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
Intracerebral hemorrhage is the most dangerous subtype of stroke,characterized by high mortality and morbidity rates,and frequently leads to significant secondary white matter injury.In recent decades,studies have rev...Intracerebral hemorrhage is the most dangerous subtype of stroke,characterized by high mortality and morbidity rates,and frequently leads to significant secondary white matter injury.In recent decades,studies have revealed that gut microbiota can communicate bidirectionally with the brain through the gut microbiota–brain axis.This axis indicates that gut microbiota is closely related to the development and prognosis of intracerebral hemorrhage and its associated secondary white matter injury.The NACHT,LRR,and pyrin domain-containing protein 3(NLRP3)inflammasome plays a crucial role in this context.This review summarizes the dysbiosis of gut microbiota following intracerebral hemorrhage and explores the mechanisms by which this imbalance may promote the activation of the NLRP3 inflammasome.These mechanisms include metabolic pathways(involving short-chain fatty acids,lipopolysaccharides,lactic acid,bile acids,trimethylamine-N-oxide,and tryptophan),neural pathways(such as the vagus nerve and sympathetic nerve),and immune pathways(involving microglia and T cells).We then discuss the relationship between the activated NLRP3 inflammasome and secondary white matter injury after intracerebral hemorrhage.The activation of the NLRP3 inflammasome can exacerbate secondary white matter injury by disrupting the blood–brain barrier,inducing neuroinflammation,and interfering with nerve regeneration.Finally,we outline potential treatment strategies for intracerebral hemorrhage and its secondary white matter injury.Our review highlights the critical role of the gut microbiota–brain axis and the NLRP3 inflammasome in white matter injury following intracerebral hemorrhage,paving the way for exploring potential therapeutic approaches.展开更多
Type 2 diabetes mellitus has central complications:Diabetes,a metabolic disorder primarily characterized by hyperglycemia due to insufficient insulin secretion,or impaired insulin signaling,has significant central com...Type 2 diabetes mellitus has central complications:Diabetes,a metabolic disorder primarily characterized by hyperglycemia due to insufficient insulin secretion,or impaired insulin signaling,has significant central complications.Type 2 diabetes mellitus(T2DM),the most prevalent type of diabetes,affects more than 38 million individuals in the United States(approximately 1 in 10)and is defined by chronic hyperglycemia and insulin resistance,which refers to a reduced cellular response to insulin.展开更多
BACKGROUND Major depressive disorder(MDD)and obesity(OB)are bidirectionally comorbid conditions with common neurobiological underpinnings.However,the neurocognitive mechanisms of their comorbidity remain poorly unders...BACKGROUND Major depressive disorder(MDD)and obesity(OB)are bidirectionally comorbid conditions with common neurobiological underpinnings.However,the neurocognitive mechanisms of their comorbidity remain poorly understood.AIM To examine regional abnormalities in spontaneous brain activity among patients with MDD-OB comorbidity.METHODS This study adopted a regional homogeneity(ReHo)analysis of resting-state functional magnetic resonance imaging.The study included 149 hospital patients divided into four groups:Patients experiencing their first episode of drug-naive MDD with OB,patients with MDD without OB,and age-and sex-matched healthy individuals with and without OB.Whole-brain ReHo analysis was conducted using SPM12 software and RESTplus toolkits,with group comparisons via ANOVA and post-hoc tests.Correlations between ReHo values and behavioral measures were examined.RESULTS ANOVA revealed significant whole-brain ReHo differences among the four groups in four key regions:The left middle temporal gyrus(MTG.L),right cuneus,left precuneus,and left thalamus.Post-hoc analyses confirmed pairwise differences between all groups across these regions(P<0.05).OB was associated with ReHo alterations in the MTG.L,right cuneus,and left thalamus,whereas abnormalities in the precuneus suggested synergistic pathological mechanisms between MDD and OB.Statistically significant correlations were found between the drive and fun-seeking dimensions of the behavioral activation system,as well as behavioral inhibition and the corresponding ReHo values.CONCLUSION Our findings provide novel evidence for the neuroadaptive mechanisms underlying the MDD-OB comorbidity.Further validation could lead to personalized interventions targeting MTG.L hyperactivity and targeting healthy food cues.展开更多
BCL2-associated anthanogene 3 facilitates the clearance of tau protein aggregates:BCL2-associated anthanogene 3(BAG3)is a ubiquitously expressed and highly conserved multi-functional co-chaperone protein involved in m...BCL2-associated anthanogene 3 facilitates the clearance of tau protein aggregates:BCL2-associated anthanogene 3(BAG3)is a ubiquitously expressed and highly conserved multi-functional co-chaperone protein involved in many biological processes that supports cellular homeostasis,including the inhibition of apoptosis by preventing mitochondrial BAX localization(Lin et al.,2022)and the promotion of the degradation of hyperphosphorylated tau aggregates by its interactions with SQSTM1(p62)(Hamano and Mutoh,2022).展开更多
Macrophages in the brain barrier system include microglia in the brain parenchyma,border-associated macrophages at the brain’s borders,and recruited macrophages.They are responsible for neural development,maintenance...Macrophages in the brain barrier system include microglia in the brain parenchyma,border-associated macrophages at the brain’s borders,and recruited macrophages.They are responsible for neural development,maintenance of homeostasis,and orchestrating immune responses.With the rapid exploitation and development of new technologies,there is a deeper understanding of macrophages in the brain barrier system.Here we review the origin,development,important molecules,and functions of macrophages,mainly focusing on microglia and border-associated macrophages.We also highlight some advances in single-cell sequencing and significant cell markers.We anticipate that more advanced methods will emerge to study resident and recruited macrophages in the future,opening new horizons for neuroimmunology and related peripheral immune fields.展开更多
Radiation-induced brain injury remains one of the most severe complications of radiotherapy for head and neck tumors,with limited options for prevention and treatment.In situ neural regeneration technology has demonst...Radiation-induced brain injury remains one of the most severe complications of radiotherapy for head and neck tumors,with limited options for prevention and treatment.In situ neural regeneration technology has demonstrated promising therapeutic effects in various neurodegenerative and neurotrauma conditions.In this study,we overexpressed the neural transcription factor NeuroD1 using in situ neural regeneration technology in a radiation-induced brain injury mouse model.This approach converted reactive astrocytes into neurons,increased neuronal density,protected endogenous neurons,decreased microglial activation,reduced peripheral CD8+T cell infiltration,and diminished angiogenesis in the injured area,leading to a significant reduction in lesion volume.Additionally,we explored the potential mechanisms of NeuroD1 in situ neural regeneration technology through bulk RNA sequencing,which showed an upregulation of neurogenesis-related genes and a downregulation of immune response-related and angiogenesis-related genes.Furthermore,our findings suggested that NeuroD1 in situ neural regeneration technology converted reactive astrocytes into neurons and reduced microglial activation in a thalamic hemorrhagic stroke mouse model.In summary,this study supports NeuroD1 in situ neural regeneration technology as a potential therapeutic approach for treating radiation-induced brain injury and hemorrhagic stroke,and offers new insights into the therapeutic role of NeuroD1 in delayed brain injury.展开更多
The organization of biological neuronal networks into functional modules has intrigued scientists and inspired engineers to develop artificial systems.These networks are characterized by two key properties.First,they ...The organization of biological neuronal networks into functional modules has intrigued scientists and inspired engineers to develop artificial systems.These networks are characterized by two key properties.First,they exhibit dense interconnectivity(Braitenburg and Schüz,1998;Campagnola et al.,2022).The strength and probability of connectivity depend on cell type,inter-neuronal distance,and species.Still,every cortical neuron receives input from thousands of other neurons while transmitting output to a similar number of neurons.Second,communication between neurons occurs primarily via chemical or electrical synapses.展开更多
Subarachnoid hemorrhage(SAH) is a devastating condition that affects a total of 8 million people worldwide each year(Lauzier and Athiraman, 2024). Etiologies of SAH can be traumatic or nontraumatic, with the majority ...Subarachnoid hemorrhage(SAH) is a devastating condition that affects a total of 8 million people worldwide each year(Lauzier and Athiraman, 2024). Etiologies of SAH can be traumatic or nontraumatic, with the majority of non-traumatic SAH occurring due to intracranial aneurysm rupture(Rutledge et al., 2014).展开更多
Alzheimer’s disease(AD)is a complex neurodegenerative disorder associated with changes in inflammation,oxidative stress,and gut microbiota composition.Butyrolactone Ⅰ(BTL-Ⅰ),a fungal metabolite,has shown anti-infla...Alzheimer’s disease(AD)is a complex neurodegenerative disorder associated with changes in inflammation,oxidative stress,and gut microbiota composition.Butyrolactone Ⅰ(BTL-Ⅰ),a fungal metabolite,has shown anti-inflammatory,microbiota regulating,and memory-improving potentials in previous in vitro and AlCl3-induced zebrafish studies.However,its effects of memory-improving and gutbrain axis regulating on Aβ-induced mammalian AD models have not been explored.In this study,intragastric administrated BTL-Ⅰ ameliorated cognitive deficits related to recognition and spatial memory impaired by Aβ_(1-42)intracerebroventricular injection in mice.BTL-Ⅰ maintained gut microbiota balance by increasing the abundance of Blautia,Muribaculaceae,Bacteroides,Akkermansia,etc.,and decreasing CAG-352,Clostridia UCG-014,different Lachnospiraceae groups,etc.,and Firmicutes/Bacteroidota ratio and elevated the levels of short-chain fatty acids.Additionally,it alleviated intestinal oxidative stress,inflammatory responses,and pathological damage.Furthermore,BTL-I reversed Aβ_(1-42)-induced activation of microglia and astrocytes in the hippocampus and inhibited the elevated oxidative stress and proinflammatory cytokines in both plasma and brain.The correlation analysis between the regulated taxa and biomarkers supports the role of gut microbiota in adjusting inflammation,oxidative stress,and memory.In conclusion,BTL-I may serve as a valuable drug lead for treating Alzheimer’s disease by systematically inhibiting microbiota imbalance,inflammation,and oxidative stress along the gut-brain axis.展开更多
Gut-brain communication via the peripheral neural network is vital for regulating local digestive function and systemic physiology.Gut microbiota,which produces a wide array of neuroactive compounds,is a critical modu...Gut-brain communication via the peripheral neural network is vital for regulating local digestive function and systemic physiology.Gut microbiota,which produces a wide array of neuroactive compounds,is a critical modulator in this bidirectional dialog.Perturbations in the gut microbiota have been implicated in neurological disorders such as depression and stress.Distinct from humans and other monogastric animals,ruminants possess a unique,microbially dense gastrointestinal compartment,the rumen,that facilitates the digestion of fibrous plant materials.These ruminal microbes are likely key contributors to rumen-brain crosstalk.Unlike certain microbe-derived neuroactive compounds produced in the hindgut that are minimally absorbed and primarily excreted in feces,those generated in rumen can reach the small intestine,where they are largely absorbed and affect central nervous system through systemic regulation in addition to the vagal pathway.Notably,emerging evidence suggests that rumen microbiota dysbiosis under stress is associated with abnormal behavior,altered hormonal and neurotransmitter levels.In this review,we introduce the concept of the rumen-microbiome-brain axis by comparing the anatomical structures and microbial characteristics of the intestine and the rumen,emphasizing the neuroactive potential of rumen microbiome and underlying mechanisms.Advances in this frontier hold tremendous promise to reveal a novel dimension of the gut-microbiome-brain axis,providing transformative opportunities to improve ruminant welfare,productivity,and agricultural sustainability.展开更多
Brain-computer interfaces(BCIs)represent an emerging technology that facilitates direct communication between the brain and external devices.In recent years,numerous review articles have explored various aspects of BC...Brain-computer interfaces(BCIs)represent an emerging technology that facilitates direct communication between the brain and external devices.In recent years,numerous review articles have explored various aspects of BCIs,including their fundamental principles,technical advancements,and applications in specific domains.However,these reviews often focus on signal processing,hardware development,or limited applications such as motor rehabilitation or communication.This paper aims to offer a comprehensive review of recent electroencephalogram(EEG)-based BCI applications in the medical field across 8 critical areas,encompassing rehabilitation,daily communication,epilepsy,cerebral resuscitation,sleep,neurodegenerative diseases,anesthesiology,and emotion recognition.Moreover,the current challenges and future trends of BCIs were also discussed,including personal privacy and ethical concerns,network security vulnerabilities,safety issues,and biocompatibility.展开更多
Dear Editor,Sturge-Weber Syndrome(SWS)is a rare congenital neurocutaneous syndrome[1,2],with an estimated prevalence of 0.19 in 100,000 annually[3].It is a non-hereditary disease linked to a somatic mutation in the GN...Dear Editor,Sturge-Weber Syndrome(SWS)is a rare congenital neurocutaneous syndrome[1,2],with an estimated prevalence of 0.19 in 100,000 annually[3].It is a non-hereditary disease linked to a somatic mutation in the GNAQ,GNA11,or GNB2 gene[1],leading to vascular malformations in the cutaneous forehead,cerebral cortex,and eye[1,2].Notably,~70%of pediatric patients diagnosed with SWS exhibit brain calcification(BC)[4],though the prevalence of BC ranges from only 1%in young individuals to>20%in the senior population(>60 years old)[5].Similar to the elderly,BC in pediatric SWS patients is identified as vascular calcification[6,7],whereas BC in pediatric patients with tuberous sclerosis and tumors has been previously described as dystrophic calcification[6].展开更多
Dear Editor,The mammalian brain exhibits cross-scale complexity in neuronal morphology and connectivity,the study of which demands high-resolution morphological reconstruction of individual neurons across the entire b...Dear Editor,The mammalian brain exhibits cross-scale complexity in neuronal morphology and connectivity,the study of which demands high-resolution morphological reconstruction of individual neurons across the entire brain[1-4].Current commonly used approaches for such mesoscale brain mapping include two main types of three-dimensional fluorescence microscopy:the block-face methods,and the lightsheet-based methods[5,6].In general,the high imaging speed and light efficiency of light-sheet microscopy make it a suitable tool for high-throughput volumetric imaging,especially when combined with tissue-clearing techniques.However,large brain samples pose major challenges to this approach.展开更多
Brain,the material foundation of human intelligence,is the most complex tissue in the human body.Brain diseases are among the leading threats to human life,yet our understanding of their pathogenic mechanisms and drug...Brain,the material foundation of human intelligence,is the most complex tissue in the human body.Brain diseases are among the leading threats to human life,yet our understanding of their pathogenic mechanisms and drug development remains limited,largely due to the lack of accurate brain-like tissue models that replicate its complex structure and functions.Therefore,constructing brain-like models—both in morphology and function—possesses significant scientific value for advancing brain science and pathological pharmacology research,representing the frontiers in the biomanufacturing field.This review outlines the primary requirements and challenges in biomanufacturing brain-like tissue,addressing its complex structures,functions,and environments.Also,the existing biomanufacturing technologies,strategies,and characteristics for brain-like models are depicted,and cutting-edge developments in biomanufacturing central neural repair prosthetics,brain development models,brain disease models,and brain-inspired biocomputing models are systematically reviewed.Finally,the paper concludes with future perspectives on the biomanufacturing of brain-like tissue transitioning from structural manufacturing to intelligent functioning.展开更多
Brain calcification is frequently detected by neuroimaging in patients with hereditary and nonhereditary disorders or in normal individuals with aging.Its prevalence ranges from approximately 1%in young people to over...Brain calcification is frequently detected by neuroimaging in patients with hereditary and nonhereditary disorders or in normal individuals with aging.Its prevalence ranges from approximately 1%in young people to over 20%in the elderly(Yamada et al.,2013),yet the underlying mechanisms of brain calcification remain poorly understood.Specifically,calcification in the basal ganglia is detected in approximately 5.5%-20%of CT scans in patients over 50 years old(Auffray-Calvier et al.,2020).展开更多
Acquired brain injury(ABI)is an injury that affects the brain structure and function.Traditional ABI treatment strategies,including medications and rehabilitation therapy,exhibit their ability to improve its impairmen...Acquired brain injury(ABI)is an injury that affects the brain structure and function.Traditional ABI treatment strategies,including medications and rehabilitation therapy,exhibit their ability to improve its impairments in cognition,emotion,and physical activity.Recently,near-infrared(NIR)photobiomodulation(PBM)has emerged as a promising physical intervention method for ABI,demonstrating that low-level light therapy can modulate cellular metabolic processes,reduce the in flammation and reactive oxygen species of ABI microenvironments,and promote neural repair and regeneration.Preclinical studies using ABI models have been carried out,revealing the potential of PBM in promoting brain injury recovery although its clinical application is still in its early stages.In this review,we first inspected the possible physical and biological mechanisms of NIR-PBM,and then reported the pathophysiology and physiology of ABI underlying NIR-PBM intervention.Therefore,the potential of NIR-PBM as a therapeutic intervention in ABI was demonstrated and it is also expected that further work can facilitate its clinical applications.展开更多
The hypothalamic-pituitary-adrenal axis regulates the secretion of glucoco rticoids in response to environmental challenges.In the brain,a nuclear receptor transcription fa ctor,the glucocorticoid recepto r,is an impo...The hypothalamic-pituitary-adrenal axis regulates the secretion of glucoco rticoids in response to environmental challenges.In the brain,a nuclear receptor transcription fa ctor,the glucocorticoid recepto r,is an important component of the hypothalamicpituitary-a d renal axis's negative feedback loop and plays a key role in regulating cognitive equilibrium and neuroplasticity.The glucoco rticoid receptor influences cognitive processes,including glutamate neurotransmission,calcium signaling,and the activation of brain-derived neurotrophic factor-mediated pathways,through a combination of genomic and non-genomic mechanisms.Protein interactions within the central nervous system can alter the expression and activity of the glucocorticoid receptor,there by affecting the hypothalamic-pituitary-a d renal axis and stress-related cognitive functions.An appropriate level of glucocorticoid receptor expression can improve cognitive function,while excessive glucocorticoid receptors or long-term exposure to glucoco rticoids may lead to cognitive impairment.Patients with cognitive impairment-associated diseases,such as Alzheimer's disease,aging,depression,Parkinson's disease,Huntington's disease,stroke,and addiction,often present with dysregulation of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor expression.This review provides a comprehensive overview of the functions of the glucoco rticoid receptor in the hypothalamic-pituitary-a d renal axis and cognitive activities.It emphasizes that appropriate glucocorticoid receptor signaling fa cilitates learning and memory,while its dysregulation can lead to cognitive impairment.This provides clues about how glucocorticoid receptor signaling can be targeted to ove rcome cognitive disability-related disorders.展开更多
Repetitive traumatic brain injury impacts adult neurogenesis in the hippocampal dentate gyrus,leading to long-term cognitive impairment.However,the mechanism underlying this neurogenesis impairment remains unknown.In ...Repetitive traumatic brain injury impacts adult neurogenesis in the hippocampal dentate gyrus,leading to long-term cognitive impairment.However,the mechanism underlying this neurogenesis impairment remains unknown.In this study,we established a male mouse model of repetitive traumatic brain injury and performed long-term evaluation of neurogenesis of the hippocampal dentate gyrus after repetitive traumatic brain injury.Our results showed that repetitive traumatic brain injury inhibited neural stem cell proliferation and development,delayed neuronal maturation,and reduced the complexity of neuronal dendrites and spines.Mice with repetitive traumatic brain injuryalso showed deficits in spatial memory retrieval.Moreover,following repetitive traumatic brain injury,neuroinflammation was enhanced in the neurogenesis microenvironment where C1q levels were increased,C1q binding protein levels were decreased,and canonical Wnt/β-catenin signaling was downregulated.An inhibitor of C1 reversed the long-term impairment of neurogenesis induced by repetitive traumatic brain injury and improved neurological function.These findings suggest that repetitive traumatic brain injury–induced C1-related inflammation impairs long-term neurogenesis in the dentate gyrus and contributes to spatial memory retrieval dysfunction.展开更多
Although microglial polarization and neuroinflammation are crucial cellular responses after traumatic brain injury,the fundamental regulatory and functional mechanisms remain insufficiently understood.As potent anti-i...Although microglial polarization and neuroinflammation are crucial cellular responses after traumatic brain injury,the fundamental regulatory and functional mechanisms remain insufficiently understood.As potent anti-inflammato ry agents,the use of glucoco rticoids in traumatic brain injury is still controversial,and their regulatory effects on microglial polarization are not yet known.In the present study,we sought to determine whether exacerbation of traumatic brain injury caused by high-dose dexamethasone is related to its regulatory effects on microglial polarization and its mechanisms of action.In vitro cultured BV2 cells and primary microglia and a controlled cortical impact mouse model were used to investigate the effects of dexamethasone on microglial polarization.Lipopolysaccharide,dexamethasone,RU486(a glucocorticoid receptor antagonist),and ruxolitinib(a Janus kinase 1 antagonist)were administered.RNA-sequencing data obtained from a C57BL/6 mouse model of traumatic brain injury were used to identify potential targets of dexamethasone.The Morris water maze,quantitative reverse transcription-polymerase chain reaction,western blotting,immunofluorescence and confocal microscopy analysis,and TUNEL,Nissl,and Golgi staining were performed to investigate our hypothesis.High-throughput sequencing results showed that arginase 1,a marker of M2 microglia,was significantly downregulated in the dexamethasone group compared with the traumatic brain injury group at3 days post-traumatic brain injury.Thus dexamethasone inhibited M1 and M2 microglia,with a more pronounced inhibitory effect on M2microglia in vitro and in vivo.Glucocorticoid receptor plays an indispensable role in microglial polarization after dexamethasone treatment following traumatic brain injury.Additionally,glucocorticoid receptor activation increased the number of apoptotic cells and neuronal death,and also decreased the density of dendritic spines.A possible downstream receptor signaling mechanism is the GR/JAK1/STAT3 pathway.Overactivation of glucocorticoid receptor by high-dose dexamethasone reduced the expression of M2 microglia,which plays an antiinflammatory role.In contrast,inhibiting the activation of glucocorticoid receptor reduced the number of apoptotic glia and neurons and decreased the loss of dendritic spines after traumatic brain injury.Dexamethasone may exe rt its neurotoxic effects by inhibiting M2 microglia through the GR/JAK1/STAT3 signaling pathway.展开更多
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 Guangdong Basic and Applied Basic Research Foundation,No.2023A1515030045(to HS)Presidential Foundation of Zhujiang Hospital of Southern Medical University,No.yzjj2022ms4(to HS)。
文摘Intracerebral hemorrhage is the most dangerous subtype of stroke,characterized by high mortality and morbidity rates,and frequently leads to significant secondary white matter injury.In recent decades,studies have revealed that gut microbiota can communicate bidirectionally with the brain through the gut microbiota–brain axis.This axis indicates that gut microbiota is closely related to the development and prognosis of intracerebral hemorrhage and its associated secondary white matter injury.The NACHT,LRR,and pyrin domain-containing protein 3(NLRP3)inflammasome plays a crucial role in this context.This review summarizes the dysbiosis of gut microbiota following intracerebral hemorrhage and explores the mechanisms by which this imbalance may promote the activation of the NLRP3 inflammasome.These mechanisms include metabolic pathways(involving short-chain fatty acids,lipopolysaccharides,lactic acid,bile acids,trimethylamine-N-oxide,and tryptophan),neural pathways(such as the vagus nerve and sympathetic nerve),and immune pathways(involving microglia and T cells).We then discuss the relationship between the activated NLRP3 inflammasome and secondary white matter injury after intracerebral hemorrhage.The activation of the NLRP3 inflammasome can exacerbate secondary white matter injury by disrupting the blood–brain barrier,inducing neuroinflammation,and interfering with nerve regeneration.Finally,we outline potential treatment strategies for intracerebral hemorrhage and its secondary white matter injury.Our review highlights the critical role of the gut microbiota–brain axis and the NLRP3 inflammasome in white matter injury following intracerebral hemorrhage,paving the way for exploring potential therapeutic approaches.
基金supported by grants from NIH T32(DK007260,to WC)the Steno North American Fellowship awarded by the Novo Nordisk Foundation(NNF23OC0087108,to WC)+6 种基金STI2030-Major Projects(2021ZD0202700,to HY)the National Natural Science Foundation of China(32241004,to HY)the Natural Science Foundation of Zhejiang Province of China(LR24C090001,to HY)Key R&D Program of Zhejiang Province(2024SSYS0017,to HY)CAMS Innovation Fund for Medical Sciences(2019-12M-5-057,to HY)Fundamental Research Funds for the Central Universities(226-2022-00193,to HY)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2023-PT310-01,to HY)。
文摘Type 2 diabetes mellitus has central complications:Diabetes,a metabolic disorder primarily characterized by hyperglycemia due to insufficient insulin secretion,or impaired insulin signaling,has significant central complications.Type 2 diabetes mellitus(T2DM),the most prevalent type of diabetes,affects more than 38 million individuals in the United States(approximately 1 in 10)and is defined by chronic hyperglycemia and insulin resistance,which refers to a reduced cellular response to insulin.
基金Supported by Provincial Key Research Project of Henan Province,No.232102310081.
文摘BACKGROUND Major depressive disorder(MDD)and obesity(OB)are bidirectionally comorbid conditions with common neurobiological underpinnings.However,the neurocognitive mechanisms of their comorbidity remain poorly understood.AIM To examine regional abnormalities in spontaneous brain activity among patients with MDD-OB comorbidity.METHODS This study adopted a regional homogeneity(ReHo)analysis of resting-state functional magnetic resonance imaging.The study included 149 hospital patients divided into four groups:Patients experiencing their first episode of drug-naive MDD with OB,patients with MDD without OB,and age-and sex-matched healthy individuals with and without OB.Whole-brain ReHo analysis was conducted using SPM12 software and RESTplus toolkits,with group comparisons via ANOVA and post-hoc tests.Correlations between ReHo values and behavioral measures were examined.RESULTS ANOVA revealed significant whole-brain ReHo differences among the four groups in four key regions:The left middle temporal gyrus(MTG.L),right cuneus,left precuneus,and left thalamus.Post-hoc analyses confirmed pairwise differences between all groups across these regions(P<0.05).OB was associated with ReHo alterations in the MTG.L,right cuneus,and left thalamus,whereas abnormalities in the precuneus suggested synergistic pathological mechanisms between MDD and OB.Statistically significant correlations were found between the drive and fun-seeking dimensions of the behavioral activation system,as well as behavioral inhibition and the corresponding ReHo values.CONCLUSION Our findings provide novel evidence for the neuroadaptive mechanisms underlying the MDD-OB comorbidity.Further validation could lead to personalized interventions targeting MTG.L hyperactivity and targeting healthy food cues.
基金supported by the award W81XWH1910309 (to HF) from the Department of Defensethe award R01-AG075092-01 (to HF)+2 种基金the award RF1AG063521 from the National Institute of Aging at the National Institutes of Healththe Neurological Research Institute Seed grant (to HF) from The Ohio State Universitythe Summer Undergraduate Research Fellowship (to NS) from The Ohio State University Chronic Brain Injury Discovery Theme
文摘BCL2-associated anthanogene 3 facilitates the clearance of tau protein aggregates:BCL2-associated anthanogene 3(BAG3)is a ubiquitously expressed and highly conserved multi-functional co-chaperone protein involved in many biological processes that supports cellular homeostasis,including the inhibition of apoptosis by preventing mitochondrial BAX localization(Lin et al.,2022)and the promotion of the degradation of hyperphosphorylated tau aggregates by its interactions with SQSTM1(p62)(Hamano and Mutoh,2022).
基金supported by Ministry of Science and Technology China Brain Initiative Grant,No.2022ZD0204702(to ZY)the National Natural Science Foundation of China,No.82371357(to LC)+2 种基金Foundation for Military Medicine,No.16QNP085(to ZY)Navy Medical University Basic Medical College“Yi Zhang”Basic Medical Talent Development and Support Program,Nos.JCYZRC-D-022(to TC)and JCYZRC-D-024(to HD)Science and Technology Innovation Special Fund of Shanghai Baoshan District,No.2023-E-05(to YW).
文摘Macrophages in the brain barrier system include microglia in the brain parenchyma,border-associated macrophages at the brain’s borders,and recruited macrophages.They are responsible for neural development,maintenance of homeostasis,and orchestrating immune responses.With the rapid exploitation and development of new technologies,there is a deeper understanding of macrophages in the brain barrier system.Here we review the origin,development,important molecules,and functions of macrophages,mainly focusing on microglia and border-associated macrophages.We also highlight some advances in single-cell sequencing and significant cell markers.We anticipate that more advanced methods will emerge to study resident and recruited macrophages in the future,opening new horizons for neuroimmunology and related peripheral immune fields.
基金the National Natural Science Foundation of China,Nos.81925031(to YT)82330099(to YT)+7 种基金82404189(to KZ)the Key-Area Research and Development Program of Guangdong Province,No.2023B0303040003(to YT)STI 2030-Major Projects,No.2022ZD0211603(to YT)Guangzhou Key Projects of Brain Science and Brain-Like Intelligence Technology,No.202206060002(to GC and YS)Science and Technology Project of Guangdong Province,No.2018B030332001(to GC)Guangdong Provincial Pearl River Project,No.2021ZT09Y552(to GC)the Guangdong Basic and Applied Basic Research Foundation,No.2022A1515110189(to KZ)Sun Yat-sen Pilot Scientific Research Fund,No.YXQH202427(to KZ).
文摘Radiation-induced brain injury remains one of the most severe complications of radiotherapy for head and neck tumors,with limited options for prevention and treatment.In situ neural regeneration technology has demonstrated promising therapeutic effects in various neurodegenerative and neurotrauma conditions.In this study,we overexpressed the neural transcription factor NeuroD1 using in situ neural regeneration technology in a radiation-induced brain injury mouse model.This approach converted reactive astrocytes into neurons,increased neuronal density,protected endogenous neurons,decreased microglial activation,reduced peripheral CD8+T cell infiltration,and diminished angiogenesis in the injured area,leading to a significant reduction in lesion volume.Additionally,we explored the potential mechanisms of NeuroD1 in situ neural regeneration technology through bulk RNA sequencing,which showed an upregulation of neurogenesis-related genes and a downregulation of immune response-related and angiogenesis-related genes.Furthermore,our findings suggested that NeuroD1 in situ neural regeneration technology converted reactive astrocytes into neurons and reduced microglial activation in a thalamic hemorrhagic stroke mouse model.In summary,this study supports NeuroD1 in situ neural regeneration technology as a potential therapeutic approach for treating radiation-induced brain injury and hemorrhagic stroke,and offers new insights into the therapeutic role of NeuroD1 in delayed brain injury.
基金supported in part by the Rosetrees Trust(#CF-2023-I-2_113)by the Israel Ministry of Innovation,Science,and Technology(#7393)(to ES).
文摘The organization of biological neuronal networks into functional modules has intrigued scientists and inspired engineers to develop artificial systems.These networks are characterized by two key properties.First,they exhibit dense interconnectivity(Braitenburg and Schüz,1998;Campagnola et al.,2022).The strength and probability of connectivity depend on cell type,inter-neuronal distance,and species.Still,every cortical neuron receives input from thousands of other neurons while transmitting output to a similar number of neurons.Second,communication between neurons occurs primarily via chemical or electrical synapses.
文摘Subarachnoid hemorrhage(SAH) is a devastating condition that affects a total of 8 million people worldwide each year(Lauzier and Athiraman, 2024). Etiologies of SAH can be traumatic or nontraumatic, with the majority of non-traumatic SAH occurring due to intracranial aneurysm rupture(Rutledge et al., 2014).
基金Supported by the Guangdong Provincial Natural Science Foundation(No.2022A1515010783)the Sustainable Development Program of Shenzhen Science and Technology Major Program(No.KCXFZ20240903093925033)+4 种基金the Guangdong Provincial Special Project in Science and Technology(No.2021A05240)the Special Project in Key Fields of Guangdong Provincial Higher Education Institutions(No.2021ZDZX2064)the Basic Research Project of Shenzhen Science and Technology Innovation Commission(No.JCYJ20220530162014032)the Zhanjiang Marine Youth Talent Innovation Project(No.2022E05010)the Program for Scientific Research Start-up Funds of Guangdong Ocean University(Nos.R18008,060302042201)。
文摘Alzheimer’s disease(AD)is a complex neurodegenerative disorder associated with changes in inflammation,oxidative stress,and gut microbiota composition.Butyrolactone Ⅰ(BTL-Ⅰ),a fungal metabolite,has shown anti-inflammatory,microbiota regulating,and memory-improving potentials in previous in vitro and AlCl3-induced zebrafish studies.However,its effects of memory-improving and gutbrain axis regulating on Aβ-induced mammalian AD models have not been explored.In this study,intragastric administrated BTL-Ⅰ ameliorated cognitive deficits related to recognition and spatial memory impaired by Aβ_(1-42)intracerebroventricular injection in mice.BTL-Ⅰ maintained gut microbiota balance by increasing the abundance of Blautia,Muribaculaceae,Bacteroides,Akkermansia,etc.,and decreasing CAG-352,Clostridia UCG-014,different Lachnospiraceae groups,etc.,and Firmicutes/Bacteroidota ratio and elevated the levels of short-chain fatty acids.Additionally,it alleviated intestinal oxidative stress,inflammatory responses,and pathological damage.Furthermore,BTL-I reversed Aβ_(1-42)-induced activation of microglia and astrocytes in the hippocampus and inhibited the elevated oxidative stress and proinflammatory cytokines in both plasma and brain.The correlation analysis between the regulated taxa and biomarkers supports the role of gut microbiota in adjusting inflammation,oxidative stress,and memory.In conclusion,BTL-I may serve as a valuable drug lead for treating Alzheimer’s disease by systematically inhibiting microbiota imbalance,inflammation,and oxidative stress along the gut-brain axis.
基金supported by National Institute of Food and Agriculture,U.S.Department of Agriculture,under the award number 2024-67015-42622 to PFMississippi State Agricultural and Forestry Experiment Station(MAFES)Strategic Research Initiative Programsupported by the Mississippi State University College of Agriculture and Life Science/MAFES Undergraduate Research Scholars Program。
文摘Gut-brain communication via the peripheral neural network is vital for regulating local digestive function and systemic physiology.Gut microbiota,which produces a wide array of neuroactive compounds,is a critical modulator in this bidirectional dialog.Perturbations in the gut microbiota have been implicated in neurological disorders such as depression and stress.Distinct from humans and other monogastric animals,ruminants possess a unique,microbially dense gastrointestinal compartment,the rumen,that facilitates the digestion of fibrous plant materials.These ruminal microbes are likely key contributors to rumen-brain crosstalk.Unlike certain microbe-derived neuroactive compounds produced in the hindgut that are minimally absorbed and primarily excreted in feces,those generated in rumen can reach the small intestine,where they are largely absorbed and affect central nervous system through systemic regulation in addition to the vagal pathway.Notably,emerging evidence suggests that rumen microbiota dysbiosis under stress is associated with abnormal behavior,altered hormonal and neurotransmitter levels.In this review,we introduce the concept of the rumen-microbiome-brain axis by comparing the anatomical structures and microbial characteristics of the intestine and the rumen,emphasizing the neuroactive potential of rumen microbiome and underlying mechanisms.Advances in this frontier hold tremendous promise to reveal a novel dimension of the gut-microbiome-brain axis,providing transformative opportunities to improve ruminant welfare,productivity,and agricultural sustainability.
基金supported by the National Key R&D Program of China(2021YFF1200602)the National Science Fund for Excellent Overseas Scholars(0401260011)+3 种基金the National Defense Science and Technology Innovation Fund of Chinese Academy of Sciences(c02022088)the Tianjin Science and Technology Program(20JCZDJC00810)the National Natural Science Foundation of China(82202798)the Shanghai Sailing Program(22YF1404200).
文摘Brain-computer interfaces(BCIs)represent an emerging technology that facilitates direct communication between the brain and external devices.In recent years,numerous review articles have explored various aspects of BCIs,including their fundamental principles,technical advancements,and applications in specific domains.However,these reviews often focus on signal processing,hardware development,or limited applications such as motor rehabilitation or communication.This paper aims to offer a comprehensive review of recent electroencephalogram(EEG)-based BCI applications in the medical field across 8 critical areas,encompassing rehabilitation,daily communication,epilepsy,cerebral resuscitation,sleep,neurodegenerative diseases,anesthesiology,and emotion recognition.Moreover,the current challenges and future trends of BCIs were also discussed,including personal privacy and ethical concerns,network security vulnerabilities,safety issues,and biocompatibility.
基金supported by the Natural Science Foundation of Guangdong Province(2022A1515010297)the National Natural Science Foundation of China(32100765)+1 种基金the Xiamen Medical Health Science and Technology Project(3502Z20194098)the Shenzhen-Hong Kong-Macao Science and Technology Innovation Project(SGDX2020110309280100).
文摘Dear Editor,Sturge-Weber Syndrome(SWS)is a rare congenital neurocutaneous syndrome[1,2],with an estimated prevalence of 0.19 in 100,000 annually[3].It is a non-hereditary disease linked to a somatic mutation in the GNAQ,GNA11,or GNB2 gene[1],leading to vascular malformations in the cutaneous forehead,cerebral cortex,and eye[1,2].Notably,~70%of pediatric patients diagnosed with SWS exhibit brain calcification(BC)[4],though the prevalence of BC ranges from only 1%in young individuals to>20%in the senior population(>60 years old)[5].Similar to the elderly,BC in pediatric SWS patients is identified as vascular calcification[6,7],whereas BC in pediatric patients with tuberous sclerosis and tumors has been previously described as dystrophic calcification[6].
基金supported by the STI 2030-Major Project(2021ZD0204400,2022ZD0205203,2021ZD0200104,2022ZD0211900)the Shenzhen Science and Technology Program(RCYX20210706092100003,RCBS20221008093311027)+3 种基金the Shenzhen Medical Research Funds(A2303005)the Youth Innovation Promotion Association CAS(2022367)the National Natural Science Foundation of China(32100896)NSFC-Guangdong Joint Fund(U20A6005).
文摘Dear Editor,The mammalian brain exhibits cross-scale complexity in neuronal morphology and connectivity,the study of which demands high-resolution morphological reconstruction of individual neurons across the entire brain[1-4].Current commonly used approaches for such mesoscale brain mapping include two main types of three-dimensional fluorescence microscopy:the block-face methods,and the lightsheet-based methods[5,6].In general,the high imaging speed and light efficiency of light-sheet microscopy make it a suitable tool for high-throughput volumetric imaging,especially when combined with tissue-clearing techniques.However,large brain samples pose major challenges to this approach.
基金supported by the Program of the National Natural Science Foundation of China(52275291)(52435006)the Program for Innovation Team of Shaanxi Province(2023CX-TD-17)the Fundamental Research Funds for the Central Universities。
文摘Brain,the material foundation of human intelligence,is the most complex tissue in the human body.Brain diseases are among the leading threats to human life,yet our understanding of their pathogenic mechanisms and drug development remains limited,largely due to the lack of accurate brain-like tissue models that replicate its complex structure and functions.Therefore,constructing brain-like models—both in morphology and function—possesses significant scientific value for advancing brain science and pathological pharmacology research,representing the frontiers in the biomanufacturing field.This review outlines the primary requirements and challenges in biomanufacturing brain-like tissue,addressing its complex structures,functions,and environments.Also,the existing biomanufacturing technologies,strategies,and characteristics for brain-like models are depicted,and cutting-edge developments in biomanufacturing central neural repair prosthetics,brain development models,brain disease models,and brain-inspired biocomputing models are systematically reviewed.Finally,the paper concludes with future perspectives on the biomanufacturing of brain-like tissue transitioning from structural manufacturing to intelligent functioning.
基金supported by the Natural Science Foundation of China(32270663 and 31230045 to J.Y.L.)China Postdoctoral Science Foundation(2024M762007 and GZB20240453 to J.L.)Shanghai Municipal Science and Technology Major Project(2018SHZDZX05 to J.Y.L.).
文摘Brain calcification is frequently detected by neuroimaging in patients with hereditary and nonhereditary disorders or in normal individuals with aging.Its prevalence ranges from approximately 1%in young people to over 20%in the elderly(Yamada et al.,2013),yet the underlying mechanisms of brain calcification remain poorly understood.Specifically,calcification in the basal ganglia is detected in approximately 5.5%-20%of CT scans in patients over 50 years old(Auffray-Calvier et al.,2020).
基金supported by the University of Macao(MYRG2022-00054-FHS and MYRGGRG2023-00038-FHS-UMDF)the Macao Science and Technology Development Fund(FDCT0048/2021/AGJ and FDCT0020/2019/AMJ)Natural Science Foundation of Guangdong Province(EF017/FHS-YZ/2021/GDSTC).
文摘Acquired brain injury(ABI)is an injury that affects the brain structure and function.Traditional ABI treatment strategies,including medications and rehabilitation therapy,exhibit their ability to improve its impairments in cognition,emotion,and physical activity.Recently,near-infrared(NIR)photobiomodulation(PBM)has emerged as a promising physical intervention method for ABI,demonstrating that low-level light therapy can modulate cellular metabolic processes,reduce the in flammation and reactive oxygen species of ABI microenvironments,and promote neural repair and regeneration.Preclinical studies using ABI models have been carried out,revealing the potential of PBM in promoting brain injury recovery although its clinical application is still in its early stages.In this review,we first inspected the possible physical and biological mechanisms of NIR-PBM,and then reported the pathophysiology and physiology of ABI underlying NIR-PBM intervention.Therefore,the potential of NIR-PBM as a therapeutic intervention in ABI was demonstrated and it is also expected that further work can facilitate its clinical applications.
基金supported by the National Natural Science Foundation of China,No.82371444(to YZ)the Natural Science Foundation of Hubei Province,No.2022CFB216(to XC)the Key Research Project of Ministry of Science and Technology of China,No.2022ZD021160(to YZ)。
文摘The hypothalamic-pituitary-adrenal axis regulates the secretion of glucoco rticoids in response to environmental challenges.In the brain,a nuclear receptor transcription fa ctor,the glucocorticoid recepto r,is an important component of the hypothalamicpituitary-a d renal axis's negative feedback loop and plays a key role in regulating cognitive equilibrium and neuroplasticity.The glucoco rticoid receptor influences cognitive processes,including glutamate neurotransmission,calcium signaling,and the activation of brain-derived neurotrophic factor-mediated pathways,through a combination of genomic and non-genomic mechanisms.Protein interactions within the central nervous system can alter the expression and activity of the glucocorticoid receptor,there by affecting the hypothalamic-pituitary-a d renal axis and stress-related cognitive functions.An appropriate level of glucocorticoid receptor expression can improve cognitive function,while excessive glucocorticoid receptors or long-term exposure to glucoco rticoids may lead to cognitive impairment.Patients with cognitive impairment-associated diseases,such as Alzheimer's disease,aging,depression,Parkinson's disease,Huntington's disease,stroke,and addiction,often present with dysregulation of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor expression.This review provides a comprehensive overview of the functions of the glucoco rticoid receptor in the hypothalamic-pituitary-a d renal axis and cognitive activities.It emphasizes that appropriate glucocorticoid receptor signaling fa cilitates learning and memory,while its dysregulation can lead to cognitive impairment.This provides clues about how glucocorticoid receptor signaling can be targeted to ove rcome cognitive disability-related disorders.
基金supported by the Fundamental Research Program of Shanxi Province of China,No.20210302124277the Science Foundation of Shanxi Bethune Hospital,No.2021YJ13(both to JW)。
文摘Repetitive traumatic brain injury impacts adult neurogenesis in the hippocampal dentate gyrus,leading to long-term cognitive impairment.However,the mechanism underlying this neurogenesis impairment remains unknown.In this study,we established a male mouse model of repetitive traumatic brain injury and performed long-term evaluation of neurogenesis of the hippocampal dentate gyrus after repetitive traumatic brain injury.Our results showed that repetitive traumatic brain injury inhibited neural stem cell proliferation and development,delayed neuronal maturation,and reduced the complexity of neuronal dendrites and spines.Mice with repetitive traumatic brain injuryalso showed deficits in spatial memory retrieval.Moreover,following repetitive traumatic brain injury,neuroinflammation was enhanced in the neurogenesis microenvironment where C1q levels were increased,C1q binding protein levels were decreased,and canonical Wnt/β-catenin signaling was downregulated.An inhibitor of C1 reversed the long-term impairment of neurogenesis induced by repetitive traumatic brain injury and improved neurological function.These findings suggest that repetitive traumatic brain injury–induced C1-related inflammation impairs long-term neurogenesis in the dentate gyrus and contributes to spatial memory retrieval dysfunction.
基金supported by research grants from the Ningbo Science and Technology Plan Project,No.2022Z143hezuo(to BL)the National Natural Science Foundation of China,No.82201520(to XD)。
文摘Although microglial polarization and neuroinflammation are crucial cellular responses after traumatic brain injury,the fundamental regulatory and functional mechanisms remain insufficiently understood.As potent anti-inflammato ry agents,the use of glucoco rticoids in traumatic brain injury is still controversial,and their regulatory effects on microglial polarization are not yet known.In the present study,we sought to determine whether exacerbation of traumatic brain injury caused by high-dose dexamethasone is related to its regulatory effects on microglial polarization and its mechanisms of action.In vitro cultured BV2 cells and primary microglia and a controlled cortical impact mouse model were used to investigate the effects of dexamethasone on microglial polarization.Lipopolysaccharide,dexamethasone,RU486(a glucocorticoid receptor antagonist),and ruxolitinib(a Janus kinase 1 antagonist)were administered.RNA-sequencing data obtained from a C57BL/6 mouse model of traumatic brain injury were used to identify potential targets of dexamethasone.The Morris water maze,quantitative reverse transcription-polymerase chain reaction,western blotting,immunofluorescence and confocal microscopy analysis,and TUNEL,Nissl,and Golgi staining were performed to investigate our hypothesis.High-throughput sequencing results showed that arginase 1,a marker of M2 microglia,was significantly downregulated in the dexamethasone group compared with the traumatic brain injury group at3 days post-traumatic brain injury.Thus dexamethasone inhibited M1 and M2 microglia,with a more pronounced inhibitory effect on M2microglia in vitro and in vivo.Glucocorticoid receptor plays an indispensable role in microglial polarization after dexamethasone treatment following traumatic brain injury.Additionally,glucocorticoid receptor activation increased the number of apoptotic cells and neuronal death,and also decreased the density of dendritic spines.A possible downstream receptor signaling mechanism is the GR/JAK1/STAT3 pathway.Overactivation of glucocorticoid receptor by high-dose dexamethasone reduced the expression of M2 microglia,which plays an antiinflammatory role.In contrast,inhibiting the activation of glucocorticoid receptor reduced the number of apoptotic glia and neurons and decreased the loss of dendritic spines after traumatic brain injury.Dexamethasone may exe rt its neurotoxic effects by inhibiting M2 microglia through the GR/JAK1/STAT3 signaling pathway.
