While acute nociceptive pain is a crucial warning system that protects us from injury or disease,chronic pain is not protective,but a pathological condition.As such,it is now recognized as a disease in its own right,w...While acute nociceptive pain is a crucial warning system that protects us from injury or disease,chronic pain is not protective,but a pathological condition.As such,it is now recognized as a disease in its own right,which major classes refer to inflammatory,neuropathic,and idiopathic pain.It is frequent,with up to a third of the population that may suffer at one point from chronic pain.It is often associated with other pathologies,including sleep disorders,anxiety,depression,and is still difficult to treat.It thus represents a significant burden in terms of health and societal impact(Tracey et al.,2019).The mechanisms of chronic pain involve multiple diverse pathways in both the peripheral and central nervous systems(CNS),reflecting its multifaceted biology.Indeed,research over the past decades has established that central sensitization(enhancement in the function of neurons and circuits in central nociceptive pathways),in particular within the dorsal horn,the first central relay of nociceptive inputs plays a key role in the chronicity of pain(Latremoliere and Woolf,2009).展开更多
The innate immune system of the central nervous system(CNS),long viewed as primarily microgliadriven,is now increasingly recognized to include astrocytes as active participants in neuroimmune signaling.Chronic alcohol...The innate immune system of the central nervous system(CNS),long viewed as primarily microgliadriven,is now increasingly recognized to include astrocytes as active participants in neuroimmune signaling.Chronic alcohol exposure trigge rs oxidative stress,glial activation,and sustained inflammation,ultimately contributing to cognitive decline and neuronal injury.展开更多
In the human spinal cord,astrocytes are the major glial cells.In vitro studies of human astrocytes are relatively simple.However,the straightforward nature of the in vitro environment and complex nature of the in vivo...In the human spinal cord,astrocytes are the major glial cells.In vitro studies of human astrocytes are relatively simple.However,the straightforward nature of the in vitro environment and complex nature of the in vivo environment limit comprehensive investigations into the structure and function of human astrocytes.Additionally,in vivo studies of human astrocytes are further limited by ethical issues.This means there is an urgent need to develop effective in vivo models to study the structure and function of human astrocytes.Here,we first directed human embryonic stem cells to differentiate into human spinal cord dorsal neural stem/progenitor cells in vitro,before transplanting these cells into the gray matter of the cervical spinal cord(C5-T2 segments)of naïve nude rats to create a chimeric human astrocytic rat spinal cord model.The transplanted human spinal cord dorsal neural stem/progenitor cells survived for at least 20 months in the spinal cord environment of the rats,with over 90%differentiating into human astrocytes.These human astrocytes were able to migrate caudally for long distances along the white matter towards the spinal cord.They expressed astrocytic cytoskeletal proteins and functionally-related proteins,suggesting their maturation and structural integration into the rat spinal cord.Thus,this humanized astrocyte chimeric rat spinal cord model provides a valuable tool for studying the role of human spinal cord astrocytes in various spinal diseases.展开更多
The majority of individuals maintain normal physiological and behavioral function despite experiencing severe traumatic stress,demonstrating psychological resilience.Yet a clinically significant proportion develops in...The majority of individuals maintain normal physiological and behavioral function despite experiencing severe traumatic stress,demonstrating psychological resilience.Yet a clinically significant proportion develops increased vulnerability,often presenting as stress-related psychiatric conditions such as major depressive disorder(MDD)[1].The global prevalence of MDD is surging unprecedentedly,contributing substantially to the global burden of disease and disability.展开更多
Understanding the cellular mechanisms of drug addiction remains a key task in current brain research.While neuron-based mechanisms have been extensively explored over the past three decades,recent evidence indicates a...Understanding the cellular mechanisms of drug addiction remains a key task in current brain research.While neuron-based mechanisms have been extensively explored over the past three decades,recent evidence indicates a critical involvement of astrocytes,the main type of non-neuronal cells in the brain.In response to extracellular stimuli,astrocytes modulate the activity of neurons,synaptic transmission,and neural network properties,collectively influencing brain function.G protein-coupled receptors(GPCRs)expressed on astrocyte surfaces respond to neuron-and environment-derived ligands by activating or inhibiting astrocytic signaling,which in turn regulates adjacent neurons and their circuitry.In this review,we focus on the dopamine D1 receptors(D1R)and metabotropic glutamate receptor 5(mGLUR5 or GRM5)—two GPCRs that have been critically implicated in the acquisition and maintenance of addiction-related behaviors.Positioned as an introductory-level review,this article briefly discusses astrocyte biology,outlines earlier discoveries about the role of astrocytes in substance-use disorders(SUDs),and provides detailed discussion about astrocytic D1Rs and mGLUR5s in regulating synapse and network functions in the nucleus accumbens(NAc)—a brain region that mediates addictionrelated emotional and motivational responses.This review serves as a stepping stone for readers of Engineering to explore links between astrocytic GPCRs and drug addiction and other psychiatric disorders.展开更多
Vascular etiology is the second most prevalent cause of cognitive impairment globally.Endothelin-1,which is produced and secreted by endothelial cells and astrocytes,is implicated in the pathogenesis of stroke.However...Vascular etiology is the second most prevalent cause of cognitive impairment globally.Endothelin-1,which is produced and secreted by endothelial cells and astrocytes,is implicated in the pathogenesis of stroke.However,the way in which changes in astrocytic endothelin-1 lead to poststroke cognitive deficits following transient middle cerebral artery occlusion is not well understood.Here,using mice in which astrocytic endothelin-1 was overexpressed,we found that the selective overexpression of endothelin-1 by astrocytic cells led to ischemic stroke-related dementia(1 hour of ischemia;7 days,28 days,or 3 months of reperfusion).We also revealed that astrocytic endothelin-1 overexpression contributed to the role of neural stem cell proliferation but impaired neurogenesis in the dentate gyrus of the hippocampus after middle cerebral artery occlusion.Comprehensive proteome profiles and western blot analysis confirmed that levels of glial fibrillary acidic protein and peroxiredoxin 6,which were differentially expressed in the brain,were significantly increased in mice with astrocytic endothelin-1 overexpression in comparison with wild-type mice 28 days after ischemic stroke.Moreover,the levels of the enriched differentially expressed proteins were closely related to lipid metabolism,as indicated by Kyoto Encyclopedia of Genes and Genomes pathway analysis.Liquid chromatography-mass spectrometry nontargeted metabolite profiling of brain tissues showed that astrocytic endothelin-1 overexpression altered lipid metabolism products such as glycerol phosphatidylcholine,sphingomyelin,and phosphatidic acid.Overall,this study demonstrates that astrocytic endothelin-1 overexpression can impair hippocampal neurogenesis and that it is correlated with lipid metabolism in poststroke cognitive dysfunction.展开更多
Astrocytic Kir4.1 channels and spatial potassium buffering：Astrocytes play a crucial role in maintaining the structural and functional integrity of the brain,which includes formation of the blood-brain barrier,mainte...Astrocytic Kir4.1 channels and spatial potassium buffering：Astrocytes play a crucial role in maintaining the structural and functional integrity of the brain,which includes formation of the blood-brain barrier,maintenance of water and ion homeostasis,metabolism of neurotransmitters and secretion of various neuroactive molecules.展开更多
Dynamic structuring and functions of perisynaptic astrocytic processes and of the gap junction network within a single astrocyte are outlined. Motile perisynaptic astrocytic processes are generating microdomains. By c...Dynamic structuring and functions of perisynaptic astrocytic processes and of the gap junction network within a single astrocyte are outlined. Motile perisynaptic astrocytic processes are generating microdomains. By contacting and retracting of their endfeet an appropriate receptor pattern is selected that modulates the astrocytic receptor sheath for its activation by neurotransmitter substances, ions, transporters, etc. This synaptic information processing occurs in three distinct time scales of milliseconds to seconds, seconds to minutes, hours or longer. Simultaneously, the interconnecting gap junctions are activated by building a network within the astrocyte. Frequently activated gap junction cycles become embodied in gap junction plaques. The gap junction network formation and gap junction plaques are governed and controlled in the same time scales as synaptic information processing. Biomimetic computer systems may represent an alternative to limitations of brainphysiological research. The model proposed allows the interpretation of affective psychoses and schizophrenia as time disorders basically determined by a shortened, prolonged or lacking time scale of synaptic information processing.展开更多
Neurons and glial cells, particularly astrocytes, are the two main cell populations in the central nervous system. While it is established that brain functions primarily rely on neuronal activity, an active contributi...Neurons and glial cells, particularly astrocytes, are the two main cell populations in the central nervous system. While it is established that brain functions primarily rely on neuronal activity, an active contribution of astrocytes to information processing is only starting to be considered. There is growing evidence that astrocytes, as part of the tripartite synapse, participate in this challenge by receiving and integrating neuronal signals and, in turn, by sending signals that target neurons[1]. The involvement of astrocytes in information processing has mainly been studied at the level of the single astrocyte, often missing the role of astrocyte networks in this process.展开更多
Microsatellite instability (MSI) is used as a molecular marker for defective DNA mismatch repair (MMR) genes.We report here alterations of MSI in 15 malignant astrocytomas (WHO grade Ⅲ) and glioblastomas (GBM; WHO gr...Microsatellite instability (MSI) is used as a molecular marker for defective DNA mismatch repair (MMR) genes.We report here alterations of MSI in 15 malignant astrocytomas (WHO grade Ⅲ) and glioblastomas (GBM; WHO grade Ⅳ) of pediatric patients (2-21 years) and 12 GBM from adults (44-68 years) by comparative analysis of BAT25/BAT26 loci and 10 other microsatellite markers. High-level microsatellite instability (MSI-H) occurred in 4 of the 15 pediatric cases (26.7%) and in 1 of the 12 adult GBM cases (8.3%). Low-level mi-展开更多
Objective： To study the expressions of FAK and Pyk2 in human astrocytic tumors and their relationship with angiogenesis. Methods： The S-P immunohistochemical method was used to measure the expressions of FAK, Pyk2 a...Objective： To study the expressions of FAK and Pyk2 in human astrocytic tumors and their relationship with angiogenesis. Methods： The S-P immunohistochemical method was used to measure the expressions of FAK, Pyk2 and VEGF proteins in 58 human brain astrocytic tumors, and microvessel density （MVD） was detected by CD31 staining. Results： In astrocytic tumors with Ⅰ, Ⅱ, Ⅲ and Ⅳ grades, the positive rates of FAK were 20.00%, 26.67%, 44.44% and 50.00%, respectively, those of Pyk2 were 40.00%, 60.00%, 77.78% and 85.00%, respectively. FAK and Pyk2 expressions, especially Pyk2, correlated positively with VEGF expression and MVD. Conclusion： FAK and Pyk2 plays the important role in astrocytic tumor angiogenesis through regulation to VEGF.展开更多
Objective To study the neuroprotective mechanism of minocycline against vascular cognitive impairment after cerebral ischemia. Methods The rat model with vascular cognitive impairment was established by permanent bila...Objective To study the neuroprotective mechanism of minocycline against vascular cognitive impairment after cerebral ischemia. Methods The rat model with vascular cognitive impairment was established by permanent bilateral common carotid artery occlusion （BCCAO）. The observing time-points were determined at 4, 8 and 16 weeks after BCCAO. Animals were randomly divided into sham-operated group （n = 6）, model group （subdivided into 3 groups： 4 weeks after BCCAO, n = 6; 8 weeks after BCCAO, n = 6; and 16 weeks after BCCAO, n = 6）, and minocycline group （subdivided into 3 groups： 4 weeks after BCCAO, n = 6; 8 weeks after BCCAO, n = 6; and 16 weeks after BCCAO, n = 6）. Minocycline was administered by douche via stomach after BCCAO until sacrifice. Glial fibrillary acidic protein （GFAP） was examined by Western blotting and immunohistochemistry. Levels of cyclooxygenase-2 （COX-2） and nuclear factor-kappaB （NF-κB） were measured by immunohistochemistry. IL-1β and TNF-α levels were tested with ELISA method. Results Levels of GFAP, COX- 2, NF-κB, IL-1β and TNF-α were all up-regulated after permanent BCCAO, which could be significantly inhibited by minocycline. Conclusion Minocycline could ameliorate the inflammation and oxidative stress in the hippocampus of the vascular cognitive impairment rat model.展开更多
Plastics such as polyvinyl chlorides （PVC） are widely used in many indoor constructed environments; however, their unbound chemicals, such as di-（2-ethylhexyl） phthalates （DEHP）, can leach into the surrounding e...Plastics such as polyvinyl chlorides （PVC） are widely used in many indoor constructed environments; however, their unbound chemicals, such as di-（2-ethylhexyl） phthalates （DEHP）, can leach into the surrounding environment. This study focused on DEHP＇s effect on the central nervous system by determining the precise DEHP content in mice brain tissue after exposure to the chemical, to evaluate the specific exposure range. Primary neuronal-astrocyte co-culture systems were used as in vitro models for chemical hazard identification of DEHP. Oxidative stress was hypothesized as a probable mechanism involved, and therefore the total reactive oxygen species （ROS） concentration was determined as a biomarker of oxidative stress. In addition, NeuriteTracer, a neurite tracing plugin with ImageJ, was used to develop an assay for neurotoxicity to provide quantitative measurements of neurological parameters, such as neuronal number, neuron count and neurite length, all of which could indicate neurotoxic effects. The results showed that with 1 nmol/L DEHP exposure, there was a significant increase in ROS concentrations, indicating that the neuronal-astrocyte cultures were injured due to exposure to DEHP. In response, astrocyte proliferation （gliosis） was initiated, serving as a mechanism to maintain a homeostatic environment for neurons and protect neurons from toxic chemicals. There is a need to assess the cumulative effects of DEHP in animals to evaluate the possible uotake and effects on the human neuronal system from exoosure to DEHP in the indoor environment.展开更多
Astrocytes, the major component of blood-brain barriers, have presented paradoxical profiles after cerebral ischemia and reperfusion in vivo and in vitro. Our previous study showed that sevoflurane preconditioning imp...Astrocytes, the major component of blood-brain barriers, have presented paradoxical profiles after cerebral ischemia and reperfusion in vivo and in vitro. Our previous study showed that sevoflurane preconditioning improved the integrity of blood-brain barriers after ischemia and reperfusion injury in rats. This led us to investigate the effects of sevoflurane preconditioning on the astrocytic dynamics in ischemia and reperfusion rats, in order to explore astrocytic cell-based mechanisms of sevoflurane preconditioning. In the present study, 2,3,5-triphenyltetrazolium chloride staining and Garcia behavioral scores were utilized to evaluate cerebral infarction and neurological outcome from day 1 to day 3 after transient middle cerebral artery occlusion surgery. Using immunofluorescent staining, we found that sevoflurane preconditioning substantially promoted the astrocytic activation and migration from the penumbra to the infarct with microglial activation from day 3 after middle cerebral artery occlusion. The formation of astrocytic scaffolds facilitated neuroblasts migrating from the subventricular zone to the lesion sites on day 14 after injury. Neural networks increased in the infarct of sevoflurane preconditioned rats, consistent with decreased infarct volume and improved neurological scores after ischemia and reperfusion injury. These findings demonstrate that sevoflurane preconditioning confers neuroprotection, not only by accelerating astrocytic spatial and temporal dynamics, but also providing astrocytic scaffolds for neuroblasts migration to ischemic regions, which facilitates neural reconstruction after brain ischemia.展开更多
Chronic loss of sleep damages health and disturbs the quality of life.Long-lasting sleep deprivation(SD)as well as sleep abnormalities are substantial risk factors for major depressive disorder,although the underlying...Chronic loss of sleep damages health and disturbs the quality of life.Long-lasting sleep deprivation(SD)as well as sleep abnormalities are substantial risk factors for major depressive disorder,although the underlying mechanisms are not clear.Here,we showed that chronic SD in mice promotes a gradual elevation of extracellular ATP,which activates astroglial P2X7 receptors(P2X7Rs).Activated P2X7Rs,in turn,selectively down-regulated the expression of 5-HT2B receptors(5-HT2BRs)in astrocytes.Stimulation of P2X7Rs induced by SD selectively suppressed the phosphorylation of AKT and FoxO3 a in astrocytes,but not in neurons.The overexpression of FoxO3a in astrocytes inhibited the expression of 5-HT2BRs.Down-regulation of 5-HT2BsRs instigated by SD suppressed the activation of STAT3 and relieved the inhibition of Ca2+-dependent phospholipase A2.This latter cascade promoted the release of arachidonic acid and prostaglandin E2.The depression-like behaviors induced by SD were alleviated in P2X7R-KO mice.Our study reveals the mechanism underlying chronic SD-induced depression-like behaviors and suggests 5-HT2BRs as a key target for exploring therapeutic strategies aimed at the depression evoked by sleep disorders.展开更多
Major depressive disorder(MDD) is a common mood disorder that affects almost 20% of the global population.In addition,much evidence has implicated altered function of the gamma-aminobutyric acid(GABAergic) system in t...Major depressive disorder(MDD) is a common mood disorder that affects almost 20% of the global population.In addition,much evidence has implicated altered function of the gamma-aminobutyric acid(GABAergic) system in the pathophysiology of depression.Recent research has indicated that GABA_B receptors(GABA_BRs) are an emerging therapeutic target in the treatment of stress-related disorders such as MDD.However,which cell types with GABA_BRs are involved in this process is unknown.As hippocampal dysfunction is implicated in MDD,we knocked down GABA_BRs in the hippocampus and found that knocking down these receptors in astrocytes,but not in GABAergic or pyramidal neurons,caused a decrease in immobility in the forced swimming test(FST) without affecting other anxiety-and depression-related behaviors.We also generated astrocytespecific GABABR-knockout mice and found decreased immobility in the FST in these mice.Furthermore,the conditional knockout of GABA_BRs in astrocytes selectively increased the levels of brain-derived neurotrophic factor protein in hippocampal astrocytes,which controlled the decrease in immobility in the FST.Taken together,our findings contribute to the current understanding of which cell types expressing GABA_BRs modulate antidepressant activity in the FST,and they may provide new insights into the pathological mechanisms and potential targets for the treatment of depression.展开更多
Acupuncture is a medical treatment that has been widely pra cticed in China for over 3000 years,yet the neural mechanisms of acupuncture are not fully understood.We hypothesized that neurons and astrocytes act indepen...Acupuncture is a medical treatment that has been widely pra cticed in China for over 3000 years,yet the neural mechanisms of acupuncture are not fully understood.We hypothesized that neurons and astrocytes act independently and synergistically under acupuncture stimulation.To investigate this,we used two-photon in vivo calcium reco rding to observe the effects of acupuncture stimulation at ST36(Zusanli)in mice.Acupuncture stimulation in peripheral acupoints potentiated calcium signals of pyramidal neurons and astrocytes in the somatosensory cortex and resulted in late-onset calcium transients in astrocytes.Chemogenetic inhibition of neurons augmented the astrocytic activity.These findings suggest that acupuncture activates neuronal and astrocytic activity in the somatosensory co rtex and provide evidence for the involvement of both neurons and astrocytes in acupuncture treatment.展开更多
BACKGROUND:Folic acid is essential for normal functioning of the nervous system.Previous studies have focused on the effects of folic acid on astrocyte proliferation.OBJECTIVE:To explore the effects of folic acid on a...BACKGROUND:Folic acid is essential for normal functioning of the nervous system.Previous studies have focused on the effects of folic acid on astrocyte proliferation.OBJECTIVE:To explore the effects of folic acid on astrocyte differentiation of neural stem cells(NSCs)and the related mechanisms in vitro.DESIGN,TIME AND SETTING:A randomized,controlled,grouping experiment was performed in Tianjin Medical University between August 2007 and October 2008.MATERIALS:Folic acid and 5-bromo-2-deoxyuridine(BrdU)were obtained from Sigma,MO,USA.Primary antibodies[rabbit anti-rat nestin,β-tubulin-Ⅲ,glial fibrillary acidic protein,and neurogeninl(Ngnl);mouse anti-rat BrdU andβ-actin monoclonal antibodies]were purchased from Santa Cruz Biotechnology,USA.METHODS:At 6 days of NSC proliferation from 24-hour-old neonatal rats,BrdU incorporation assay was performed.Seven days after primary culture,NSCs were induced to differentiate with medium containing 5%fetal bovine serum.Cultured NSCs were assigned to three groups:control,low-dose(liquid media with 8 mg/L folic acid),and high-dose folic acid(liquid media with 44 mg/L folic acid).MAIN OUTCOME MEASURES:At day 7 after primary culture,the cells were identified as NSCs by immunocytochemical methods.Double-label immunofluorescence technique for glial fibrillary acidic protein/BrdU detected differentiated cells 7 days after induction.Western blot was used to analyze expression of Ngnl protein in NSCs.RESULTS:In serum-free suspension medium,neurospheres comprised a large number of Nestin-,glial fibrillary acidic protein-,β-tubulin-Ⅲ-,and BrdU-positive cells.Compared with the control group,high-dose folic acid supplementation led to an marked increase in the percentage of glial fibrillary acidic protein/BrdU-positive cells(P〈0.05),and significantly decreased Ngnl protein expression(P〈0.05).CONCLUSION:Folic acid promotes astrocytic differentiation of NSCs,which might be related to downregulation of Ngnl protein expression.展开更多
Spinal cord injury causes accumulation of a large number of leukocytes at the lesion site where they contribute to excessive inflammation.Overproduced chemokines are responsible for the migratory process of the leukoc...Spinal cord injury causes accumulation of a large number of leukocytes at the lesion site where they contribute to excessive inflammation.Overproduced chemokines are responsible for the migratory process of the leukocytes,but the regulatory mechanism underlying the production of chemokines from resident cells of the spinal cord has not been fully elucidated.We examined the protein levels of macrophage migration inhibitory factor and chemokine C-C motif chemokine ligand 2 in a spinal cord contusion model at different time points following spinal cord injury.The elevation of macrophage migration inhibitory factor at the lesion site coincided with the increase of chemokine C-C motif chemokine ligand 2 abundance in astrocytes.Stimulation of primary cultured astrocytes with different concentrations of macrophage migration inhibitory factor recombinant protein induced chemokine C-C motif chemokine ligand 2 production from the cells,and the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine attenuated the stimulatory effect.Further investigation into the underlying mechanism on macrophage migration inhibitory factor-mediated astrocytic production of chemokine C-C motif chemokine ligand 2 revealed that macrophage migration inhibitory factor activated intracellular JNK signaling through binding with CD74 receptor.Administration of the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine following spinal cord injury resulted in the reduction of chemokine C-C motif chemokine ligand 2-recruited microglia/macrophages at the lesion site and remarkably improved the hindlimb locomotor function of rats.Our results have provided insights into the functions of astrocyte-activated chemokines in the recruitment of leukocytes and may be beneficial to develop interventions targeting chemokine C-C motif chemokine ligand 2 for neuroinflammation after spinal cord injury.展开更多
Neuron-astrocyte interactions are vital for the brain’s connectome.Understanding astrocyte activities is crucial for comprehending the complex neural network,particularly the population-level functions of neurons in ...Neuron-astrocyte interactions are vital for the brain’s connectome.Understanding astrocyte activities is crucial for comprehending the complex neural network,particularly the population-level functions of neurons in different cortical states and associated behaviors in mammals.Studies on animal sleep and wakefulness have revealed distinct cortical synchrony patterns between neurons.Astrocytes,outnumbering neurons by nearly fivefold,support and regulate neuronal and synaptic function.Recent research on astrocyte activation during cortical state transitions has emphasized the influence of norepinephrine as a neurotransmitter and calcium waves as key components of ion channel signaling.This summary focuses on a few recent studies investigating astrocyte-neuron interactions in mouse models during sleep,wakefulness,and arousal levels,exploring the involvement of noradrenaline signaling,ion channels,and glutamatergic signaling in different cortical states.These findings highlight the significant impact of astrocytes on large-scale neuronal networks,influencing brain activity and responsiveness.Targeting astrocytic signaling pathways shows promise for treating sleep disorders and arousal dysregulation.More research is needed to understand astrocytic calcium signaling in different brain regions and its implications for dysregulated brain states,requiring future human studies to comprehensively investigate neuron-astrocyte interactions and pave the way for therapeutic interventions in sleep-and arousal-related disorders.展开更多
基金Institut National de la Santéet de la Recherche Médicale(Inserm)UniversitéClermont Auvergne(France)+2 种基金CHU Clermont-Ferrand(to RD)the French government IDEX-ISITE initiative 16-IDEX-0001(to RD)The Fondation pour la Recherche Médicale(FRM)(to SM).
文摘While acute nociceptive pain is a crucial warning system that protects us from injury or disease,chronic pain is not protective,but a pathological condition.As such,it is now recognized as a disease in its own right,which major classes refer to inflammatory,neuropathic,and idiopathic pain.It is frequent,with up to a third of the population that may suffer at one point from chronic pain.It is often associated with other pathologies,including sleep disorders,anxiety,depression,and is still difficult to treat.It thus represents a significant burden in terms of health and societal impact(Tracey et al.,2019).The mechanisms of chronic pain involve multiple diverse pathways in both the peripheral and central nervous systems(CNS),reflecting its multifaceted biology.Indeed,research over the past decades has established that central sensitization(enhancement in the function of neurons and circuits in central nociceptive pathways),in particular within the dorsal horn,the first central relay of nociceptive inputs plays a key role in the chronicity of pain(Latremoliere and Woolf,2009).
基金supported by startup funding from UNMC to Dr.PPpartially by the National Institute on Alcohol Abuse and Alcoholism (AA031444 and P50AA030407-5126,Pilot Core grant) to Dr.SS
文摘The innate immune system of the central nervous system(CNS),long viewed as primarily microgliadriven,is now increasingly recognized to include astrocytes as active participants in neuroimmune signaling.Chronic alcohol exposure trigge rs oxidative stress,glial activation,and sustained inflammation,ultimately contributing to cognitive decline and neuronal injury.
基金Ministry of Science and Technology of China(STI2030-Major Projects),No.2022ZD0204700(to WW)the National Natural Science Foundation of China,No.82301572(to XZ)China Postdoctoral Science Foundation,No.2023M731202(to XZ).
文摘In the human spinal cord,astrocytes are the major glial cells.In vitro studies of human astrocytes are relatively simple.However,the straightforward nature of the in vitro environment and complex nature of the in vivo environment limit comprehensive investigations into the structure and function of human astrocytes.Additionally,in vivo studies of human astrocytes are further limited by ethical issues.This means there is an urgent need to develop effective in vivo models to study the structure and function of human astrocytes.Here,we first directed human embryonic stem cells to differentiate into human spinal cord dorsal neural stem/progenitor cells in vitro,before transplanting these cells into the gray matter of the cervical spinal cord(C5-T2 segments)of naïve nude rats to create a chimeric human astrocytic rat spinal cord model.The transplanted human spinal cord dorsal neural stem/progenitor cells survived for at least 20 months in the spinal cord environment of the rats,with over 90%differentiating into human astrocytes.These human astrocytes were able to migrate caudally for long distances along the white matter towards the spinal cord.They expressed astrocytic cytoskeletal proteins and functionally-related proteins,suggesting their maturation and structural integration into the rat spinal cord.Thus,this humanized astrocyte chimeric rat spinal cord model provides a valuable tool for studying the role of human spinal cord astrocytes in various spinal diseases.
基金supported by the National Natural Science Foundation of China(32300851)Zhejiang Provincial Natural Science Foundation(LQ24h310008).
文摘The majority of individuals maintain normal physiological and behavioral function despite experiencing severe traumatic stress,demonstrating psychological resilience.Yet a clinically significant proportion develops increased vulnerability,often presenting as stress-related psychiatric conditions such as major depressive disorder(MDD)[1].The global prevalence of MDD is surging unprecedentedly,contributing substantially to the global burden of disease and disability.
基金partially supported by the National Institutes of Health(NIH)grants DA056213(to Alexander K.Zinsmaier),DA053388(to Eric J.Nestler),DA023206(to Yan Dong),DA060868(to Yan Dong),and DA040620(to Eric J.Nestler and Yan Dong)。
文摘Understanding the cellular mechanisms of drug addiction remains a key task in current brain research.While neuron-based mechanisms have been extensively explored over the past three decades,recent evidence indicates a critical involvement of astrocytes,the main type of non-neuronal cells in the brain.In response to extracellular stimuli,astrocytes modulate the activity of neurons,synaptic transmission,and neural network properties,collectively influencing brain function.G protein-coupled receptors(GPCRs)expressed on astrocyte surfaces respond to neuron-and environment-derived ligands by activating or inhibiting astrocytic signaling,which in turn regulates adjacent neurons and their circuitry.In this review,we focus on the dopamine D1 receptors(D1R)and metabotropic glutamate receptor 5(mGLUR5 or GRM5)—two GPCRs that have been critically implicated in the acquisition and maintenance of addiction-related behaviors.Positioned as an introductory-level review,this article briefly discusses astrocyte biology,outlines earlier discoveries about the role of astrocytes in substance-use disorders(SUDs),and provides detailed discussion about astrocytic D1Rs and mGLUR5s in regulating synapse and network functions in the nucleus accumbens(NAc)—a brain region that mediates addictionrelated emotional and motivational responses.This review serves as a stepping stone for readers of Engineering to explore links between astrocytic GPCRs and drug addiction and other psychiatric disorders.
基金financially supported by the National Natural Science Foundation of China,No.81303115,81774042 (both to XC)the Pearl River S&T Nova Program of Guangzhou,No.201806010025 (to XC)+3 种基金the Specialty Program of Guangdong Province Hospital of Chinese Medicine of China,No.YN2018ZD07 (to XC)the Natural Science Foundatior of Guangdong Province of China,No.2023A1515012174 (to JL)the Science and Technology Program of Guangzhou of China,No.20210201 0268 (to XC),20210201 0339 (to JS)Guangdong Provincial Key Laboratory of Research on Emergency in TCM,Nos.2018-75,2019-140 (to JS)
文摘Vascular etiology is the second most prevalent cause of cognitive impairment globally.Endothelin-1,which is produced and secreted by endothelial cells and astrocytes,is implicated in the pathogenesis of stroke.However,the way in which changes in astrocytic endothelin-1 lead to poststroke cognitive deficits following transient middle cerebral artery occlusion is not well understood.Here,using mice in which astrocytic endothelin-1 was overexpressed,we found that the selective overexpression of endothelin-1 by astrocytic cells led to ischemic stroke-related dementia(1 hour of ischemia;7 days,28 days,or 3 months of reperfusion).We also revealed that astrocytic endothelin-1 overexpression contributed to the role of neural stem cell proliferation but impaired neurogenesis in the dentate gyrus of the hippocampus after middle cerebral artery occlusion.Comprehensive proteome profiles and western blot analysis confirmed that levels of glial fibrillary acidic protein and peroxiredoxin 6,which were differentially expressed in the brain,were significantly increased in mice with astrocytic endothelin-1 overexpression in comparison with wild-type mice 28 days after ischemic stroke.Moreover,the levels of the enriched differentially expressed proteins were closely related to lipid metabolism,as indicated by Kyoto Encyclopedia of Genes and Genomes pathway analysis.Liquid chromatography-mass spectrometry nontargeted metabolite profiling of brain tissues showed that astrocytic endothelin-1 overexpression altered lipid metabolism products such as glycerol phosphatidylcholine,sphingomyelin,and phosphatidic acid.Overall,this study demonstrates that astrocytic endothelin-1 overexpression can impair hippocampal neurogenesis and that it is correlated with lipid metabolism in poststroke cognitive dysfunction.
基金supported in part by a Grant from AMED(17ek0109120h0003)a Grant-in-Aid for Scientific Research from the Ministry of Education,Culture,Sports,Science and Technology(17K08324 and 15H04892)
文摘Astrocytic Kir4.1 channels and spatial potassium buffering：Astrocytes play a crucial role in maintaining the structural and functional integrity of the brain,which includes formation of the blood-brain barrier,maintenance of water and ion homeostasis,metabolism of neurotransmitters and secretion of various neuroactive molecules.
文摘Dynamic structuring and functions of perisynaptic astrocytic processes and of the gap junction network within a single astrocyte are outlined. Motile perisynaptic astrocytic processes are generating microdomains. By contacting and retracting of their endfeet an appropriate receptor pattern is selected that modulates the astrocytic receptor sheath for its activation by neurotransmitter substances, ions, transporters, etc. This synaptic information processing occurs in three distinct time scales of milliseconds to seconds, seconds to minutes, hours or longer. Simultaneously, the interconnecting gap junctions are activated by building a network within the astrocyte. Frequently activated gap junction cycles become embodied in gap junction plaques. The gap junction network formation and gap junction plaques are governed and controlled in the same time scales as synaptic information processing. Biomimetic computer systems may represent an alternative to limitations of brainphysiological research. The model proposed allows the interpretation of affective psychoses and schizophrenia as time disorders basically determined by a shortened, prolonged or lacking time scale of synaptic information processing.
文摘Neurons and glial cells, particularly astrocytes, are the two main cell populations in the central nervous system. While it is established that brain functions primarily rely on neuronal activity, an active contribution of astrocytes to information processing is only starting to be considered. There is growing evidence that astrocytes, as part of the tripartite synapse, participate in this challenge by receiving and integrating neuronal signals and, in turn, by sending signals that target neurons[1]. The involvement of astrocytes in information processing has mainly been studied at the level of the single astrocyte, often missing the role of astrocyte networks in this process.
文摘Microsatellite instability (MSI) is used as a molecular marker for defective DNA mismatch repair (MMR) genes.We report here alterations of MSI in 15 malignant astrocytomas (WHO grade Ⅲ) and glioblastomas (GBM; WHO grade Ⅳ) of pediatric patients (2-21 years) and 12 GBM from adults (44-68 years) by comparative analysis of BAT25/BAT26 loci and 10 other microsatellite markers. High-level microsatellite instability (MSI-H) occurred in 4 of the 15 pediatric cases (26.7%) and in 1 of the 12 adult GBM cases (8.3%). Low-level mi-
基金the Science Research Foundation of Health Department of Hubei Province (No. JX1B019)the Science Research Foundation of Wuahn University (No. 301270064)
文摘Objective： To study the expressions of FAK and Pyk2 in human astrocytic tumors and their relationship with angiogenesis. Methods： The S-P immunohistochemical method was used to measure the expressions of FAK, Pyk2 and VEGF proteins in 58 human brain astrocytic tumors, and microvessel density （MVD） was detected by CD31 staining. Results： In astrocytic tumors with Ⅰ, Ⅱ, Ⅲ and Ⅳ grades, the positive rates of FAK were 20.00%, 26.67%, 44.44% and 50.00%, respectively, those of Pyk2 were 40.00%, 60.00%, 77.78% and 85.00%, respectively. FAK and Pyk2 expressions, especially Pyk2, correlated positively with VEGF expression and MVD. Conclusion： FAK and Pyk2 plays the important role in astrocytic tumor angiogenesis through regulation to VEGF.
基金supported in part by High Technology Research Center, Chongqing Medical University and the Ministry of Civil Affairs,China.
文摘Objective To study the neuroprotective mechanism of minocycline against vascular cognitive impairment after cerebral ischemia. Methods The rat model with vascular cognitive impairment was established by permanent bilateral common carotid artery occlusion （BCCAO）. The observing time-points were determined at 4, 8 and 16 weeks after BCCAO. Animals were randomly divided into sham-operated group （n = 6）, model group （subdivided into 3 groups： 4 weeks after BCCAO, n = 6; 8 weeks after BCCAO, n = 6; and 16 weeks after BCCAO, n = 6）, and minocycline group （subdivided into 3 groups： 4 weeks after BCCAO, n = 6; 8 weeks after BCCAO, n = 6; and 16 weeks after BCCAO, n = 6）. Minocycline was administered by douche via stomach after BCCAO until sacrifice. Glial fibrillary acidic protein （GFAP） was examined by Western blotting and immunohistochemistry. Levels of cyclooxygenase-2 （COX-2） and nuclear factor-kappaB （NF-κB） were measured by immunohistochemistry. IL-1β and TNF-α levels were tested with ELISA method. Results Levels of GFAP, COX- 2, NF-κB, IL-1β and TNF-α were all up-regulated after permanent BCCAO, which could be significantly inhibited by minocycline. Conclusion Minocycline could ameliorate the inflammation and oxidative stress in the hippocampus of the vascular cognitive impairment rat model.
基金supported by the Key Project of National Natural Science Foundation of China(No.51136002)China Key Technologies R&D Program(No.2012BAJ02B03)
文摘Plastics such as polyvinyl chlorides （PVC） are widely used in many indoor constructed environments; however, their unbound chemicals, such as di-（2-ethylhexyl） phthalates （DEHP）, can leach into the surrounding environment. This study focused on DEHP＇s effect on the central nervous system by determining the precise DEHP content in mice brain tissue after exposure to the chemical, to evaluate the specific exposure range. Primary neuronal-astrocyte co-culture systems were used as in vitro models for chemical hazard identification of DEHP. Oxidative stress was hypothesized as a probable mechanism involved, and therefore the total reactive oxygen species （ROS） concentration was determined as a biomarker of oxidative stress. In addition, NeuriteTracer, a neurite tracing plugin with ImageJ, was used to develop an assay for neurotoxicity to provide quantitative measurements of neurological parameters, such as neuronal number, neuron count and neurite length, all of which could indicate neurotoxic effects. The results showed that with 1 nmol/L DEHP exposure, there was a significant increase in ROS concentrations, indicating that the neuronal-astrocyte cultures were injured due to exposure to DEHP. In response, astrocyte proliferation （gliosis） was initiated, serving as a mechanism to maintain a homeostatic environment for neurons and protect neurons from toxic chemicals. There is a need to assess the cumulative effects of DEHP in animals to evaluate the possible uotake and effects on the human neuronal system from exoosure to DEHP in the indoor environment.
基金supported by the National Natural Science Foundation of China,No.81200937(to QY)
文摘Astrocytes, the major component of blood-brain barriers, have presented paradoxical profiles after cerebral ischemia and reperfusion in vivo and in vitro. Our previous study showed that sevoflurane preconditioning improved the integrity of blood-brain barriers after ischemia and reperfusion injury in rats. This led us to investigate the effects of sevoflurane preconditioning on the astrocytic dynamics in ischemia and reperfusion rats, in order to explore astrocytic cell-based mechanisms of sevoflurane preconditioning. In the present study, 2,3,5-triphenyltetrazolium chloride staining and Garcia behavioral scores were utilized to evaluate cerebral infarction and neurological outcome from day 1 to day 3 after transient middle cerebral artery occlusion surgery. Using immunofluorescent staining, we found that sevoflurane preconditioning substantially promoted the astrocytic activation and migration from the penumbra to the infarct with microglial activation from day 3 after middle cerebral artery occlusion. The formation of astrocytic scaffolds facilitated neuroblasts migrating from the subventricular zone to the lesion sites on day 14 after injury. Neural networks increased in the infarct of sevoflurane preconditioned rats, consistent with decreased infarct volume and improved neurological scores after ischemia and reperfusion injury. These findings demonstrate that sevoflurane preconditioning confers neuroprotection, not only by accelerating astrocytic spatial and temporal dynamics, but also providing astrocytic scaffolds for neuroblasts migration to ischemic regions, which facilitates neural reconstruction after brain ischemia.
基金the National Natural Science Foundation of China(81871852,81200935,81671862,and 81871529)Liaoning Revitalization Talents Program(XLYC1807137)+1 种基金the Scientific Research Foundation for Overseas Scholars of the Education Ministry of China(20151098)the Natural Science Foundation of Liaoning Province,China(20170541030)。
文摘Chronic loss of sleep damages health and disturbs the quality of life.Long-lasting sleep deprivation(SD)as well as sleep abnormalities are substantial risk factors for major depressive disorder,although the underlying mechanisms are not clear.Here,we showed that chronic SD in mice promotes a gradual elevation of extracellular ATP,which activates astroglial P2X7 receptors(P2X7Rs).Activated P2X7Rs,in turn,selectively down-regulated the expression of 5-HT2B receptors(5-HT2BRs)in astrocytes.Stimulation of P2X7Rs induced by SD selectively suppressed the phosphorylation of AKT and FoxO3 a in astrocytes,but not in neurons.The overexpression of FoxO3a in astrocytes inhibited the expression of 5-HT2BRs.Down-regulation of 5-HT2BsRs instigated by SD suppressed the activation of STAT3 and relieved the inhibition of Ca2+-dependent phospholipase A2.This latter cascade promoted the release of arachidonic acid and prostaglandin E2.The depression-like behaviors induced by SD were alleviated in P2X7R-KO mice.Our study reveals the mechanism underlying chronic SD-induced depression-like behaviors and suggests 5-HT2BRs as a key target for exploring therapeutic strategies aimed at the depression evoked by sleep disorders.
基金supported by grants from the National Natural Science Foundation of China (31430032,31830033, 81671356,and 31600864)the Program for Changjiang Scholars and Innovative Research Teams in University (IRT_16R37)+2 种基金the Science and Technology Program of Guangdong Province,China (2018B030334001)the Guangzhou Municipal Science and Technology Project (201707020027)the Postdoctoral Science Foundation of China (2018M633072)。
文摘Major depressive disorder(MDD) is a common mood disorder that affects almost 20% of the global population.In addition,much evidence has implicated altered function of the gamma-aminobutyric acid(GABAergic) system in the pathophysiology of depression.Recent research has indicated that GABA_B receptors(GABA_BRs) are an emerging therapeutic target in the treatment of stress-related disorders such as MDD.However,which cell types with GABA_BRs are involved in this process is unknown.As hippocampal dysfunction is implicated in MDD,we knocked down GABA_BRs in the hippocampus and found that knocking down these receptors in astrocytes,but not in GABAergic or pyramidal neurons,caused a decrease in immobility in the forced swimming test(FST) without affecting other anxiety-and depression-related behaviors.We also generated astrocytespecific GABABR-knockout mice and found decreased immobility in the FST in these mice.Furthermore,the conditional knockout of GABA_BRs in astrocytes selectively increased the levels of brain-derived neurotrophic factor protein in hippocampal astrocytes,which controlled the decrease in immobility in the FST.Taken together,our findings contribute to the current understanding of which cell types expressing GABA_BRs modulate antidepressant activity in the FST,and they may provide new insights into the pathological mechanisms and potential targets for the treatment of depression.
基金National Key Research and Development Program of China,No.2016YFC1306702(to KFS and LZ)the National Natural Science Foundation of China,No.81771455(to KFS)+1 种基金Science and Technology Program of Guangdong Province of China,No.2018B030334001(to KFS)the Natural Science Foundation of Guangdong of China,No.2019A1515011772(to LZ)。
文摘Acupuncture is a medical treatment that has been widely pra cticed in China for over 3000 years,yet the neural mechanisms of acupuncture are not fully understood.We hypothesized that neurons and astrocytes act independently and synergistically under acupuncture stimulation.To investigate this,we used two-photon in vivo calcium reco rding to observe the effects of acupuncture stimulation at ST36(Zusanli)in mice.Acupuncture stimulation in peripheral acupoints potentiated calcium signals of pyramidal neurons and astrocytes in the somatosensory cortex and resulted in late-onset calcium transients in astrocytes.Chemogenetic inhibition of neurons augmented the astrocytic activity.These findings suggest that acupuncture activates neuronal and astrocytic activity in the somatosensory co rtex and provide evidence for the involvement of both neurons and astrocytes in acupuncture treatment.
基金the National Natural Science Foundation of China,No.30571563,30771797the grant from Tianjin Education Commission,China,No.20070208
文摘BACKGROUND:Folic acid is essential for normal functioning of the nervous system.Previous studies have focused on the effects of folic acid on astrocyte proliferation.OBJECTIVE:To explore the effects of folic acid on astrocyte differentiation of neural stem cells(NSCs)and the related mechanisms in vitro.DESIGN,TIME AND SETTING:A randomized,controlled,grouping experiment was performed in Tianjin Medical University between August 2007 and October 2008.MATERIALS:Folic acid and 5-bromo-2-deoxyuridine(BrdU)were obtained from Sigma,MO,USA.Primary antibodies[rabbit anti-rat nestin,β-tubulin-Ⅲ,glial fibrillary acidic protein,and neurogeninl(Ngnl);mouse anti-rat BrdU andβ-actin monoclonal antibodies]were purchased from Santa Cruz Biotechnology,USA.METHODS:At 6 days of NSC proliferation from 24-hour-old neonatal rats,BrdU incorporation assay was performed.Seven days after primary culture,NSCs were induced to differentiate with medium containing 5%fetal bovine serum.Cultured NSCs were assigned to three groups:control,low-dose(liquid media with 8 mg/L folic acid),and high-dose folic acid(liquid media with 44 mg/L folic acid).MAIN OUTCOME MEASURES:At day 7 after primary culture,the cells were identified as NSCs by immunocytochemical methods.Double-label immunofluorescence technique for glial fibrillary acidic protein/BrdU detected differentiated cells 7 days after induction.Western blot was used to analyze expression of Ngnl protein in NSCs.RESULTS:In serum-free suspension medium,neurospheres comprised a large number of Nestin-,glial fibrillary acidic protein-,β-tubulin-Ⅲ-,and BrdU-positive cells.Compared with the control group,high-dose folic acid supplementation led to an marked increase in the percentage of glial fibrillary acidic protein/BrdU-positive cells(P〈0.05),and significantly decreased Ngnl protein expression(P〈0.05).CONCLUSION:Folic acid promotes astrocytic differentiation of NSCs,which might be related to downregulation of Ngnl protein expression.
基金supported by the China Postdoctoral Science Foundation,No.2020M681689(to YMH)the Basic Scientific Research Projects of Nantong,Nos.JC2020015(to HX)and JC2020041(to YMH)。
文摘Spinal cord injury causes accumulation of a large number of leukocytes at the lesion site where they contribute to excessive inflammation.Overproduced chemokines are responsible for the migratory process of the leukocytes,but the regulatory mechanism underlying the production of chemokines from resident cells of the spinal cord has not been fully elucidated.We examined the protein levels of macrophage migration inhibitory factor and chemokine C-C motif chemokine ligand 2 in a spinal cord contusion model at different time points following spinal cord injury.The elevation of macrophage migration inhibitory factor at the lesion site coincided with the increase of chemokine C-C motif chemokine ligand 2 abundance in astrocytes.Stimulation of primary cultured astrocytes with different concentrations of macrophage migration inhibitory factor recombinant protein induced chemokine C-C motif chemokine ligand 2 production from the cells,and the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine attenuated the stimulatory effect.Further investigation into the underlying mechanism on macrophage migration inhibitory factor-mediated astrocytic production of chemokine C-C motif chemokine ligand 2 revealed that macrophage migration inhibitory factor activated intracellular JNK signaling through binding with CD74 receptor.Administration of the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine following spinal cord injury resulted in the reduction of chemokine C-C motif chemokine ligand 2-recruited microglia/macrophages at the lesion site and remarkably improved the hindlimb locomotor function of rats.Our results have provided insights into the functions of astrocyte-activated chemokines in the recruitment of leukocytes and may be beneficial to develop interventions targeting chemokine C-C motif chemokine ligand 2 for neuroinflammation after spinal cord injury.
基金supported by the Corbett Estate Fund(62285-531021-41800,to EW)the Helen Vosburg McCrillus Plummer and Robert Edward Lee Plummer,Jr.Chair Fund(to JHH).
文摘Neuron-astrocyte interactions are vital for the brain’s connectome.Understanding astrocyte activities is crucial for comprehending the complex neural network,particularly the population-level functions of neurons in different cortical states and associated behaviors in mammals.Studies on animal sleep and wakefulness have revealed distinct cortical synchrony patterns between neurons.Astrocytes,outnumbering neurons by nearly fivefold,support and regulate neuronal and synaptic function.Recent research on astrocyte activation during cortical state transitions has emphasized the influence of norepinephrine as a neurotransmitter and calcium waves as key components of ion channel signaling.This summary focuses on a few recent studies investigating astrocyte-neuron interactions in mouse models during sleep,wakefulness,and arousal levels,exploring the involvement of noradrenaline signaling,ion channels,and glutamatergic signaling in different cortical states.These findings highlight the significant impact of astrocytes on large-scale neuronal networks,influencing brain activity and responsiveness.Targeting astrocytic signaling pathways shows promise for treating sleep disorders and arousal dysregulation.More research is needed to understand astrocytic calcium signaling in different brain regions and its implications for dysregulated brain states,requiring future human studies to comprehensively investigate neuron-astrocyte interactions and pave the way for therapeutic interventions in sleep-and arousal-related disorders.
