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
Oxytocin has been found to modulate and improve pain in humans,but the mechanisms underlying these antinociceptive properties,especially in visceral hypersensitivity,are still unclear.Irritable bowel syndrome(IBS)mode...Oxytocin has been found to modulate and improve pain in humans,but the mechanisms underlying these antinociceptive properties,especially in visceral hypersensitivity,are still unclear.Irritable bowel syndrome(IBS)models were established by colorectal distention in newborn rats aged 8 to 14 days,and visceral hypersensitivity was assessed using electromyogram(EMG).Oxytocin or saclofen was administered intrathecally to evaluate visceral hypersensitivity in the rats.The protein expressions of oxytocin receptor(OTR),γ-aminobutyric acid type B1 receptor(GABAB1),and transient receptor potential vanilloid 1(TRPV1)in the lumbosacral spinal cord regions were measured.IBS rats exhibited a unique spinal cord molecular signature comprising decreased OTR/GABAB1 and increased TRPV1 expression.Intrathecal oxytocin treatment not only normalized these molecular alterations(increasing GABAB1 while decreasing TRPV1)but also ameliorated visceral pain behaviors.Crucially,this therapeutic effect was fully reversed by GABAB1 inhibition,establishing the necessity of intact GABAergic signaling for oxytocin-mediated analgesia.Collectively,these findings indicate that oxytocin relieves visceral hypersensitivity through the regulation of GABAB1 and TRPV1 in the spinal cord of IBS rats.展开更多
Chronic migraine(CM)is a prevalent and highly debilitating neurological disorder.Functional magnetic resonance imaging(fMRI)studies have demonstrated associations between abnormal brain region activation and CM,yet th...Chronic migraine(CM)is a prevalent and highly debilitating neurological disorder.Functional magnetic resonance imaging(fMRI)studies have demonstrated associations between abnormal brain region activation and CM,yet the underlying complex neural circuitry mechanisms remain unclear.The spinal trigeminal nucleus caudalis(Sp5C)serves as the primary central hub for orofacial nociceptive input,receiving trigeminal pain signals and projecting to higher-order centers such as the thalamus.Therefore,we sought to investigate whether the Sp5C region and its associated circuits were involved in CM pathogenesis.In this study,we established a CM mouse model through repeated intraperitoneal injections of nitroglycerin(NTG).Using a combination of in vivo fiber photometry and in vitro c-Fos immunohistochemistry,we found a marked periorbital and plantar mechanical allodynia in CM mice,accompanied by increased glutamatergic neuronal activity in Sp5C.Chemogenetic manipulation of Sp5C glutamatergic neurons(Sp5CV^(glut2))bidirectionally modulated migraine-like behaviors and induced pain-related affective states,as evidenced by conditioned place preference/aversion(CPP/CPA)paradigms.Anterograde viral tracing revealed dense projections from Sp5C^(Vglut2)to the subthalamic nucleus(STN),which was activated in CM mice.Optogenetic activation of the Sp5C-STN pathway similarly produced migraine-like behaviors and pain-related aversive memory in mice.Altogether,we revealed a critical role of the Sp5CVglut2-STN circuit in the development and modulation of CM.Our findings provide novel mechanistic insights into the central mechanisms underlying CM,establishing potential theoretical foundations for clinical diagnosis and therapeutic development.展开更多
Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in s...Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in spinal cord injury.Previous studies have shown that microglia can promote neuronal survival by phagocytosing dead cells and debris and by releasing neuroprotective and anti-inflammatory factors.However,excessive activation of microglia can lead to persistent inflammation and contribute to the formation of glial scars,which hinder axonal regeneration.Despite this,the precise role and mechanisms of microglia during the acute phase of spinal cord injury remain controversial and poorly understood.To elucidate the role of microglia in spinal cord injury,we employed the colony-stimulating factor 1 receptor inhibitor PLX5622 to deplete microglia.We observed that sustained depletion of microglia resulted in an expansion of the lesion area,downregulation of brain-derived neurotrophic factor,and impaired functional recovery after spinal cord injury.Next,we generated a transgenic mouse line with conditional overexpression of brain-derived neurotrophic factor specifically in microglia.We found that brain-derived neurotrophic factor overexpression in microglia increased angiogenesis and blood flow following spinal cord injury and facilitated the recovery of hindlimb motor function.Additionally,brain-derived neurotrophic factor overexpression in microglia reduced inflammation and neuronal apoptosis during the acute phase of spinal cord injury.Furthermore,through using specific transgenic mouse lines,TMEM119,and the colony-stimulating factor 1 receptor inhibitor PLX73086,we demonstrated that the neuroprotective effects were predominantly due to brain-derived neurotrophic factor overexpression in microglia rather than macrophages.In conclusion,our findings suggest the critical role of microglia in the formation of protective glial scars.Depleting microglia is detrimental to recovery of spinal cord injury,whereas targeting brain-derived neurotrophic factor overexpression in microglia represents a promising and novel therapeutic strategy to enhance motor function recovery in patients with spinal cord injury.展开更多
After spinal cord injury,impairment of the sensorimotor circuit can lead to dysfunction in the motor,sensory,proprioceptive,and autonomic nervous systems.Functional recovery is often hindered by constraints on the tim...After spinal cord injury,impairment of the sensorimotor circuit can lead to dysfunction in the motor,sensory,proprioceptive,and autonomic nervous systems.Functional recovery is often hindered by constraints on the timing of interventions,combined with the limitations of current methods.To address these challenges,various techniques have been developed to aid in the repair and reconstruction of neural circuits at different stages of injury.Notably,neuromodulation has garnered considerable attention for its potential to enhance nerve regeneration,provide neuroprotection,restore neurons,and regulate the neural reorganization of circuits within the cerebral cortex and corticospinal tract.To improve the effectiveness of these interventions,the implementation of multitarget early interventional neuromodulation strategies,such as electrical and magnetic stimulation,is recommended to enhance functional recovery across different phases of nerve injury.This review concisely outlines the challenges encountered following spinal cord injury,synthesizes existing neurostimulation techniques while emphasizing neuroprotection,repair,and regeneration of impaired connections,and advocates for multi-targeted,task-oriented,and timely interventions.展开更多
Spinal cord injury results in permanent loss of neurological functions due to severance of neural networks.Transplantation of neural stem cells holds promise to repair disrupted connections.Yet,ensuring the survival a...Spinal cord injury results in permanent loss of neurological functions due to severance of neural networks.Transplantation of neural stem cells holds promise to repair disrupted connections.Yet,ensuring the survival and integration of neural stem cells into the host neural circuit remains a formidable challenge.Here,we investigated whether modifying the intrinsic properties of neural stem cells could enhance their integration post-transplantation.We focused on phosphatase and tensin homolog(PTEN),a well-characterized tumor suppressor known to critically regulate neuronal survival and axonal regeneration.By deleting Pten in mouse neural stem cells,we observed increased neurite outgrowth and enhanced resistance to neurotoxic environments in culture.Upon transplantation into injured spinal cords,Pten-deficient neural stem cells exhibited higher survival and more extensive rostrocaudal distribution.To examine the potential influence of partial PTEN suppression,rat neural stem cells were treated with short hairpin RNA targeting PTEN,and the PTEN knockdown resulted in significant improvements in neurite growth,survival,and neurosphere motility in vitro.Transplantation of sh PTEN-treated neural stem cells into the injured spinal cord also led to an increase in graft survival and migration to an extent similar to that of complete deletion.Moreover,PTEN suppression facilitated neurite elongation from NSC-derived neurons migrating from the lesion epicenter.These findings suggest that modifying intrinsic signaling pathways,such as PTEN,within neural stem cells could bolster their therapeutic efficacy,offering potential avenues for future regenerative strategies for spinal cord injury.展开更多
The spinal cord links the brain and the peripheral nervous system and has important sensory and motor functions.Impairments in the spinal cord occur in different diseases,such as spinal cord injury,multiple sclerosis,...The spinal cord links the brain and the peripheral nervous system and has important sensory and motor functions.Impairments in the spinal cord occur in different diseases,such as spinal cord injury,multiple sclerosis,pain,motor neuron diseases,and neurodegenerative diseases.Imaging of the spinal cord has been challenging,partly due to its small size and deep anatomical location.Additionally,in an animal model,motion artifacts further influence the in vivo imaging quality of the spinal cord.Recent advances have pushed boundaries for in vivo imaging in living animals(even behaving animals).展开更多
Human spinal cord organoids(hSCOs)offer a promising platform to study neurotrauma by addressing many limitations of traditional research models.These organoids provide access to human-specific physiological and geneti...Human spinal cord organoids(hSCOs)offer a promising platform to study neurotrauma by addressing many limitations of traditional research models.These organoids provide access to human-specific physiological and genetic mechanisms and can be derived from an individual's somatic cells(e.g.,blood or skin).This enables patient-specific paradigms for precision neurotrauma research,pa rticula rly relevant to the over 300,000 people in the United States living with chronic effects of spinal cord injury(SCI).展开更多
Spinal cord injury(SCI)interrupts the flow of information between the brain and the spinal cord,thus leading to a loss of sensory information and motor paralysis of the body below the lesion.Surprisingly,most SCIs are...Spinal cord injury(SCI)interrupts the flow of information between the brain and the spinal cord,thus leading to a loss of sensory information and motor paralysis of the body below the lesion.Surprisingly,most SCIs are incomplete and spare supraspinal pathways,especially those located within the peripheral white matter of the spinal cord,which includes reticulospinal pathways originating from the medullary reticular formation.Whereas there is abundant literature about the motor cortex,its corticospinal pathway,and its capacity to modulate functional recovery after SCI,less is known about the medullary reticular formation and its reticulospinal pathway.展开更多
In the human spinal cord,astrocytes are the major glial cells.In vitro studies of human astrocytes are relatively simple.However,the straightforward nature of the in vitro environment and complex nature of the in vivo...In the human spinal cord,astrocytes are the major glial cells.In vitro studies of human astrocytes are relatively simple.However,the straightforward nature of the in vitro environment and complex nature of the in vivo environment limit comprehensive investigations into the structure and function of human astrocytes.Additionally,in vivo studies of human astrocytes are further limited by ethical issues.This means there is an urgent need to develop effective in vivo models to study the structure and function of human astrocytes.Here,we first directed human embryonic stem cells to differentiate into human spinal cord dorsal neural stem/progenitor cells in vitro,before transplanting these cells into the gray matter of the cervical spinal cord(C5-T2 segments)of naïve nude rats to create a chimeric human astrocytic rat spinal cord model.The transplanted human spinal cord dorsal neural stem/progenitor cells survived for at least 20 months in the spinal cord environment of the rats,with over 90%differentiating into human astrocytes.These human astrocytes were able to migrate caudally for long distances along the white matter towards the spinal cord.They expressed astrocytic cytoskeletal proteins and functionally-related proteins,suggesting their maturation and structural integration into the rat spinal cord.Thus,this humanized astrocyte chimeric rat spinal cord model provides a valuable tool for studying the role of human spinal cord astrocytes in various spinal diseases.展开更多
Professor Zhan Hongsheng(詹红生),as the national representative inheritor of Shanghai Shi’s Orthopedics and Traumatology,has led his team in long-term dedication to the research of Chinese spinal manipulative medicin...Professor Zhan Hongsheng(詹红生),as the national representative inheritor of Shanghai Shi’s Orthopedics and Traumatology,has led his team in long-term dedication to the research of Chinese spinal manipulative medicine.He has achieved outstanding accomplishments in areas such as school inheritance,theoretical construction,technological innovation,standard establishment,scientific research translation,and talent cultivation,thereby advancing the modernization,standardization,and internationalization of Chinese spinal manipulative medicine.展开更多
Spinal cord injury(SCI) often results in permanent dysfunction of locomotion,sensation,and autonomic regulation,imposing a substantial burden on both individuals and society(Anjum et al.,2020).SCI has a complex pathop...Spinal cord injury(SCI) often results in permanent dysfunction of locomotion,sensation,and autonomic regulation,imposing a substantial burden on both individuals and society(Anjum et al.,2020).SCI has a complex pathophysiology:an initial primary injury(mechanical trauma,axonal disruption,and hemorrhage) is followed by a progressive secondary injury cascade that involves ischemia,neuronal loss,and inflammation.Given the challenges in achieving regeneration of the injured spinal cord,neuroprotection has been at the forefront of clinical research.展开更多
Biological sex is increasingly recognized as a crucial factor in evaluating the translational value of preclinical spinal cord injury(SCI)studies.The rising incidence of SCI in females challenges the historical preced...Biological sex is increasingly recognized as a crucial factor in evaluating the translational value of preclinical spinal cord injury(SCI)studies.The rising incidence of SCI in females challenges the historical precedent of SCI being a male-dominated condition.In contrast,most basic science researchers utilize single-sex studies to minimize complications associated with bladder care in males(Stewart et al.,2020).The findings of our recent publication identify sexually dimorphic immune responses to SCI in both mice and pigs(Kumari et al.,2025).Here,we will highlight these findings and discuss the impact of sex on SCI inflammation and recovery.展开更多
Traumatic spinal cord injury(SCI)is a debilitating condition characterized by the impairment of neural circuits,leading to the loss of motor and sensory functions and accompanied by severe complications.Substantial re...Traumatic spinal cord injury(SCI)is a debilitating condition characterized by the impairment of neural circuits,leading to the loss of motor and sensory functions and accompanied by severe complications.Substantial research has reported the therapeutic potential of Omega-3 fatty acids for the central nervous system,particularly after traumatic SCI.Omega-3 fatty acids may contribute to improving SCI recovery through their anti-inflammatory,anti-oxidative,neurotrophic,and membrane integrity-preserving properties.These functions of Omega-3 fatty acids are primarily mediated via the activation of G protein-coupled receptor 120(GPR120),commonly known as the fish oil-specific receptor.Advancements in understanding of the molecular mechanisms of GPR120’s recognition of Omega-3 fatty acids and its downstream signaling mechanisms has significantly promoted research on the pharmacological potential of Omega-3 fatty acids and the development of highly selective and high-affinity alternatives.This review aims to provide in-depth analysis of the comprehensive therapeutic potential of Omega-3 fatty acids for SCI and its accompanying complications,and the prospects for developing novel drugs based on the recognition of Omega-3 fatty acids by GPR120.展开更多
During aging,the spine undergoes degenerative changes,particularly with vertebral endplate bone expansion and sclerosis,that are associated with nonspecific low back pain.We report that parathyroid hormone(PTH)treatme...During aging,the spine undergoes degenerative changes,particularly with vertebral endplate bone expansion and sclerosis,that are associated with nonspecific low back pain.We report that parathyroid hormone(PTH)treatment reduced vertebral endplate sclerosis and improved pain behaviors in three mouse models of spinal degeneration(aged,SM/J,and young lumbar spine instability mice).Aberrant innervation in the vertebral body and endplate during spinal degeneration was decreased with PTH treatment as quantified by PGP9.5^(+)and CGRP^(+)nerve fibers,as well as CGRP expression in dorsal root ganglia.The neuronal repulsion factor Slit3 significantly increased in response to PTH treatment mediated by transcriptional factor FoxA2.PTH type 1 receptor and Slit3 deletion in osteocalcin-expressing cells prevented PTH-reduction of endplate porosity and improvement in behavior tests.Altogether,PTH stimulated osteoblast production of Slit3,decreased aberrant sensory nerve innervation,and provided symptomatic relief of LBP associated with mouse spinal degeneration.展开更多
Spinal cord injury(SCI)is a debilitating ailment that leads to the loss of motor and sensory functions,often leaving the patient paralyzed below the injury site(Chen et al.,2013).Globally around 250,000-300,000 people...Spinal cord injury(SCI)is a debilitating ailment that leads to the loss of motor and sensory functions,often leaving the patient paralyzed below the injury site(Chen et al.,2013).Globally around 250,000-300,000 people are diagnosed with SCI annually(Singh et al.,2014),and while this number appears quite low,the effect that an SCI has on the patient’s quality of life is drastic,due to the current difficulties to comprehensively treat this illness.The cost of patient care can also be quite costly,amounting to an estimated$1.69 billion in healthcare costs in the USA alone(Mahabaleshwarkar and Khanna,2014).展开更多
Neuronal degeneration and inflammation are hallmark features of spinal cord injury that severely hinder functional recovery.As key regulators of the post-injury microenvironment,macrophages can promote either tissue r...Neuronal degeneration and inflammation are hallmark features of spinal cord injury that severely hinder functional recovery.As key regulators of the post-injury microenvironment,macrophages can promote either tissue repair or exacerbate damage.Among macrophage secreted factors,transforming growth factor-beta 1 has emerged as a critical mediator of pathological changes.In this study,we show the pivotal role of macrophage-derived transforming growth factor-beta 1 in driving neuronal senescence and impairing functional recovery after spinal cord injury.In a mouse spinal cord injury model,transforming growth factor-beta 1 levels were significantly increased at the injury site,accompanied by increased mothers against decapentaplegic homolog 2(SMAD2)phosphorylation and upregulation of neuronal senescence markers such as p16INK4a andβ-galactosidase activity.Treatment with LY-364947,a SMAD2 phosphorylation inhibitor,markedly reduced the number of senescent neurons,mitigated tissue degeneration,and improved motor function recovery.Additionally,macrophage depletion using clodronate liposomes lowered transforming growth factor-beta 1 levels at the injury site and attenuated neuronal senescence.These findings highlight the transforming growth factor-beta 1-SMAD2 signaling axis as a potential therapeutic target to reduce neuronal senescence and enhance functional recovery following spinal cord injury.展开更多
Spared regions of the damaged central nervous system undergo dynamic remodelling and exhibit a remarkable potential for therapeutic exploitation1.Lesion-remote astrocytes(LRAs),which interact with viable neurons and g...Spared regions of the damaged central nervous system undergo dynamic remodelling and exhibit a remarkable potential for therapeutic exploitation1.Lesion-remote astrocytes(LRAs),which interact with viable neurons and glia,undergo reactive transformations whose molecular and functional properties are poorly understood2.Here,using multiple transcriptional profiling methods,we investigated LRAs from spared regions of mouse spinal cord following traumatic spinal cord injury.展开更多
Chronic pain following a spinal cord injury refers to pain that persists or recurs after the injury.This pain can manifest as burning,stinging,or sensations similar to electric shocks.Recent studies have shown that sp...Chronic pain following a spinal cord injury refers to pain that persists or recurs after the injury.This pain can manifest as burning,stinging,or sensations similar to electric shocks.Recent studies have shown that spinal cord stimulation is an effective way to treat chronic pain after spinal cord injury.The purpose of this review is to introduce the technique of spinal cord stimulation,the clinical manifestations of spinal cord injury,and the role of spinal cord stimulation in the treatment of spinal cord injury.The mechanism and clinical application of spinal cord stimulation in the treatment of pain after spinal cord injury are discussed.The mechanism of spinal cord stimulation primarily involves three aspects:neuromodulation,neurochemical regulation,and anti-inflammatory effects,along with nerve repair.In terms of neuromodulation,spinal cord stimulation is based on the gate control theory of pain.It activates large-diameter amyloid-βnerve fibers to promote the release of inhibitory neurotransmitters by gamma-aminobutyric acidergic inhibitory interneurons in the spinal cord,thereby blocking the transmission of pain signals from small-diameter C fibers.Neurochemical studies indicate that spinal cord stimulation can regulate the balance of neurotransmitters within the spinal cord,increasing the release of inhibitory neurotransmitters such as gamma-aminobutyric acid,serotonin,and acetylcholine while reducing the levels of excitatory neurotransmitters.Additionally,spinal cord stimulation exhibits significant anti-inflammatory and neuroprotective effects,downregulating pro-inflammatory factor levels,upregulating anti-inflammatory factor expression,alleviating neuroinflammatory responses,and repairing damaged neural circuits by promoting the secretion of neurotrophic factors and axonal regeneration.Spinal cord stimulation have demonstrated remarkable efficacy in the clinical treatment of pain after spinal cord injury,but there are still limitations such as small sample size and high heterogeneity in clinical studies,as well as insufficient long-term efficacy data.Future research should conduct multi-center large-sample randomized controlled trials,and establish long-term follow-up mechanisms to improve evidence-based medical evidence.展开更多
Central nervous system(CNS) axons fail to regenerate following brain or spinal cord injury(SCI),which typically leads to permanent neurological deficits.Peripheral nervous system axons,howeve r,can regenerate followin...Central nervous system(CNS) axons fail to regenerate following brain or spinal cord injury(SCI),which typically leads to permanent neurological deficits.Peripheral nervous system axons,howeve r,can regenerate following injury.Understanding the mechanisms that underlie this difference is key to developing treatments for CNS neurological diseases and injuries characterized by axonal damage.To initiate repair after peripheral nerve injury,dorsal root ganglion(DRG) neurons mobilize a pro-regenerative gene expression program,which facilitates axon outgrowth.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 the National Natural Science Foundation of China(No.82471229)Science and Technology Collaborative Innovation Fund of Fujian Province(No.2021Y9172)the Natural Science Foundation of Fujian Province,China(No.2023J01169)。
文摘Oxytocin has been found to modulate and improve pain in humans,but the mechanisms underlying these antinociceptive properties,especially in visceral hypersensitivity,are still unclear.Irritable bowel syndrome(IBS)models were established by colorectal distention in newborn rats aged 8 to 14 days,and visceral hypersensitivity was assessed using electromyogram(EMG).Oxytocin or saclofen was administered intrathecally to evaluate visceral hypersensitivity in the rats.The protein expressions of oxytocin receptor(OTR),γ-aminobutyric acid type B1 receptor(GABAB1),and transient receptor potential vanilloid 1(TRPV1)in the lumbosacral spinal cord regions were measured.IBS rats exhibited a unique spinal cord molecular signature comprising decreased OTR/GABAB1 and increased TRPV1 expression.Intrathecal oxytocin treatment not only normalized these molecular alterations(increasing GABAB1 while decreasing TRPV1)but also ameliorated visceral pain behaviors.Crucially,this therapeutic effect was fully reversed by GABAB1 inhibition,establishing the necessity of intact GABAergic signaling for oxytocin-mediated analgesia.Collectively,these findings indicate that oxytocin relieves visceral hypersensitivity through the regulation of GABAB1 and TRPV1 in the spinal cord of IBS rats.
基金supported by the National Natural Science Foundation of China(No.32571336 and 32271048)Research Funds of Centre for Leading Medicine and Advanced Technologies of IHM(No.2025IHM01100)。
文摘Chronic migraine(CM)is a prevalent and highly debilitating neurological disorder.Functional magnetic resonance imaging(fMRI)studies have demonstrated associations between abnormal brain region activation and CM,yet the underlying complex neural circuitry mechanisms remain unclear.The spinal trigeminal nucleus caudalis(Sp5C)serves as the primary central hub for orofacial nociceptive input,receiving trigeminal pain signals and projecting to higher-order centers such as the thalamus.Therefore,we sought to investigate whether the Sp5C region and its associated circuits were involved in CM pathogenesis.In this study,we established a CM mouse model through repeated intraperitoneal injections of nitroglycerin(NTG).Using a combination of in vivo fiber photometry and in vitro c-Fos immunohistochemistry,we found a marked periorbital and plantar mechanical allodynia in CM mice,accompanied by increased glutamatergic neuronal activity in Sp5C.Chemogenetic manipulation of Sp5C glutamatergic neurons(Sp5CV^(glut2))bidirectionally modulated migraine-like behaviors and induced pain-related affective states,as evidenced by conditioned place preference/aversion(CPP/CPA)paradigms.Anterograde viral tracing revealed dense projections from Sp5C^(Vglut2)to the subthalamic nucleus(STN),which was activated in CM mice.Optogenetic activation of the Sp5C-STN pathway similarly produced migraine-like behaviors and pain-related aversive memory in mice.Altogether,we revealed a critical role of the Sp5CVglut2-STN circuit in the development and modulation of CM.Our findings provide novel mechanistic insights into the central mechanisms underlying CM,establishing potential theoretical foundations for clinical diagnosis and therapeutic development.
基金supported by the National Natural Science Foundation of China,Nos.82072165 and 82272256(both to XM)the Key Project of Xiangyang Central Hospital,No.2023YZ03(to RM)。
文摘Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in spinal cord injury.Previous studies have shown that microglia can promote neuronal survival by phagocytosing dead cells and debris and by releasing neuroprotective and anti-inflammatory factors.However,excessive activation of microglia can lead to persistent inflammation and contribute to the formation of glial scars,which hinder axonal regeneration.Despite this,the precise role and mechanisms of microglia during the acute phase of spinal cord injury remain controversial and poorly understood.To elucidate the role of microglia in spinal cord injury,we employed the colony-stimulating factor 1 receptor inhibitor PLX5622 to deplete microglia.We observed that sustained depletion of microglia resulted in an expansion of the lesion area,downregulation of brain-derived neurotrophic factor,and impaired functional recovery after spinal cord injury.Next,we generated a transgenic mouse line with conditional overexpression of brain-derived neurotrophic factor specifically in microglia.We found that brain-derived neurotrophic factor overexpression in microglia increased angiogenesis and blood flow following spinal cord injury and facilitated the recovery of hindlimb motor function.Additionally,brain-derived neurotrophic factor overexpression in microglia reduced inflammation and neuronal apoptosis during the acute phase of spinal cord injury.Furthermore,through using specific transgenic mouse lines,TMEM119,and the colony-stimulating factor 1 receptor inhibitor PLX73086,we demonstrated that the neuroprotective effects were predominantly due to brain-derived neurotrophic factor overexpression in microglia rather than macrophages.In conclusion,our findings suggest the critical role of microglia in the formation of protective glial scars.Depleting microglia is detrimental to recovery of spinal cord injury,whereas targeting brain-derived neurotrophic factor overexpression in microglia represents a promising and novel therapeutic strategy to enhance motor function recovery in patients with spinal cord injury.
基金supported by the National Key Research and Development Program of China,No.2023YFC3603705(to DX)the National Natural Science Foundation of China,No.82302866(to YZ).
文摘After spinal cord injury,impairment of the sensorimotor circuit can lead to dysfunction in the motor,sensory,proprioceptive,and autonomic nervous systems.Functional recovery is often hindered by constraints on the timing of interventions,combined with the limitations of current methods.To address these challenges,various techniques have been developed to aid in the repair and reconstruction of neural circuits at different stages of injury.Notably,neuromodulation has garnered considerable attention for its potential to enhance nerve regeneration,provide neuroprotection,restore neurons,and regulate the neural reorganization of circuits within the cerebral cortex and corticospinal tract.To improve the effectiveness of these interventions,the implementation of multitarget early interventional neuromodulation strategies,such as electrical and magnetic stimulation,is recommended to enhance functional recovery across different phases of nerve injury.This review concisely outlines the challenges encountered following spinal cord injury,synthesizes existing neurostimulation techniques while emphasizing neuroprotection,repair,and regeneration of impaired connections,and advocates for multi-targeted,task-oriented,and timely interventions.
基金supported by the National Research Foundation of Korea,Nos.2021R1A2C2006110,2021M3E5D9021364,2019R1A5A2026045(to BGK)the Korea Initiative for Fostering University of Research and Innovation(KIURI)Program of the NRF funded by the MSIT(to HK),No.NRF2021M3H1A104892211(to HSK)。
文摘Spinal cord injury results in permanent loss of neurological functions due to severance of neural networks.Transplantation of neural stem cells holds promise to repair disrupted connections.Yet,ensuring the survival and integration of neural stem cells into the host neural circuit remains a formidable challenge.Here,we investigated whether modifying the intrinsic properties of neural stem cells could enhance their integration post-transplantation.We focused on phosphatase and tensin homolog(PTEN),a well-characterized tumor suppressor known to critically regulate neuronal survival and axonal regeneration.By deleting Pten in mouse neural stem cells,we observed increased neurite outgrowth and enhanced resistance to neurotoxic environments in culture.Upon transplantation into injured spinal cords,Pten-deficient neural stem cells exhibited higher survival and more extensive rostrocaudal distribution.To examine the potential influence of partial PTEN suppression,rat neural stem cells were treated with short hairpin RNA targeting PTEN,and the PTEN knockdown resulted in significant improvements in neurite growth,survival,and neurosphere motility in vitro.Transplantation of sh PTEN-treated neural stem cells into the injured spinal cord also led to an increase in graft survival and migration to an extent similar to that of complete deletion.Moreover,PTEN suppression facilitated neurite elongation from NSC-derived neurons migrating from the lesion epicenter.These findings suggest that modifying intrinsic signaling pathways,such as PTEN,within neural stem cells could bolster their therapeutic efficacy,offering potential avenues for future regenerative strategies for spinal cord injury.
文摘The spinal cord links the brain and the peripheral nervous system and has important sensory and motor functions.Impairments in the spinal cord occur in different diseases,such as spinal cord injury,multiple sclerosis,pain,motor neuron diseases,and neurodegenerative diseases.Imaging of the spinal cord has been challenging,partly due to its small size and deep anatomical location.Additionally,in an animal model,motion artifacts further influence the in vivo imaging quality of the spinal cord.Recent advances have pushed boundaries for in vivo imaging in living animals(even behaving animals).
基金supported by the Belle Carnell Regenerative Neurorehabilitation Fundthe National Institutes of Health(R01NS113935 to CKF)。
文摘Human spinal cord organoids(hSCOs)offer a promising platform to study neurotrauma by addressing many limitations of traditional research models.These organoids provide access to human-specific physiological and genetic mechanisms and can be derived from an individual's somatic cells(e.g.,blood or skin).This enables patient-specific paradigms for precision neurotrauma research,pa rticula rly relevant to the over 300,000 people in the United States living with chronic effects of spinal cord injury(SCI).
基金supported by Craig H.Neilsen Foundation,Wings for Life Foundation,Canadian Institutes of Health Research,and Fonds de Recherche Québec-Santé(to FB).
文摘Spinal cord injury(SCI)interrupts the flow of information between the brain and the spinal cord,thus leading to a loss of sensory information and motor paralysis of the body below the lesion.Surprisingly,most SCIs are incomplete and spare supraspinal pathways,especially those located within the peripheral white matter of the spinal cord,which includes reticulospinal pathways originating from the medullary reticular formation.Whereas there is abundant literature about the motor cortex,its corticospinal pathway,and its capacity to modulate functional recovery after SCI,less is known about the medullary reticular formation and its reticulospinal pathway.
基金Ministry of Science and Technology of China(STI2030-Major Projects),No.2022ZD0204700(to WW)the National Natural Science Foundation of China,No.82301572(to XZ)China Postdoctoral Science Foundation,No.2023M731202(to XZ).
文摘In the human spinal cord,astrocytes are the major glial cells.In vitro studies of human astrocytes are relatively simple.However,the straightforward nature of the in vitro environment and complex nature of the in vivo environment limit comprehensive investigations into the structure and function of human astrocytes.Additionally,in vivo studies of human astrocytes are further limited by ethical issues.This means there is an urgent need to develop effective in vivo models to study the structure and function of human astrocytes.Here,we first directed human embryonic stem cells to differentiate into human spinal cord dorsal neural stem/progenitor cells in vitro,before transplanting these cells into the gray matter of the cervical spinal cord(C5-T2 segments)of naïve nude rats to create a chimeric human astrocytic rat spinal cord model.The transplanted human spinal cord dorsal neural stem/progenitor cells survived for at least 20 months in the spinal cord environment of the rats,with over 90%differentiating into human astrocytes.These human astrocytes were able to migrate caudally for long distances along the white matter towards the spinal cord.They expressed astrocytic cytoskeletal proteins and functionally-related proteins,suggesting their maturation and structural integration into the rat spinal cord.Thus,this humanized astrocyte chimeric rat spinal cord model provides a valuable tool for studying the role of human spinal cord astrocytes in various spinal diseases.
文摘Professor Zhan Hongsheng(詹红生),as the national representative inheritor of Shanghai Shi’s Orthopedics and Traumatology,has led his team in long-term dedication to the research of Chinese spinal manipulative medicine.He has achieved outstanding accomplishments in areas such as school inheritance,theoretical construction,technological innovation,standard establishment,scientific research translation,and talent cultivation,thereby advancing the modernization,standardization,and internationalization of Chinese spinal manipulative medicine.
文摘Spinal cord injury(SCI) often results in permanent dysfunction of locomotion,sensation,and autonomic regulation,imposing a substantial burden on both individuals and society(Anjum et al.,2020).SCI has a complex pathophysiology:an initial primary injury(mechanical trauma,axonal disruption,and hemorrhage) is followed by a progressive secondary injury cascade that involves ischemia,neuronal loss,and inflammation.Given the challenges in achieving regeneration of the injured spinal cord,neuroprotection has been at the forefront of clinical research.
基金supported by University of Kentucky-SCoBIRC Endowed Chair#5Craig H.Neilsen 1173493 and NIH RF1NS135504(to JCG).
文摘Biological sex is increasingly recognized as a crucial factor in evaluating the translational value of preclinical spinal cord injury(SCI)studies.The rising incidence of SCI in females challenges the historical precedent of SCI being a male-dominated condition.In contrast,most basic science researchers utilize single-sex studies to minimize complications associated with bladder care in males(Stewart et al.,2020).The findings of our recent publication identify sexually dimorphic immune responses to SCI in both mice and pigs(Kumari et al.,2025).Here,we will highlight these findings and discuss the impact of sex on SCI inflammation and recovery.
基金supported by the National Key Research and Development Project of Stem Cell and Transformation Research(2019YFA0112100)Taishan Scholars Programof Shandong Province-Young Taishan Scholars(tsqn201909197)+1 种基金Cutting Edge Development Fund of Advanced Medical Research Institute(Shandong University)National Natural Science Foundation of China(82220108005)。
文摘Traumatic spinal cord injury(SCI)is a debilitating condition characterized by the impairment of neural circuits,leading to the loss of motor and sensory functions and accompanied by severe complications.Substantial research has reported the therapeutic potential of Omega-3 fatty acids for the central nervous system,particularly after traumatic SCI.Omega-3 fatty acids may contribute to improving SCI recovery through their anti-inflammatory,anti-oxidative,neurotrophic,and membrane integrity-preserving properties.These functions of Omega-3 fatty acids are primarily mediated via the activation of G protein-coupled receptor 120(GPR120),commonly known as the fish oil-specific receptor.Advancements in understanding of the molecular mechanisms of GPR120’s recognition of Omega-3 fatty acids and its downstream signaling mechanisms has significantly promoted research on the pharmacological potential of Omega-3 fatty acids and the development of highly selective and high-affinity alternatives.This review aims to provide in-depth analysis of the comprehensive therapeutic potential of Omega-3 fatty acids for SCI and its accompanying complications,and the prospects for developing novel drugs based on the recognition of Omega-3 fatty acids by GPR120.
基金supported by the U.S.Department of Health&Human Services NIH National Institute on Aging under Award Number P01AG066603(to J.C.)。
文摘During aging,the spine undergoes degenerative changes,particularly with vertebral endplate bone expansion and sclerosis,that are associated with nonspecific low back pain.We report that parathyroid hormone(PTH)treatment reduced vertebral endplate sclerosis and improved pain behaviors in three mouse models of spinal degeneration(aged,SM/J,and young lumbar spine instability mice).Aberrant innervation in the vertebral body and endplate during spinal degeneration was decreased with PTH treatment as quantified by PGP9.5^(+)and CGRP^(+)nerve fibers,as well as CGRP expression in dorsal root ganglia.The neuronal repulsion factor Slit3 significantly increased in response to PTH treatment mediated by transcriptional factor FoxA2.PTH type 1 receptor and Slit3 deletion in osteocalcin-expressing cells prevented PTH-reduction of endplate porosity and improvement in behavior tests.Altogether,PTH stimulated osteoblast production of Slit3,decreased aberrant sensory nerve innervation,and provided symptomatic relief of LBP associated with mouse spinal degeneration.
基金supported by the Irish Research Council under the Government of Ireland Postdoctoral Fellowship Project ID-GOIPD/2023/1431(to AS).
文摘Spinal cord injury(SCI)is a debilitating ailment that leads to the loss of motor and sensory functions,often leaving the patient paralyzed below the injury site(Chen et al.,2013).Globally around 250,000-300,000 people are diagnosed with SCI annually(Singh et al.,2014),and while this number appears quite low,the effect that an SCI has on the patient’s quality of life is drastic,due to the current difficulties to comprehensively treat this illness.The cost of patient care can also be quite costly,amounting to an estimated$1.69 billion in healthcare costs in the USA alone(Mahabaleshwarkar and Khanna,2014).
基金supported by grants from Tianjin Key Medical Discipline(Specialty)Construct Project,No.TJYXZDXK-027A(to SF)National Key Research and Development Project of Stem Cell and Transformation Research,No.2019YFA0112100(to SF)+3 种基金the National Natural Science Foundation of China,Nos.81930070(to SF),82402825(to XS)Tianjin Health Science and Technology Project Key Discipline Special Project,No.hUCMSC preferred subgroup,No.TJWJ2022XK002(to SF)2022 Beijing-Tianjin-Hebei Basic Research Cooperation Project,No.22JCZXJC00050(to SF)Youth Research Incubation Fund of School of Basic Medical Sciences,Tianjin Medical University,No.023FY05(to XS).
文摘Neuronal degeneration and inflammation are hallmark features of spinal cord injury that severely hinder functional recovery.As key regulators of the post-injury microenvironment,macrophages can promote either tissue repair or exacerbate damage.Among macrophage secreted factors,transforming growth factor-beta 1 has emerged as a critical mediator of pathological changes.In this study,we show the pivotal role of macrophage-derived transforming growth factor-beta 1 in driving neuronal senescence and impairing functional recovery after spinal cord injury.In a mouse spinal cord injury model,transforming growth factor-beta 1 levels were significantly increased at the injury site,accompanied by increased mothers against decapentaplegic homolog 2(SMAD2)phosphorylation and upregulation of neuronal senescence markers such as p16INK4a andβ-galactosidase activity.Treatment with LY-364947,a SMAD2 phosphorylation inhibitor,markedly reduced the number of senescent neurons,mitigated tissue degeneration,and improved motor function recovery.Additionally,macrophage depletion using clodronate liposomes lowered transforming growth factor-beta 1 levels at the injury site and attenuated neuronal senescence.These findings highlight the transforming growth factor-beta 1-SMAD2 signaling axis as a potential therapeutic target to reduce neuronal senescence and enhance functional recovery following spinal cord injury.
文摘Spared regions of the damaged central nervous system undergo dynamic remodelling and exhibit a remarkable potential for therapeutic exploitation1.Lesion-remote astrocytes(LRAs),which interact with viable neurons and glia,undergo reactive transformations whose molecular and functional properties are poorly understood2.Here,using multiple transcriptional profiling methods,we investigated LRAs from spared regions of mouse spinal cord following traumatic spinal cord injury.
基金supported by Key Tackling Project of the Education Department of Liaoning Province,No.2024C011the Medical-Industrial Joint Innovation Funding Project of the First Hospital of Dalian Medical University and Dalian Institute of Chemical Physics,No.DMU-1&DICP UN202311(both to ZL).
文摘Chronic pain following a spinal cord injury refers to pain that persists or recurs after the injury.This pain can manifest as burning,stinging,or sensations similar to electric shocks.Recent studies have shown that spinal cord stimulation is an effective way to treat chronic pain after spinal cord injury.The purpose of this review is to introduce the technique of spinal cord stimulation,the clinical manifestations of spinal cord injury,and the role of spinal cord stimulation in the treatment of spinal cord injury.The mechanism and clinical application of spinal cord stimulation in the treatment of pain after spinal cord injury are discussed.The mechanism of spinal cord stimulation primarily involves three aspects:neuromodulation,neurochemical regulation,and anti-inflammatory effects,along with nerve repair.In terms of neuromodulation,spinal cord stimulation is based on the gate control theory of pain.It activates large-diameter amyloid-βnerve fibers to promote the release of inhibitory neurotransmitters by gamma-aminobutyric acidergic inhibitory interneurons in the spinal cord,thereby blocking the transmission of pain signals from small-diameter C fibers.Neurochemical studies indicate that spinal cord stimulation can regulate the balance of neurotransmitters within the spinal cord,increasing the release of inhibitory neurotransmitters such as gamma-aminobutyric acid,serotonin,and acetylcholine while reducing the levels of excitatory neurotransmitters.Additionally,spinal cord stimulation exhibits significant anti-inflammatory and neuroprotective effects,downregulating pro-inflammatory factor levels,upregulating anti-inflammatory factor expression,alleviating neuroinflammatory responses,and repairing damaged neural circuits by promoting the secretion of neurotrophic factors and axonal regeneration.Spinal cord stimulation have demonstrated remarkable efficacy in the clinical treatment of pain after spinal cord injury,but there are still limitations such as small sample size and high heterogeneity in clinical studies,as well as insufficient long-term efficacy data.Future research should conduct multi-center large-sample randomized controlled trials,and establish long-term follow-up mechanisms to improve evidence-based medical evidence.
基金supported by the Canada Foundation for Innovation (Project#44220)the Natural Sciences and Engineering Research Council of Canada (RGPIN-2024-03986)+3 种基金the Michael Smith Foundation for Health Research BCthe financial support of Health Canada,through the Canada Brain Research Fund,an innovative partnership between the Government of Canada (through Health Canada),Brain Canada Foundationthe Azrieli Foundationsupported by a Canadian Institutes of Health Research (CIHR) Canada Graduate Scholarship–Master’s Award。
文摘Central nervous system(CNS) axons fail to regenerate following brain or spinal cord injury(SCI),which typically leads to permanent neurological deficits.Peripheral nervous system axons,howeve r,can regenerate following injury.Understanding the mechanisms that underlie this difference is key to developing treatments for CNS neurological diseases and injuries characterized by axonal damage.To initiate repair after peripheral nerve injury,dorsal root ganglion(DRG) neurons mobilize a pro-regenerative gene expression program,which facilitates axon outgrowth.
