摘要：Lysophosphatidic acid (LPA) is a pleiotropic lipid agonist essential for functions of the central nervous system (CNS). It is abundant in the developing and adult brain while its concentration in biological fluids,including cerebrospinal fluid,varies significantly (Figure 1Α;Yung et al.,2014).LPA actually corresponds to a variety of lipid species that include different stereoisomers with either saturated or unsaturated fatty acids bearing likely differentiated biological activities (Figure 1Α;Yung et al.,2014;Hernández-Araiza et al.,2018). During CNS development,LPA influences critical processes such as cell proliferation,survival,and differentiation,promotes neuronal migration,and affects neuronal morphology(Yung et al.,2014). Furthermore,LPA mediates cortical development,myelination,pain,synaptic transmission,and plasticity (Yung et al.,2014).Deregulation of LPA signaling contributes to a myriad of CNS pathologies including psychiatric diseases,neurodegeneration,neuropathic pain,neuroinflammatory,and traumatic conditions(Yung et al.,2014).

摘要：Adult neurogenesis continuously produces new neurons critical for cognitive plasticity in adult rodents.While it is known transforming growth factor-β signaling is important in embryonic neurogenesis,its role in postnatal neurogenesis remains unclear.In this study,to define the precise role of transforming growth factor-β signaling in postnatal neurogenesis at distinct stages of the neurogenic cascade both in vitro and in vivo,we developed two novel inducible and cell type-specific mouse models to specifically silence transforming growth factor-β signaling in neural stem cells in(mGFAPcre-ALK5fl/fl-Ai9)or immature neuroblasts in(DCXcreERT2-ALK5fl/fl-Ai9).Our data showed that exogenous transforming growth factor-β treatment led to inhibition of the proliferation of primary neural stem cells while stimulating their migration.These effects were abolished in activin-like kinase 5(ALK5)knockout primary neural stem cells.Consistent with this,inhibition of transforming growth factor-β signaling with SB-431542 in wild-type neural stem cells stimulated proliferation while inhibited the migration of neural stem cells.Interestingly,deletion of transforming growth factor-β receptor in neural stem cells in vivo inhibited the migration of postnatal born neurons in mGFAPcre-ALK5fl/fl-Ai9 mice,while abolishment of transforming growth factor-β signaling in immature neuroblasts in DCXcreERT2-ALK5fl/fl-Ai9 mice did not affect the migration of these cells in the hippocampus.In summary,our data supports a dual role of transforming growth factor-β signaling in the proliferation and migration of neural stem cells in vitro.Moreover,our data provides novel insights on cell type-specific-dependent requirements of transforming growth factor-β signaling on neural stem cell proliferation and migration in vivo.

摘要：The dentate gyrus of the hippocampus is a plastic structure that displays modifications at different levels in response to positive stimuli as well as to negative conditions such as brain damage.The latter involves global alterations,making understanding plastic responses triggered by local damage difficult.One key feature of the dentate gyrus is that it contains a well-defined neurogenic niche,the subgranular zone,and beyond neurogenesis,newly born granule cells may maintain a"young"phenotype throughout life,adding to the plastic nature of the structure.Here,we present a novel experimental model of local brain damage in organotypic entorhino-hippocampal cultures that results in the activation of adjacent newly born granule cells.A small piece of filter paper was placed on the surface of the granule cell layer of the dentate gyrus,which evoked a foreign body reaction of astrocytes,along with the activation of local young neurons expressing doublecortin.Forty-eight hours after foreign body placement,the number of doublecortin-immunoreactive cells increased in the subgranular zone in the direct vicinity of the foreign body,whereas overall increased doublecortin immunoreactivity was observed in the granule cell layer and molecular layer of the dentate gyrus.Foreign body placement in the pyramidal layer of the CA1 region evoked a comparable local astroglial reaction but did not lead to an increase in doublecortin-immunoreactive in either the CA1 region or the adjacent dentate gyrus.Seven days after foreign body placement in the dentate gyrus,the increase in doublecortin-immunoreactivity was no longer observed,indicating the transient activation of young cells.However,7 days after foreign body placement,the number of doublecortin-immunoreactive granule cells coimmunoreactive for calbindin was lower than that under the control conditions.As calbindin is a marker for mature granule cells,this result suggests that activated young cells remain at a more immature stage following foreign body placement.Live imaging of retrovirally green fluorescent protein-labeled newly born granule cells revealed the orientation and growth of their dendrites toward the foreign body placement.This novel experimental model of foreign body placement in organotypic entorhino-hippocampal cultures could serve as a valuable tool for studying both glial reactivity and neuronal plasticity,specifically of newly born neurons under controlled in vitro conditions.

摘要：Unwarranted death of neurons is a major cause of neurodegenerative diseases.Since mature neurons are postmitotic and do not replicate,their death usually constitutes an irreversible step in pathology.A logical strategy to prevent neurodegeneration would then be to save all neurons that are still alive,i.e.protecting the ones that are still healthy as well as trying to rescue the ones that are damaged and in the process of dying.Regarding the latter,recent experiments have indicated that the possibility of reversing the cell death process and rescuing dying cells is more significant than previously anticipated.In many situations,the elimination of the cell death trigger alone enables dying cells to spontaneously repair their damage,recover,and survive.In this review,we explore the factors,which determine the fate of neurons engaged in the cell death process.A deeper insight into cell death mechanisms and the intrinsic capacity of cells to recover could pave the way for novel therapeutic approaches to neurodegenerative diseases.

摘要：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 multi-target 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.

摘要：Stroke is the leading cause of mortality globally,ultimately leading to severe,lifelong neurological impairments.Patients often suffer from a secondary cascade of damage,including neuroinflammation,cytotoxicity,oxidative stress,and mitochondrial dysfunction.Regrettably,there is a paucity of clinically available therapeutics to address these issues.Emerging evidence underscores the pivotal roles of astrocytes,the most abundant glial cells in the brain,throughout the various stages of ischemic stroke.In this comprehensive review,we initially provide an overview of the fundamental physiological functions of astrocytes in the brain,emphasizing their critical role in modulating neuronal homeostasis,synaptic activity,and blood-brain barrier integrity.We then delve into the growing body of evidence that highlights the functional diversity and heterogeneity of astrocytes in the context of ischemic stroke.Their well-established contributions to energy provision,metabolic regulation,and neurotransmitter homeostasis,as well as their emerging roles in mitochondrial recovery,neuroinflammation regulation,and oxidative stress modulation following ischemic injury,are discussed in detail.We also explore the cellular and molecular mechanisms underpinning these functions,with particular emphasis on recently identified targets within astrocytes that offer promising prospects for therapeutic intervention.In the final section of this review,we offer a detailed overview of the current therapeutic strategies targeting astrocytes in the treatment of ischemic stroke.These astrocyte-targeting strategies are categorized into traditional small-molecule drugs,microRNAs(miRNAs),stem cell-based therapies,cellular reprogramming,hydrogels,and extracellular vesicles.By summarizing the current understanding of astrocyte functions and therapeutic targeting approaches,we aim to highlight the critical roles of astrocytes during and after stroke,particularly in the pathophysiological development in ischemic stroke.We also emphasize promising avenues for novel,astrocyte-targeted therapeutics that could become clinically available options,ultimately improving outcomes for patients with stroke.

摘要：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).

摘要：The nervous system function requires a precise but plastic neural architecture. The neuronal shape dictates how neurons interact with each other and with other cells,being the morphology of dendrites and axons the central determinant of the functional properties of neurons and neural circuits. The topological and structural morphology of axons and dendrites defines and determines how synapses are conformed. The morphological diversity of axon and dendrite arborization governs the neuron's inputs,synaptic integration,neuronal computation,signal transmission,and network circuitry,hence defining the particular connectivity and function of the different brain areas.

摘要：Intrathecal administration of human umbilical cord mesenchymal stem cells may be a promising approach for the treatment of stroke,but its safety,effectiveness,and mechanism remain to be elucidated.In this study,good manufacturing practice-grade human umbilical cord mesenchymal stem cells(5×105 and 1×106 cells)and saline were administered by cerebellomedullary cistern injection 72 hours after stroke induced by middle cerebral artery occlusion in rats.The results showed(1)no significant difference in mortality or general conditions among the three groups.There was no abnormal differentiation or tumor formation in various organs of rats in any group.(2)Compared with saline-treated animals,those treated with human umbilical cord mesenchymal stem cells showed significant functional recovery and reduced infarct volume,with no significant differences between different human umbilical cord mesenchymal stem cell doses.(3)Human umbilical cord mesenchymal stem cells were found in the ischemic brain after 14 and 28 days of follow-up,and the number of positive cells significantly decreased over time.(4)Neuronal nuclei expression in the human umbilical cord mesenchymal stem cell group was greater than that in the saline group,while glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1 expression levels decreased.(5)Human umbilical cord mesenchymal stem cell treatment increased the number of CD31+microvessels and doublecortin-positive cells after ischemic stroke.Human umbilical cord mesenchymal stem cells also upregulated the expression of CD31+/Ki67+.(6)At 14 days after intrathecal administration,brain-derived neurotrophic factor expression in the peri-infarct area and the concentrations of brain-derived neurotrophic factor in the cerebrospinal fluid in both human umbilical cord mesenchymal stem cell groups were significantly greater than those in the saline group and persisted until the 28th day.Taken together,these results indicate that the intrathecal administration of human umbilical cord mesenchymal stem cells via cerebellomedullary cistern injection is safe and effective for the treatment of ischemic stroke in rats.The mechanisms may include alleviating the local inflammatory response in the peri-infarct region,promoting neurogenesis and angiogenesis,and enhancing the production of neurotrophic factors.

摘要：For many decades,Alzheimer's disease research has primarily focused on impairments within cortical and hippocampal regions,which are thought to be related to cognitive dysfunctions such as memory and language deficits.The exact cause of Alzheimer's disease is still under debate,making it challenging to establish an effective therapy or early diagnosis.It is widely accepted that the accumulation of amyloid-beta peptide in the brain parenchyma leads to synaptic dysfunction,a critical step in Alzheimer's disease development.The traditional amyloid cascade model is initiated by accumulating extracellular amyloid-beta in brain areas essential for memory and language.However,while it is possible to reduce the presence of amyloid-beta plaques in the brain with newer immunotherapies,cognitive symptoms do not necessarily improve.Interestingly,recent studies support the notion that early alterations in subcortical brain regions also contribute to brain damage and precognitive decline in Alzheimer's disease.A body of recent evidence suggests that early Alzheimer's disease is associated with alterations(e.g.,motivation,anxiety,and motor impairment)in subcortical areas,such as the striatum and amygdala,in both human and animal models.Also,recent data indicate that intracellular amyloid-beta appears early in subcortical regions such as the nucleus accumbens,locus coeruleus,and raphe nucleus,even without extracellular amyloid plaques.The reported effects are mainly excitatory,increasing glutamatergic transmission and neuronal excitability.In agreement,data in Alzheimer's disease patients and animal models show an increase in neuronal synchronization that leads to electroencephalogram disturbances and epilepsy.The data indicate that early subcortical brain dysfunctions might be associated with non-cognitive symptoms such as anxiety,irritability,and motivation deficits,which precede memory loss and language alterations.Overall,the evidence reviewed suggests that subcortical brain regions could explain early dysfunctions and perhaps be targets for therapies to slow disease progression.Future research should focus on these non-traditional brain regions to reveal early pathological alterations and underlying mechanisms to advance our understanding of Alzheimer's disease beyond the traditionally studied hippocampal and cortical circuits.

摘要：Charcot-Marie-Tooth disease(CMT)is a heterogeneous group of inherited peripheral neuropathies;it is characterized by muscle weakness and wasting,as well as sensory dysfunction,that typically begins during adolescence and ultimately leads to lifelong disability.Occurring in～1 in 2500 individuals,CMT is the most common hereditary neuromuscular condition and results from mutations in＞100 different genes.CMT is grouped into type 1(CMT1),where demyelination and loss of nerve conduction velocity occur,type 2(CMT2),where motor and sensory axons degenerate without loss of myelination/nerve conduction velocity,and intermediate CMT,where both demyelination and axon loss present alongside intermediate nerve conduction velocities.

摘要：Cerebral small vessel disease(SVD)represents a range of pathological changes in the small blood vessels of the brain.SVD can be detected on MRI,which includes white matter hyperintensities,lacunes,and cerebral microbleeds(Duering et al.,2023).Patients with SVD exhibit significant clinical heterogeneity,often presenting with cognitive impairment,apathy,gait dysfunction,and lacunar stroke(Wardlaw et al.,2019).

摘要：Neuroserpin,a secreted protein that belongs to the serpin superfamily of serine protease inhibitors,is highly expressed in the central nervous system and plays multiple roles in brain development and pathology.As a natural inhibitor of recombinant tissue plasminogen activator,neuroserpin inhibits the increased activity of tissue plasminogen activator in ischemic conditions and extends the therapeutic windows of tissue plasminogen activator for brain ischemia.However,the neuroprotective mechanism of neuroserpin against ischemic stroke remains unclear.In this study,we used a mouse model of middle cerebral artery occlusion and oxygen-glucose deprivation/reperfusion-injured cortical neurons as in vivo and in vitro ischemia-reperfusion models,respectively.The models were used to investigate the neuroprotective effects of neuroserpin.Our findings revealed that endoplasmic reticulum stress was promptly triggered following ischemia,initially manifesting as the acute activation of endoplasmic reticulum stress transmembrane sensors and the suppression of protein synthesis,which was followed by a later apoptotic response.Notably,ischemic stroke markedly downregulated the expression of neuroserpin in cortical neurons.Exogenous neuroserpin reversed the activation of multiple endoplasmic reticulum stress signaling molecules,the reduction in protein synthesis,and the upregulation of apoptotic transcription factors.This led to a reduction in neuronal death induced by oxygen/glucose deprivation and reperfusion,as well as decreased cerebral infarction and neurological dysfunction in mice with middle cerebral artery occlusion.However,the neuroprotective effects of neuroserpin were markedly inhibited by endoplasmic reticulum stress activators thapsigargin and tunicamycin.Our findings demonstrate that neuroserpin exerts neuroprotective effects on ischemic stroke by suppressing endoplasmic reticulum stress.

摘要：Every year,around the world,between 250,000 and 500,000 people suffer a spinal cord injury(SCI).SCI is a devastating medical condition that arises from trauma or disease-induced damage to the spinal cord,disrupting the neural connections that allow communication between the brain and the rest of the body,which results in varying degrees of motor and sensory impairment.Disconnection in the spinal tracts is an irreversible condition owing to the poor capacity for spontaneous axonal regeneration in the affected neurons.This is due to several causes:(ⅰ)intrinsic neuronal deficits in the expression of genes involved in axon regrowth/regeneration;(ⅱ)the presence of inhibitory factors as well as the lack of trophic factors for neuroprotection and regeneration in the affected area;and(ⅲ)a physical impediment due to the formation of the glial scar(Varadarajan et al.,2022).

摘要：Neuronal plasticity,the brain's ability to adapt structurally and functionally,is essential for learning,memory,and recovery from injuries.In neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease,this plasticity is disrupted,leading to cognitive and motor deficits.This review explores the mechanisms of neuronal plasticity and its effect on Alzheimer's disease and Parkinson's disease.Alzheimer's disease features amyloid-beta plaques and tau tangles that impair synaptic function,while Parkinson's disease involves the loss of dopaminergic neurons affecting motor control.Enhancing neuronal plasticity offers therapeutic potential for these diseases.A systematic literature review was conducted using databases such as PubMed,Scopus,and Google Scholar,focusing on studies of neuronal plasticity in Alzheimer's disease and Parkinson's disease.Data synthesis identified key themes such as synaptic mechanisms,neurogenesis,and therapeutic strategies,linking molecular insights to clinical applications.Results highlight that targeting synaptic plasticity mechanisms,such as long-term potentiation and long-term depression,shows promise.Neurotrophic factors,advanced imaging techniques,and molecular tools(e.g.,clustered regularly interspaced short palindromic repeats and optogenetics)are crucial in understanding and enhancing plasticity.Current therapies,including dopamine replacement,deep brain stimulation,and lifestyle interventions,demonstrate the potential to alleviate symptoms and improve outcomes.In conclusion,enhancing neuronal plasticity through targeted therapies holds significant promise for treating neurodegenerative diseases.Future research should integrate multidisciplinary approaches to fully harness the therapeutic potential of neuronal plasticity in Alzheimer's disease and Parkinson's disease.

摘要：Epilepsy is a leading cause of disability and mortality worldwide.However,despite the availability of more than 20 antiseizure medications,more than one-third of patients continue to experience seizures.Given the urgent need to explore new treatment strategies for epilepsy,recent research has highlighted the potential of targeting gliosis,metabolic disturbances,and neural circuit abnormalities as therapeutic strategies.Astrocytes,the largest group of nonneuronal cells in the central nervous system,play several crucial roles in maintaining ionic and energy metabolic homeostasis in neurons,regulating neurotransmitter levels,and modulating synaptic plasticity.This article briefly reviews the critical role of astrocytes in maintaining balance within the central nervous system.Building on previous research,we discuss how astrocyte dysfunction contributes to the onset and progression of epilepsy through four key aspects:the imbalance between excitatory and inhibitory neuronal signaling,dysregulation of metabolic homeostasis in the neuronal microenvironment,neuroinflammation,and the formation of abnormal neural circuits.We summarize relevant basic research conducted over the past 5 years that has focused on modulating astrocytes as a therapeutic approach for epilepsy.We categorize the therapeutic targets proposed by these studies into four areas:restoration of the excitation-inhibition balance,reestablishment of metabolic homeostasis,modulation of immune and inflammatory responses,and reconstruction of abnormal neural circuits.These targets correspond to the pathophysiological mechanisms by which astrocytes contribute to epilepsy.Additionally,we need to consider the potential challenges and limitations of translating these identified therapeutic targets into clinical treatments.These limitations arise from interspecies differences between humans and animal models,as well as the complex comorbidities associated with epilepsy in humans.We also highlight valuable future research directions worth exploring in the treatment of epilepsy and the regulation of astrocytes,such as gene therapy and imaging strategies.The findings presented in this review may help open new therapeutic avenues for patients with drug-resistant epilepsy and for those suffering from other central nervous system disorders associated with astrocytic dysfunction.

摘要：Neural machine interface technology is a pioneering approach that aims to address the complex challenges of neurological dysfunctions and disabilities resulting from conditions such as congenital disorders,traumatic injuries,and neurological diseases.Neural machine interface technology establishes direct connections with the brain or peripheral nervous system to restore impaired motor,sensory,and cognitive functions,significantly improving patients' quality of life.This review analyzes the chronological development and integration of various neural machine interface technologies,including regenerative peripheral nerve interfaces,targeted muscle and sensory reinnervation,agonist-antagonist myoneural interfaces,and brain-machine interfaces.Recent advancements in flexible electronics and bioengineering have led to the development of more biocompatible and high-resolution electrodes,which enhance the performance and longevity of neural machine interface technology.However,significant challenges remain,such as signal interference,fibrous tissue encapsulation,and the need for precise anatomical localization and reconstruction.The integration of advanced signal processing algorithms,particularly those utilizing artificial intelligence and machine learning,has the potential to improve the accuracy and reliability of neural signal interpretation,which will make neural machine interface technologies more intuitive and effective.These technologies have broad,impactful clinical applications,ranging from motor restoration and sensory feedback in prosthetics to neurological disorder treatment and neurorehabilitation.This review suggests that multidisciplinary collaboration will play a critical role in advancing neural machine interface technologies by combining insights from biomedical engineering,clinical surgery,and neuroengineering to develop more sophisticated and reliable interfaces.By addressing existing limitations and exploring new technological frontiers,neural machine interface technologies have the potential to revolutionize neuroprosthetics and neurorehabilitation,promising enhanced mobility,independence,and quality of life for individuals with neurological impairments.By leveraging detailed anatomical knowledge and integrating cutting-edge neuroengineering principles,researchers and clinicians can push the boundaries of what is possible and create increasingly sophisticated and long-lasting prosthetic devices that provide sustained benefits for users.

摘要：Long noncoding RNA and microRNA are regulatory noncoding RNAs that are implicated in Alzheimer's disease,but the role of long noncoding RNA-associated competitive endogenous RNA has not been fully elucidated.The long noncoding RNA growth arrest-specific 5(GAS5)is a member of the 5'-terminal oligopyrimidine gene family that may be involved in neurological disorders,but its role in Alzheimer's disease remains unclear.This study aimed to investigate the function of GAS5 and construct a GAS5-associated competitive endogenous RNA network comprising potential targets.RNA sequencing results showed that GAS5 was upregulated in five familial Alzheimer's disease(5xFAD)mice,APPswe/PSEN1dE9(APP/PS1)mice,Alzheimer's disease-related APPswe cells,and serum from patients with Alzheimer's disease.Functional experiments with targeted overexpression and silencing demonstrated that GAS5 played a role in cognitive dysfunction and multiple Alzheimer's disease-associated pathologies,including tau hyperphosphorylation,amyloid-beta accumulation,and neuronal apoptosis.Mechanistic studies indicated that GAS5 acted as an endogenous sponge by competing for microRNA-23b-3p(miR-23b-3p)binding to regulate its targets glycogen synthase kinase 3beta(GSK-3β)and phosphatase and tensin homologue deleted on chromosome 10(PTEN)expression in an Argonaute 2-induced RNA silencing complex(RISC)-dependent manner.GAS5 inhibited miR-23b-3p-mediated GSK-3β and PTEN cascades with a feedforward PTEN/protein kinase B(Akt)/GSK-3β linkage.Furthermore,recovery of GAS5/miR-23b-3p/GSK-3β/PTEN pathways relieved Alzheimer's disease-like symptoms in vivo,indicated by the amelioration of spatial cognition,neuronal degeneration,amyloid-beta load,and tau phosphorylation.Together,these findings suggest that GAS5 promotes Alzheimer's disease pathogenesis.This study establishes the functional convergence of the GAS5/miR-23b-3p/GSK-3β/PTEN pathway on multiple pathologies,suggesting a candidate therapeutic target in Alzheimer's disease.

摘要：Alzheimer's disease is the primary cause of dementia and imposes a significant socioeconomic burden globally.Physical exercise,as an effective strategy for improving general health,has been largely reported for its effectiveness in slowing neurodegeneration and increasing brain functional plasticity,particularly in aging brains.However,the underlying mechanisms of exercise in cognitive aging remain largely unclear.Adiponectin,a cell-secreted protein hormone,has recently been found to regulate synaptic plasticity and mediate the antidepressant effects of physical exercise.Studies on the neuroprotective effects of adiponectin have revealed potential innovative treatments for Alzheimer's disease.Here,we reviewed the functions of adiponectin and its receptor in the brains of human and animal models of cognitive impairment.We summarized the role of adiponectin in Alzheimer's disease,focusing on its impact on energy metabolism,insulin resistance,and inflammation.We also discuss how exercise increases adiponectin secretion and its potential benefits for learning and memory.Finally,we highlight the latest research on chemical compounds that mimic exercise-enhanced secretion of adiponectin and its receptor in Alzheimer's disease.

摘要：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.