicated dynamic and frequency-specific directional interactions among the inferior parietal lobule,ventral temporal cortex,and hippocampus that varied across task phases.Our study provides unique electrophysiological evidence for close interactions between dorsal and ventral streams,supporting an integrated processing model in which both streams contribute to memory-guided actions.
基金supported by the Young Scientists Fund of the National Natural Science Foundation of China(32200789)the National Natural Science Foundation of China(32070990).
文摘The thalamic reticular nucleus(TRN)plays a crucial role in regulating sensory encoding,even at the earliest stages of visual processing,as evidenced by numerous studies.Orientation selectivity,a vital neural response,is essential for detecting objects through edge perception.Here,we demonstrate that somatostatin(SOM)-expressing and parvalbumin(PV)-expressing neurons in the TRN project to the dorsal lateral geniculate nucleus and modulate orientation selectivity and the capacity for visual information processing in the primary visual cortex(V1).These findings show that SOM-positive and PV-positive neurons in the TRN are powerful modulators of visual information encoding in V1,revealing a novel role for this thalamic nucleus in influencing visual processing.
基金supported by the Natural Science Foundation of Zhejiang Province(No.LY23H270007)。
文摘Objective:Preventing the transition from acute to chronic pain(pain transition)is a new strategy for treating chronic pain.The present study aimed to investigate the role of K+-Cl−Cotransporter Isoform 2(KCC2)andγ-aminobutyric acid receptor type A(GABAAR)in the spinal cord dorsal horn(SCDH)in pain transition and the intervention effect of electroacupuncture(EA),and to understand the mechanism of EA in preventing acute and chronic pain transition in the spinal center.Methods:A rat model of hyperalgesic priming(HP)was established by injecting carrageenan(Car)into the plantar area of rats,followed by the injection of prostaglandin E2(PGE2)into the dorsal foot 7 days later.The GABAAR agonist(muscimol)and KCC2 activator(CLP257)were intrathecally injected for three consecutive days after PGE2 injection.EA was applied at a frequency of 2/100 Hz to the bilateral foot Zusanli(ST36)and Kunlun(BL60).A von Frey filament was used to detect the pain threshold in each group of rats.Western blotting(WB)and immunofluorescence(IF)were used to detect GABAAR and KCC2 expression in each rats group.By combining EA intervention with a KCC2 inhibitor(VU0240551),we explored the mechanism of pain transition of EA regulation of GABAAR and KCC2 expression in SCDH.Results:The HP model was established by injecting mice with Car/PGE2.Compared to the normal saline(NS)+NS and NS+PGE2 groups,the pain threshold of the Car+PGE2 group decreased significantly 48 hours after PGE2 injection(P<0.01).The WB results indicated that intrathecal injection of a GABAAR agonist upregulated GABAAR expression in the SCDH of HP model rats(P<0.05).WB and IF results revealed that intrathecal injection of the KCC2 activator significantly increased GABAAR and KCC2 expression in the SCDH of HP model rats(P<0.01)and that GABAAR and KCC2 were co-expressed in the same SCDH cells.Compared to the Car+PGE2 group,EA intervention significantly increased MWTs from 48 to 72 hours after the first injection and 4,24,and 48 hours after the second injection(P<0.01).EA upregulated GABAAR and KCC2 expression in the SCDH of rats with HP(P<0.05).Intrathecal injection of the KCC2 inhibitor blocked the analgesic effect of EA in HP model rats(P<0.01).Conclusions:In SCDH,KCC2 expression was downregulated,causing downregulation of GABAAR expression and resulting in pain transition.EA upregulates KCC2 and GABAAR expression and prevents pain transition.
基金funded by the Key Project from the Hebei Provincial Department of Science and Technology,China(Grant No.:21372601D)the Foundation Postdoctoral Mobile Station of Basic Medical Sciences,Hebei Medical University,China(Grant No.:20123120019)+4 种基金the Natural Science Foundation of Hebei Province,China(Grant No.:H2021206352)the Science and Technology Research Project of Colleges and Universities in Hebei Province,China(Grant No.:QN2023197)Hebei Medical University,Science and Technology,China(Grant No.:CYQD2023014)Hebei Provincial Department of Human Resources and Social Security,China(Grant No.:B2023003034)the Consultative Foundation from Hebei Province,China(Grant No.:2020TXZH01).
文摘This research study focuses on addressing the limitations of current neuropathic pain(NP)treatments by developing a novel dual-target modulator,E0199,targeting both Na_(V)1.7,Na_(V)1.8,and Na_(V)1.9 and K_(V)7 channels,a crucial regulator in controlling NP symptoms.The objective of the study was to synthesize a compound capable of modulating these channels to alleviate NP.Through an experimental design involving both in vitro and in vivo methods,E0199 was tested for its efficacy on ion channels and its therapeutic potential in a chronic constriction injury(CCI)mouse model.The results demonstrated that E0199 significantly inhibited Na_(V)1.7,Na_(V)1.8,and Na_(V)1.9 channels with a particularly low half maximal inhibitory concentration(IC50)for Na_(V)1.9 by promoting sodium channel inactivation,and also effectively increased K_(V)7.2/7.3,K_(V)7.2,and K_(V)7.5 channels,excluding K_(V)7.1 by promoting potassium channel activation.This dual action significantly reduced the excitability of dorsal root ganglion neurons and alleviated pain hypersensitivity in mice at low doses,indicating a potent analgesic effect without affecting heart and skeletal muscle ion channels critically.The safety of E0199 was supported by neurobehavioral evaluations.Conclusively,E0199 represents a ground-breaking approach in NP treatment,showcasing the potential of dual-target small-molecule compounds in providing a more effective and safe therapeutic option for NP.This study introduces a promising direction for the future development of NP therapeutics.
