Attention is the cornerstone of effective functioning in a complex and information-rich world.While the neural activity of attention has been extensively studied in the cortex,the brain-wide neural activity patterns a...Attention is the cornerstone of effective functioning in a complex and information-rich world.While the neural activity of attention has been extensively studied in the cortex,the brain-wide neural activity patterns are largely unknown.In this study,we conducted a comprehensive analysis of neural activity across the mouse brain during attentional processing using EEG and c-Fos staining,utilizing hierarchical clustering and c-Fos-based functional network analysis to evaluate the c-Fos activation patterns.Our findings reveal that a wide range of brain regions are activated,notably in the high-order cortex,thalamus,and brain stem regions involved in advanced cognition and arousal regulation,with the central lateral nucleus of the thalamus as a strong hub,suggesting the crucial role of the thalamus in attention control.These results provide valuable insights into the neural network mechanisms underlying attention,offering a foundation for formulating functional hypotheses and conducting circuit-level testing.展开更多
N^(6)-methyladenosine RNA methylation,an essential post-transcriptional modification,dynamically regulates RNA metabolism and plays a crucial role in neuronal function.Growing evidence suggests that dysregulated N^(6)...N^(6)-methyladenosine RNA methylation,an essential post-transcriptional modification,dynamically regulates RNA metabolism and plays a crucial role in neuronal function.Growing evidence suggests that dysregulated N^(6)-methyladenosine modification contributes to the pathogenesis of neurodegenerative diseases,including Alzheimer’s disease,Parkinson’s disease,multiple sclerosis,and amyotrophic lateral sclerosis.However,the precise mechanisms by which N^(6)-methyladenosine modification influences these conditions remain unclear.This review summarizes the role of m6A modification and its associated regulators in neurodegeneration,focusing on their involvement in key pathological processes.In Alzheimer’s disease,m6A modification contributes to synaptic dysfunction,mitochondrial damage,and neuronal apoptosis.Evidence from APP/PS1,5xFAD,tau transgenic,and Drosophila models demonstrates that regulators such as methyltransferase-like 3 and fat mass and obesity-associated protein influence Alzheimer’s disease progression through neuroinflammation,circular RNAs dysregulation,and autophagy-related mechanisms.In Parkinson’s disease,altered N^(6)-methyladenosine regulator expression affects dopaminergic neuron survival and stress responses by modulating mRNA stability and autophagy-related lncRNAs.In multiple sclerosis and amyotrophic lateral sclerosis,N^(6)-methyladenosine affects immune activation,myelin repair,and the regulation of disease-associated genes such as TDP-43.Beyond N^(6)-methyladenosine,other RNA methylation modifications-such as m1A,m5C,m7G,uracil,and pseudouridine-are implicated in neurodegenerative diseases through their regulation of mitochondrial function,RNA metabolism,and neuronal stress responses.Additionally,N^(6)-methyladenosine exhibits cell type-specific functions:in microglia,it regulates inflammatory activation and phagocytic function;in astrocytes,it modulates metabolic homeostasis and glutamate-associated neurotoxicity;in neurons,it affects synaptic function and neurodegeneration-related gene expression;and in adult neural stem cells,it controls differentiation,neurogenesis,and cognitive plasticity.Recently,several small-molecule inhibitors targeting methyltransferase-like 3 or fat mass and obesity-associated protein have been developed to modulate N^(6)-methyladenosine modification,providing new opportunities for disease intervention,with the targeting of N⁶-methyladenosine-related pathways emerging as a promising therapeutic strategy.However,challenges persist in optimizing the specificity and delivery of these therapeutic approaches.展开更多
Neuroscientists have emphasized visceral influences on consciousness and attention,but the potential neurophysiological pathways remain under exploration.Here,we found two neurophysiological pathways of heartbrain int...Neuroscientists have emphasized visceral influences on consciousness and attention,but the potential neurophysiological pathways remain under exploration.Here,we found two neurophysiological pathways of heartbrain interaction based on the relationship between oxygen-transport by red blood cells(RBCs)and consciousness/attention.To this end,we collected a dataset based on the routine physical examination,the breaking continuous flash suppression(b-CFS)paradigm,and an attention network test(ANT)in 140 immigrants under the hypoxic Tibetan environment.We combined electroencephalography and multilevel mediation analysis to investigate the relationship between RBC properties and consciousness/attention.The results showed that RBC function,via two independent neurophysiological pathways,not only triggered interoceptive re-representations in the insula and awareness connected to orienting attention but also induced an immune response corresponding to consciousness and executive control.Importantly,consciousness played a fundamental role in executive function which might be associated with the level of perceived stress.These results indicated the important role of oxygen-transport in heart-brain interactions,in which the related stress response affected consciousness and executive control.The findings provide new insights into the neurophysiological schema of heartbrain interactions.展开更多
Chronic cerebral hypoperfusion leads to white matter injury(WMI),which plays a significant role in contributing to vascular cognitive impairment.While 13-docosenamide is a type of fatty acid amide,it remains unclear w...Chronic cerebral hypoperfusion leads to white matter injury(WMI),which plays a significant role in contributing to vascular cognitive impairment.While 13-docosenamide is a type of fatty acid amide,it remains unclear whether it has therapeutic effects on chronic cerebral hypoperfusion.In this study,we conducted bilateral common carotid artery stenosis(BCAS)surgery to simulate chronic cerebral hypoperfusion-induced WMI and cognitive impairment.Our findings showed that 13-docosenamide alleviates WMI and cognitive impairment in BCAS mice.Mechanistically,13-docosenamide specifically binds to cannabinoid receptor 1(CNR1)in oligodendrocyte precursor cells(OPCs).This interaction results in an upregulation of ubiquitin-specific peptidase 33(USP33)-mediated CNR1 deubiquitination,subsequently increasing CNR1 protein expression,activating the phosphorylation of the AKT/mTOR pathway,and promoting the differentiation of OPCs.In conclusion,our study suggests that 13-docosenamide can ameliorate chronic cerebral hypoperfusion-induced WMI and cognitive impairment by enhancing OPC differentiation and could serve as a potential therapeutic drug.展开更多
Lactate,a byproduct of glycolysis,was thought to be a metabolic waste until the discovery of the Warburg effect.Lactate not only functions as a metabolic substrate to provide energy but can also function as a signalin...Lactate,a byproduct of glycolysis,was thought to be a metabolic waste until the discovery of the Warburg effect.Lactate not only functions as a metabolic substrate to provide energy but can also function as a signaling molecule to modulate cellular functions under pathophysiological conditions.The Astrocyte-Neuron Lactate Shuttle has cla rified that lactate plays a pivotal role in the central nervous system.Moreover,protein lactylation highlights the novel role of lactate in regulating transcription,cellular functions,and disease development.This review summarizes the recent advances in lactate metabolism and its role in neurodegenerative diseases,thus providing optimal pers pectives for future research.展开更多
Previous studies have shown that the ATP-P2 X4 receptor signaling pathway mediates the activation of the Nod-like receptor family protein 3(NLRP3)inflammasome.The NLRP3 inflammasome may promote renal interstitial infl...Previous studies have shown that the ATP-P2 X4 receptor signaling pathway mediates the activation of the Nod-like receptor family protein 3(NLRP3)inflammasome.The NLRP3 inflammasome may promote renal interstitial inflammation in diabetic nephropathy.As inflammation also plays an important role in the pathogenesis of Parkinson's disease,we hypothesized that the ATP-P2 X4 receptor signaling pathway may activate the NLRP3 inflammasome in Parkinson's disease.A male rat model of Parkinson's disease was induced by stereotactic injection of 6-hydroxydopamine into the pars compacta of the substantia nigra.The P2 X4 receptor and the NLRP3 inflammasome(interleukin-1βand interleukin-18)were activated.Intracerebroventricular injection of the selective P2 X4 receptor antagonist 5-(3-bromophenyl)-1,3-dihydro-2 H-benzofuro[3,2-e]-1,4-diazepin-2-one(5-BDBD)or knockdown of P2 X4 receptor expression by si RNA inhibited the activation of the NLRP3 inflammasome and alleviated dopaminergic neurodegeneration and neuroinflammation.Our results suggest that the ATP-P2 X4 receptor signaling pathway mediates NLRP3 inflammasome activation,dopaminergic neurodegeneration,and dopamine levels.These findings reveal a novel role of the ATP-P2 X4 axis in the molecular mechanisms underlying Parkinson's disease,thus providing a new target for treatment.This study was approved by the Animal Ethics Committee of Qingdao University,China,on March 5,2015(approval No.QYFYWZLL 26119).展开更多
Microglia-mediated neuroinflammation is widely perceived as a contributor to numerous neurological diseases and mental disorders including depression.Discs large homolog 1(Dlg1),an adaptor protein,regulates cell polar...Microglia-mediated neuroinflammation is widely perceived as a contributor to numerous neurological diseases and mental disorders including depression.Discs large homolog 1(Dlg1),an adaptor protein,regulates cell polarization and the function of K?channels,which are reported to regulate the activation of microglia.However,little is known about the role of Dlg1 in microglia and the maintenance of central nervous system homeostasis.In this study,we found that Dlg1 knockdown suppressed lipopolysaccharide(LPS)-induced inflammation by downregulating the activation of nuclear factor-jB signaling and the mitogen-activated protein kinase pathway in microglia.Moreover,using an inducible Dlg1 microglia-specific knockout(Dlg1flox/flox;CX3CR1CreER)mouse line,we found that microglial Dlg1 knockout reduced the activation of microglia and alleviated the LPS-induced depressionlike behavior.In summary,our results demonstrated that Dlg1 plays a critical role in microglial activation and thus provides a potential therapeutic target for the clinical treatment of depression.展开更多
Microglia and macrophages in the development of maladaptive plastic changes after peripheral nerve injury:Microglia and macrophages encompass the innate immune response to injury in the central and peripheral nervous ...Microglia and macrophages in the development of maladaptive plastic changes after peripheral nerve injury:Microglia and macrophages encompass the innate immune response to injury in the central and peripheral nervous systems,respectively,and are intimately involved in the pathogenesis of maladaptive changes(Tsuda,2019).These dynamic cells can influence neuronal activity in active and quiescent states.Conflicting findings argue that peripheral macrophages facilitate the development of nerve injury-induced neuropathic pain,as opposed to central microglia(Lopes et al.,2017;Yu et al.,2020).展开更多
Multiple Sclerosis（MS） is a major cause of neurological disability in adults and has an annual cost of approximately $28 billion in the United States. MS is a very complex disorder as demyelination can happen in a v...Multiple Sclerosis（MS） is a major cause of neurological disability in adults and has an annual cost of approximately $28 billion in the United States. MS is a very complex disorder as demyelination can happen in a variety of locations throughout the brain; therefore, this disease is never the same in two patients making it very hard to predict disease progression. A modeling approach which combines clinical, biological and imaging measures to help treat and fight this disorder is needed. In this paper, I will outline MS as a very heterogeneous disorder, review some potential solutions from the literature, demonstrate the need for a biomarker and will discuss how computational modeling combined with biological, clinical and imaging data can help link disparate observations and decipher complex mechanisms whose solutions are not amenable to simple reductionism.展开更多
With the constant development of multiphoton microscopy,our ability to observe complex and dynamic biological processes deeper within living tissue,is steadily improving.Researchers use multiphoton microscopy,because ...With the constant development of multiphoton microscopy,our ability to observe complex and dynamic biological processes deeper within living tissue,is steadily improving.Researchers use multiphoton microscopy,because experiments can be conducted with little to no invasiveness or tissue damage over a long period of time with no photodamage(Mancuso et al.,2009).This allows for the introduction of tissue into the context of a three-dimensional 3D environment in which visualization of cellular activation and interaction is viable.By circumventing a distorted reconstruction with limited z-stacks,multiphoton imaging provides enhanced spatiotemporal resolution.展开更多
To enhance the anesthetic efficacy and reduce toxic side effects,a strategy is proposed involving the utilization of general anesthetics of Propofol(Pro)and Eto-midate(Eto)to synergistic inhibition GABA receptors simul...To enhance the anesthetic efficacy and reduce toxic side effects,a strategy is proposed involving the utilization of general anesthetics of Propofol(Pro)and Eto-midate(Eto)to synergistic inhibition GABA receptors simultaneously.Four-in-one molecular aggregates were prepared to implement this strategy,which comprised of Pro and Eto with the bridging molecule monoglyceride monooleate(GMO)and sur-factant F127 through intermolecular forces.The blood-brain barrier(BBB)targeted lactoferrin(LF)is affixed to their surface,obtaining thefinal molecular aggregates.By employing lactoferrin enrich aggregates to the BBB,followed by ultrasound combine microbubbles to open the BBB,a remarkable 4.5-fold enhancement in brain drug delivery was achieved.The molecular aggregates group maintained sta-ble parameters of heart rate,diastolic blood pressure,and systolic blood pressure.A notable increase of more than twice therapeutic index(TI)value was observed,implying their higher anesthesia efficiency and reduced toxicity.Electroencephalo-gram(EEG)experiments demonstrate a significant elevation in the proportion of θ waves from 28%to 80%for aggregates,accompanied by a nearlyfivefold reduc-tion in the proportion ofθwaves,meaning a significant improvement in synergistic anesthesia effectiveness(interaction index 0.289)with lower drug dosage.Further-more,mouse immunofluorescence brain slice experiments suggest Pro and Eto enter the GABA receptor simultaneously,resulting in synergistic inhibition of GABA receptors.展开更多
Astrocytes are an abundant subgroup of cells in the central nervous system(CNS)that play a critical role in controlling neuronal circuits involved in emotion,learning,and memory.In clinical cases,multiple chronic brai...Astrocytes are an abundant subgroup of cells in the central nervous system(CNS)that play a critical role in controlling neuronal circuits involved in emotion,learning,and memory.In clinical cases,multiple chronic brain diseases may cause psychosocial and cognitive impairment,such as depression and Alzheimer’s disease(AD).For years,complex pathological conditions driven by depression and AD have been widely perceived to contribute to a high risk of disability,resulting in gradual loss of self-care ability,lower life qualities,and vast burden on human society.Interestingly,correlational research on depression and AD has shown that depression might be a prodrome of progressive degenerative neurological disease.As a kind of multifunctional glial cell in the CNS,astrocytes maintain physiological function via supporting neuronal cells,modulating pathologic niche,and regulating energy metabolism.Mounting evidence has shown that astrocytic dysfunction is involved in the progression of depression and AD.We herein review the current findings on the roles and mechanisms of astrocytes in the development of depression and AD,with an implication of potential therapeutic avenue for these diseases by targeting astrocytes.展开更多
Dear Editor,Glutamate excitotoxicity due to its accumulation in the extracellular space is a major factor to the brain damage that occurs during the early stages of cerebral ischemia1.GLT-1 is mainly expressed in astr...Dear Editor,Glutamate excitotoxicity due to its accumulation in the extracellular space is a major factor to the brain damage that occurs during the early stages of cerebral ischemia1.GLT-1 is mainly expressed in astrocytes,and it is responsible for almost 90%of glutamate uptake in the brain2.Although GLT-1 upregulation under the administration of ceftriaxone reduces ischemic brain damage,translational application of ceftriaxone in acute ischemia treatment is limited because several days are needed for the upregulation of GLT-1^(3),which misses the critical time window during which suppression of excitotoxicity will be effective.展开更多
Transcription factors(TFs)control an array of expressed genes.However,the specifics of how a gene is expressed in time and space as controlled by a TF remain largely unknown.Here,in TRPC6-regulated proline oxidase 1(P...Transcription factors(TFs)control an array of expressed genes.However,the specifics of how a gene is expressed in time and space as controlled by a TF remain largely unknown.Here,in TRPC6-regulated proline oxidase 1(POX)transcription in human glioma,we report that OIP5-AS1,a long noncoding RNA,determines the specificity of p53-driven POX expression.The OIP5-AS1/p53 complex via its 24 nucleotides binds to the POX promoter and is necessary for POX expression but not for p21 transcription.An O-site in the POX promoter to which OIP5-AS1 binds was identified that is required for OIP5-AS1/p53 binding and POX transcription.Blocking OIP5-AS1 binding to the O-site inhibits POX transcription and promotes glioma development.Thus,the OIP5-AS1/O-site module decides p53-controlled POX expression as regulated by TRPC6 and affects glioma development.展开更多
文摘Attention is the cornerstone of effective functioning in a complex and information-rich world.While the neural activity of attention has been extensively studied in the cortex,the brain-wide neural activity patterns are largely unknown.In this study,we conducted a comprehensive analysis of neural activity across the mouse brain during attentional processing using EEG and c-Fos staining,utilizing hierarchical clustering and c-Fos-based functional network analysis to evaluate the c-Fos activation patterns.Our findings reveal that a wide range of brain regions are activated,notably in the high-order cortex,thalamus,and brain stem regions involved in advanced cognition and arousal regulation,with the central lateral nucleus of the thalamus as a strong hub,suggesting the crucial role of the thalamus in attention control.These results provide valuable insights into the neural network mechanisms underlying attention,offering a foundation for formulating functional hypotheses and conducting circuit-level testing.
基金supported by the National Nature Science Foundation of China(General Program),Nos.82271237,82071218(both to JC),and 82230042(to ZY)the Foundation of Key Laboratory of Neurology,Hebei Medical University,Ministry of Education,China,No.2023001(to JC).
文摘N^(6)-methyladenosine RNA methylation,an essential post-transcriptional modification,dynamically regulates RNA metabolism and plays a crucial role in neuronal function.Growing evidence suggests that dysregulated N^(6)-methyladenosine modification contributes to the pathogenesis of neurodegenerative diseases,including Alzheimer’s disease,Parkinson’s disease,multiple sclerosis,and amyotrophic lateral sclerosis.However,the precise mechanisms by which N^(6)-methyladenosine modification influences these conditions remain unclear.This review summarizes the role of m6A modification and its associated regulators in neurodegeneration,focusing on their involvement in key pathological processes.In Alzheimer’s disease,m6A modification contributes to synaptic dysfunction,mitochondrial damage,and neuronal apoptosis.Evidence from APP/PS1,5xFAD,tau transgenic,and Drosophila models demonstrates that regulators such as methyltransferase-like 3 and fat mass and obesity-associated protein influence Alzheimer’s disease progression through neuroinflammation,circular RNAs dysregulation,and autophagy-related mechanisms.In Parkinson’s disease,altered N^(6)-methyladenosine regulator expression affects dopaminergic neuron survival and stress responses by modulating mRNA stability and autophagy-related lncRNAs.In multiple sclerosis and amyotrophic lateral sclerosis,N^(6)-methyladenosine affects immune activation,myelin repair,and the regulation of disease-associated genes such as TDP-43.Beyond N^(6)-methyladenosine,other RNA methylation modifications-such as m1A,m5C,m7G,uracil,and pseudouridine-are implicated in neurodegenerative diseases through their regulation of mitochondrial function,RNA metabolism,and neuronal stress responses.Additionally,N^(6)-methyladenosine exhibits cell type-specific functions:in microglia,it regulates inflammatory activation and phagocytic function;in astrocytes,it modulates metabolic homeostasis and glutamate-associated neurotoxicity;in neurons,it affects synaptic function and neurodegeneration-related gene expression;and in adult neural stem cells,it controls differentiation,neurogenesis,and cognitive plasticity.Recently,several small-molecule inhibitors targeting methyltransferase-like 3 or fat mass and obesity-associated protein have been developed to modulate N^(6)-methyladenosine modification,providing new opportunities for disease intervention,with the targeting of N⁶-methyladenosine-related pathways emerging as a promising therapeutic strategy.However,challenges persist in optimizing the specificity and delivery of these therapeutic approaches.
基金supported by the National Natural Science Foundation of China(31660274,31771247,and 31600907)the Reformation and Development Funds for Local Region Universities from the Chinese Government in 2020(00060607,ZCJK 2020-11).
文摘Neuroscientists have emphasized visceral influences on consciousness and attention,but the potential neurophysiological pathways remain under exploration.Here,we found two neurophysiological pathways of heartbrain interaction based on the relationship between oxygen-transport by red blood cells(RBCs)and consciousness/attention.To this end,we collected a dataset based on the routine physical examination,the breaking continuous flash suppression(b-CFS)paradigm,and an attention network test(ANT)in 140 immigrants under the hypoxic Tibetan environment.We combined electroencephalography and multilevel mediation analysis to investigate the relationship between RBC properties and consciousness/attention.The results showed that RBC function,via two independent neurophysiological pathways,not only triggered interoceptive re-representations in the insula and awareness connected to orienting attention but also induced an immune response corresponding to consciousness and executive control.Importantly,consciousness played a fundamental role in executive function which might be associated with the level of perceived stress.These results indicated the important role of oxygen-transport in heart-brain interactions,in which the related stress response affected consciousness and executive control.The findings provide new insights into the neurophysiological schema of heartbrain interactions.
基金supported by the National Natural Science Foundation of China(82130036)the STI2030-Major Projects(2022ZD0211800)Jiangsu Province Key Medical Discipline(ZDXK202216).
文摘Chronic cerebral hypoperfusion leads to white matter injury(WMI),which plays a significant role in contributing to vascular cognitive impairment.While 13-docosenamide is a type of fatty acid amide,it remains unclear whether it has therapeutic effects on chronic cerebral hypoperfusion.In this study,we conducted bilateral common carotid artery stenosis(BCAS)surgery to simulate chronic cerebral hypoperfusion-induced WMI and cognitive impairment.Our findings showed that 13-docosenamide alleviates WMI and cognitive impairment in BCAS mice.Mechanistically,13-docosenamide specifically binds to cannabinoid receptor 1(CNR1)in oligodendrocyte precursor cells(OPCs).This interaction results in an upregulation of ubiquitin-specific peptidase 33(USP33)-mediated CNR1 deubiquitination,subsequently increasing CNR1 protein expression,activating the phosphorylation of the AKT/mTOR pathway,and promoting the differentiation of OPCs.In conclusion,our study suggests that 13-docosenamide can ameliorate chronic cerebral hypoperfusion-induced WMI and cognitive impairment by enhancing OPC differentiation and could serve as a potential therapeutic drug.
基金supported by the National Natural Science Foundation of China,Nos.82230042 and 81930029(to ZY),U2004201(to FG and RYP)the China Postdoctoral Science Foundation,No.2020M683748(to RYP)。
文摘Lactate,a byproduct of glycolysis,was thought to be a metabolic waste until the discovery of the Warburg effect.Lactate not only functions as a metabolic substrate to provide energy but can also function as a signaling molecule to modulate cellular functions under pathophysiological conditions.The Astrocyte-Neuron Lactate Shuttle has cla rified that lactate plays a pivotal role in the central nervous system.Moreover,protein lactylation highlights the novel role of lactate in regulating transcription,cellular functions,and disease development.This review summarizes the recent advances in lactate metabolism and its role in neurodegenerative diseases,thus providing optimal pers pectives for future research.
基金supported by the National Natural Science Foundation of China,No.81971192(to AMX)。
文摘Previous studies have shown that the ATP-P2 X4 receptor signaling pathway mediates the activation of the Nod-like receptor family protein 3(NLRP3)inflammasome.The NLRP3 inflammasome may promote renal interstitial inflammation in diabetic nephropathy.As inflammation also plays an important role in the pathogenesis of Parkinson's disease,we hypothesized that the ATP-P2 X4 receptor signaling pathway may activate the NLRP3 inflammasome in Parkinson's disease.A male rat model of Parkinson's disease was induced by stereotactic injection of 6-hydroxydopamine into the pars compacta of the substantia nigra.The P2 X4 receptor and the NLRP3 inflammasome(interleukin-1βand interleukin-18)were activated.Intracerebroventricular injection of the selective P2 X4 receptor antagonist 5-(3-bromophenyl)-1,3-dihydro-2 H-benzofuro[3,2-e]-1,4-diazepin-2-one(5-BDBD)or knockdown of P2 X4 receptor expression by si RNA inhibited the activation of the NLRP3 inflammasome and alleviated dopaminergic neurodegeneration and neuroinflammation.Our results suggest that the ATP-P2 X4 receptor signaling pathway mediates NLRP3 inflammasome activation,dopaminergic neurodegeneration,and dopamine levels.These findings reveal a novel role of the ATP-P2 X4 axis in the molecular mechanisms underlying Parkinson's disease,thus providing a new target for treatment.This study was approved by the Animal Ethics Committee of Qingdao University,China,on March 5,2015(approval No.QYFYWZLL 26119).
基金the National Natural Science Foundation of China(82071218,81630026,and 81930029).
文摘Microglia-mediated neuroinflammation is widely perceived as a contributor to numerous neurological diseases and mental disorders including depression.Discs large homolog 1(Dlg1),an adaptor protein,regulates cell polarization and the function of K?channels,which are reported to regulate the activation of microglia.However,little is known about the role of Dlg1 in microglia and the maintenance of central nervous system homeostasis.In this study,we found that Dlg1 knockdown suppressed lipopolysaccharide(LPS)-induced inflammation by downregulating the activation of nuclear factor-jB signaling and the mitogen-activated protein kinase pathway in microglia.Moreover,using an inducible Dlg1 microglia-specific knockout(Dlg1flox/flox;CX3CR1CreER)mouse line,we found that microglial Dlg1 knockout reduced the activation of microglia and alleviated the LPS-induced depressionlike behavior.In summary,our results demonstrated that Dlg1 plays a critical role in microglial activation and thus provides a potential therapeutic target for the clinical treatment of depression.
基金supported by NIH grant K22NS096030(MDB)American Pain Society Future Leaders Grant(MDB)+1 种基金Rita Allen Foundation Award in Pain(MDB)The University of Texas System STARS program research support grant(MDB).
文摘Microglia and macrophages in the development of maladaptive plastic changes after peripheral nerve injury:Microglia and macrophages encompass the innate immune response to injury in the central and peripheral nervous systems,respectively,and are intimately involved in the pathogenesis of maladaptive changes(Tsuda,2019).These dynamic cells can influence neuronal activity in active and quiescent states.Conflicting findings argue that peripheral macrophages facilitate the development of nerve injury-induced neuropathic pain,as opposed to central microglia(Lopes et al.,2017;Yu et al.,2020).
文摘Multiple Sclerosis（MS） is a major cause of neurological disability in adults and has an annual cost of approximately $28 billion in the United States. MS is a very complex disorder as demyelination can happen in a variety of locations throughout the brain; therefore, this disease is never the same in two patients making it very hard to predict disease progression. A modeling approach which combines clinical, biological and imaging measures to help treat and fight this disorder is needed. In this paper, I will outline MS as a very heterogeneous disorder, review some potential solutions from the literature, demonstrate the need for a biomarker and will discuss how computational modeling combined with biological, clinical and imaging data can help link disparate observations and decipher complex mechanisms whose solutions are not amenable to simple reductionism.
基金NIH grant K22NS096030(to MDB)American Pain Society Future Leaders Grant(MDB)+1 种基金Rita Allen Foundation Award in Pain(to MDB)The University of Texas System STARS program research support grant(to MDB)。
文摘With the constant development of multiphoton microscopy,our ability to observe complex and dynamic biological processes deeper within living tissue,is steadily improving.Researchers use multiphoton microscopy,because experiments can be conducted with little to no invasiveness or tissue damage over a long period of time with no photodamage(Mancuso et al.,2009).This allows for the introduction of tissue into the context of a three-dimensional 3D environment in which visualization of cellular activation and interaction is viable.By circumventing a distorted reconstruction with limited z-stacks,multiphoton imaging provides enhanced spatiotemporal resolution.
基金Young Top-notch Talents of“High-level Talents Special Support Program”of Shaanxi ProvinceNational Natural Science Foundation of China,Grant/Award Numbers:81971290,82102074。
文摘To enhance the anesthetic efficacy and reduce toxic side effects,a strategy is proposed involving the utilization of general anesthetics of Propofol(Pro)and Eto-midate(Eto)to synergistic inhibition GABA receptors simultaneously.Four-in-one molecular aggregates were prepared to implement this strategy,which comprised of Pro and Eto with the bridging molecule monoglyceride monooleate(GMO)and sur-factant F127 through intermolecular forces.The blood-brain barrier(BBB)targeted lactoferrin(LF)is affixed to their surface,obtaining thefinal molecular aggregates.By employing lactoferrin enrich aggregates to the BBB,followed by ultrasound combine microbubbles to open the BBB,a remarkable 4.5-fold enhancement in brain drug delivery was achieved.The molecular aggregates group maintained sta-ble parameters of heart rate,diastolic blood pressure,and systolic blood pressure.A notable increase of more than twice therapeutic index(TI)value was observed,implying their higher anesthesia efficiency and reduced toxicity.Electroencephalo-gram(EEG)experiments demonstrate a significant elevation in the proportion of θ waves from 28%to 80%for aggregates,accompanied by a nearlyfivefold reduc-tion in the proportion ofθwaves,meaning a significant improvement in synergistic anesthesia effectiveness(interaction index 0.289)with lower drug dosage.Further-more,mouse immunofluorescence brain slice experiments suggest Pro and Eto enter the GABA receptor simultaneously,resulting in synergistic inhibition of GABA receptors.
基金We sincerely thank the National Natural Science Foundation of China(Nos.81930029,81630026,and 81501200)the Beijing Nature Science Foundation(No.7161009).
文摘Astrocytes are an abundant subgroup of cells in the central nervous system(CNS)that play a critical role in controlling neuronal circuits involved in emotion,learning,and memory.In clinical cases,multiple chronic brain diseases may cause psychosocial and cognitive impairment,such as depression and Alzheimer’s disease(AD).For years,complex pathological conditions driven by depression and AD have been widely perceived to contribute to a high risk of disability,resulting in gradual loss of self-care ability,lower life qualities,and vast burden on human society.Interestingly,correlational research on depression and AD has shown that depression might be a prodrome of progressive degenerative neurological disease.As a kind of multifunctional glial cell in the CNS,astrocytes maintain physiological function via supporting neuronal cells,modulating pathologic niche,and regulating energy metabolism.Mounting evidence has shown that astrocytic dysfunction is involved in the progression of depression and AD.We herein review the current findings on the roles and mechanisms of astrocytes in the development of depression and AD,with an implication of potential therapeutic avenue for these diseases by targeting astrocytes.
基金the National Natural Science Foundation of China(81830034)Shenzhen-Hong Kong Institute of Brain ScienceShenzhen Fundamental Research Institutions(2021SHIBS0002)Shenzhen Science and Technology Innovation Committee Research Grants(JCYJ20180504165806229,KQJSCX20180322151111754 to S.T.H.).
文摘Dear Editor,Glutamate excitotoxicity due to its accumulation in the extracellular space is a major factor to the brain damage that occurs during the early stages of cerebral ischemia1.GLT-1 is mainly expressed in astrocytes,and it is responsible for almost 90%of glutamate uptake in the brain2.Although GLT-1 upregulation under the administration of ceftriaxone reduces ischemic brain damage,translational application of ceftriaxone in acute ischemia treatment is limited because several days are needed for the upregulation of GLT-1^(3),which misses the critical time window during which suppression of excitotoxicity will be effective.
基金This work was partially supported by the grant(81830043)from the National Natural Science Foundation of China(NSFC).
文摘Transcription factors(TFs)control an array of expressed genes.However,the specifics of how a gene is expressed in time and space as controlled by a TF remain largely unknown.Here,in TRPC6-regulated proline oxidase 1(POX)transcription in human glioma,we report that OIP5-AS1,a long noncoding RNA,determines the specificity of p53-driven POX expression.The OIP5-AS1/p53 complex via its 24 nucleotides binds to the POX promoter and is necessary for POX expression but not for p21 transcription.An O-site in the POX promoter to which OIP5-AS1 binds was identified that is required for OIP5-AS1/p53 binding and POX transcription.Blocking OIP5-AS1 binding to the O-site inhibits POX transcription and promotes glioma development.Thus,the OIP5-AS1/O-site module decides p53-controlled POX expression as regulated by TRPC6 and affects glioma development.
