Demyelination and remyelination have been major focal points in the study of peripheral nerve regeneration following peripheral nerve injury.Notably,the gene regulatory network of regenerated myelin differs from that ...Demyelination and remyelination have been major focal points in the study of peripheral nerve regeneration following peripheral nerve injury.Notably,the gene regulatory network of regenerated myelin differs from that of native myelin.Silencing of enhancer of zeste homolog 2(EZH2)hinders the differentiation,maturation,and myelination of Schwann cells in vitro.To further determine the role of EZH2 in myelination and recovery post-peripheral nerve injury,conditional knockout mice lacking Ezh2 in Schwann cells(Ezh2^(fl/fl);Dhh-Cre and Ezh2^(fl/fl);Mpz-Cre)were generated.Our results show that a significant proportion of axons in the sciatic nerve of Ezh2-depleted mice remain unmyelinated.This highlights the crucial role of Ezh2 in initiating Schwann cell myelination.Furthermore,we observed that 21 days after inducing a sciatic nerve crush injury in these mice,most axons had remyelinated at the injury site in the control nerve,while Ezh2^(fl/fl);Mpz-Cre mice had significantly fewer remyelinated axons compared with their wild-type littermates.This suggests that the absence of Ezh2 in Schwann cells impairs myelin formation and remyelination.In conclusion,EZH2 has emerged as a pivotal regulatory factor in the process of demyelination and myelin regeneration following peripheral nerve injury.Modulating EZH2 activity during these processes may offer a promising therapeutic target for the treatment of peripheral nerve injuries.展开更多
Astrocytes are indispensable for central nervous system development and homeostasis.In response to injury and disease,astrocytes are integral to the immunological-and the,albeit limited,repair response.In this review,...Astrocytes are indispensable for central nervous system development and homeostasis.In response to injury and disease,astrocytes are integral to the immunological-and the,albeit limited,repair response.In this review,we will examine some of the functions reactive astrocytes play in the context of multiple sclerosis and related animal models.We will consider the heterogeneity or plasticity of astrocytes and the mechanisms by which they promote or mitigate demyelination.Finally,we will discuss a set of biomedical strategies that can stimulate astrocytes in their promyelinating response.展开更多
Myelin is the protective sheath surrounding nerve fibers, and its damage(demyelination) occurs in many central nervous system(CNS) diseases, including multiple sclerosis(MS), traumatic injury, neurodegenerative diseas...Myelin is the protective sheath surrounding nerve fibers, and its damage(demyelination) occurs in many central nervous system(CNS) diseases, including multiple sclerosis(MS), traumatic injury, neurodegenerative diseases such as Alzheimer's disease, and mental disorders such as schizophrenia(Barateiro et al., 2016). Repair of damaged myelin sheaths(remyelination) often fails in MS, leading to neuronal loss and irreversible functional deficits.展开更多
Introduction:Astrocytes,the predominant glial cell in the brain,play a vital role in a plethora of central nervous system functions.They are the major storage site of glycogen in the central nervous system.They produc...Introduction:Astrocytes,the predominant glial cell in the brain,play a vital role in a plethora of central nervous system functions.They are the major storage site of glycogen in the central nervous system.They produce L-lactate by glycogenolysis and glycolysis which is then transported to neurons(Magistretti and Allaman,2018).Multiple evidence using diverse behavioral paradigms,such as fear conditioning,conditioned place avoidance,rat gambling task(RGT),and flavor-place paired associate(PA)learning suggest that L-lactate has a beneficial effect on various aspects of cognition(Wang et al.,2017;Akter et al.,2023b).While the molecular mechanisms underlying the cognitive benefits of L-lactate are still emerging,it is well-established that astrocytic L-lactate can be used as an energy substrate by neurons and can induce N-methyl-D-aspartate receptor-dependent plasticity-driven gene expression during cognition(Magistretti and Allaman,2018).Additionally,recent evidence has revealed more roles of L-lactate which include myelination,neuronal mitochondrial biogenesis,and antioxidant defense(Sanchez-Abarca et al.,2001;Ichihara et al.,2017;Akter et al.,2023a,b).Myelin in the central nervous system is a specialized lipid-rich membrane formed by oligodendrocytes.展开更多
Circular RNAs(circRNAs)play a vital role in diabetic peripheral neuropathy.However,their expression and function in Schwann cells in individuals with diabetic peripheral neuropathy remain poorly understood.Here,we per...Circular RNAs(circRNAs)play a vital role in diabetic peripheral neuropathy.However,their expression and function in Schwann cells in individuals with diabetic peripheral neuropathy remain poorly understood.Here,we performed protein profiling and circRNA sequencing of sural nerves in patients with diabetic peripheral neuropathy and controls.Protein profiling revealed 265 differentially expressed proteins in the diabetic peripheral neuropathy group.Gene Ontology indicated that differentially expressed proteins were mainly enriched in myelination and mitochondrial oxidative phosphorylation.A real-time polymerase chain reaction assay performed to validate the circRNA sequencing results yielded 11 differentially expressed circRNAs.circ_0002538 was markedly downregulated in patients with diabetic peripheral neuropathy.Further in vitro experiments showed that overexpression of circ_0002538 promoted the migration of Schwann cells by upregulating plasmolipin(PLLP)expression.Moreover,overexpression of circ_0002538 in the sciatic nerve in a streptozotocin-induced mouse model of diabetic peripheral neuropathy alleviated demyelination and improved sciatic nerve function.The results of a mechanistic experiment showed that circ_0002538 promotes PLLP expression by sponging miR-138-5p,while a lack of circ_0002538 led to a PLLP deficiency that further suppressed Schwann cell migration.These findings suggest that the circ_0002538/miR-138-5p/PLLP axis can promote the migration of Schwann cells in diabetic peripheral neuropathy patients,improving myelin sheath structure and nerve function.Thus,this axis is a potential target for therapeutic treatment of diabetic peripheral neuropathy.展开更多
Spinal cord injuries affect nearly five to ten individuals per million every year. Spinal cord injury causes damage to the nerves, muscles, and the tissue surrounding the spinal cord. Depending on the severity, spinal...Spinal cord injuries affect nearly five to ten individuals per million every year. Spinal cord injury causes damage to the nerves, muscles, and the tissue surrounding the spinal cord. Depending on the severity, spinal injuries are linked to degeneration of axons and myelin, resulting in neuronal impairment and skeletal muscle weakness and atrophy. The protection of neurons and promotion of myelin regeneration during spinal cord injury is important for recovery of function following spinal cord injury. Current treatments have little to no effect on spinal cord injury and neurogenic muscle loss. Clemastine, an Food and Drug Administration-approved antihistamine drug, reduces inflammation, protects cells, promotes remyelination, and preserves myelin integrity. Recent clinical evidence suggests that clemastine can decrease the loss of axons after spinal cord injury, stimulating the differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes that are capable of myelination. While clemastine can aid not only in the remyelination and preservation of myelin sheath integrity, it also protects neurons. However, its role in neurogenic muscle loss remains unclear. This review discusses the pathophysiology of spinal cord injury, and the role of clemastine in the protection of neurons, myelin, and axons as well as attenuation of skeletal muscle loss following spinal cord injury.展开更多
Piezo1 is a mechanically-gated calcium channel.Recent studies have shown that Piezo1,a mechanically-gated calcium channel,can attenuate both psychosineand lipopolysaccharide-induced demyelination.Because oligodendrocy...Piezo1 is a mechanically-gated calcium channel.Recent studies have shown that Piezo1,a mechanically-gated calcium channel,can attenuate both psychosineand lipopolysaccharide-induced demyelination.Because oligodendrocyte damage and demyelination occur in intracerebral hemorrhage,in this study,we investigated the role of Piezo1 in intracerebral hemorrhage.We established a mouse model of cerebral hemorrhage by injecting autologous blood into the right basal ganglia and found that Piezo1 was largely expressed soon(within 48 hours)after intracerebral hemorrhage,primarily in oligodendrocytes.Intraperitoneal injection of Dooku1 to inhibit Piezo1 resulted in marked alleviation of brain edema,myelin sheath loss,and degeneration in injured tissue,a substantial reduction in oligodendrocyte apoptosis,and a significant improvement in neurological function.In addition,we found that Dooku1-mediated Piezo1 suppression reduced intracellular endoplasmic reticulum stress and cell apoptosis through the PERK-ATF4-CHOP and inositol-requiring enzyme 1 signaling pathway.These findings suggest that Piezo1 is a potential therapeutic target for intracerebral hemorrhage,as its suppression reduces intracellular endoplasmic reticulum stress and cell apoptosis and protects the myelin sheath,thereby improving neuronal function after intracerebral hemorrhage.展开更多
Remyelination and need to access it:A range of diseases such as Guillain-Barre syndrome,Pelizaeus Merzbacher disease,relapsing-remitting and secondary progressive multiple sclerosis is associated with various degrees ...Remyelination and need to access it:A range of diseases such as Guillain-Barre syndrome,Pelizaeus Merzbacher disease,relapsing-remitting and secondary progressive multiple sclerosis is associated with various degrees of nerve demyelination.These diseases present with various degrees of demyelination and differentclinical manifestations.展开更多
In this review, we outline the major neural plasticity mechanisms that have been identified in the adult central nervous system (CNS), and offer a perspective on how they regulate CNS function. In particular we exam...In this review, we outline the major neural plasticity mechanisms that have been identified in the adult central nervous system (CNS), and offer a perspective on how they regulate CNS function. In particular we examine how myelin plasticity can operate alongside neurogenesis and synaptic plasticity to influence information processing and transfer in the mature CNS.展开更多
Delay of axon regeneration after peripheral nerve injury usually leads to progressive muscle atrophy and poor functional recovery. The Wnt/β-catenin signaling pathway is considered to be one of the main molecular mec...Delay of axon regeneration after peripheral nerve injury usually leads to progressive muscle atrophy and poor functional recovery. The Wnt/β-catenin signaling pathway is considered to be one of the main molecular mechanisms that lead to skeletal muscle atrophy in the elderly. We hold the hypothesis that the innervation of target muscle can be promoted by accelerating axon regeneration and decelerating muscle cell degeneration so as to improve functional recovery of skeletal muscle following peripheral nerve injury. This process may be associated with the Wnt/β-catenin signaling pathway. Our study designed in vitro cell models to simulate myelin regeneration and muscle atrophy. We investigated the effects of SB216763, a glycogen synthase kinase 3 beta inhibitor, on the two major murine cell lines RSC96 and C2C12 derived from Schwann cells and muscle satellite cells. The results showed that SB216763 stimulated the Schwann cell migra- tion and myotube contraction. Quantitative polymerase chain reaction results demonstrated that myelin related genes, myelin associated glycoprotein and cyclin-D1, muscle related gene myogenin and endplate-associated gene nicotinic acetylcholine receptors levels were stimulated by SB216763. Immunocytochemical staining revealed that the expressions of ^-catenin in the RSC96 and C2C12 cytosolic and nuclear compartments were increased in the SB216763-treated cells. These findings confirm that the glycogen synthase kinase 3 beta in- hibitor, SB216763, promoted the myelination and myotube differentiation through the Wnt/β-catenin signaling pathway and contributed to nerve remyelination and reduced denervated muscle atrophy after peripheral nerve injury.展开更多
Fast and efficient transmission of electrical signals in the nervous system is mediated through myelinated nerve fibers.In neuronal diseases such as multiple sclerosis,the conduction properties of axons are disturbed ...Fast and efficient transmission of electrical signals in the nervous system is mediated through myelinated nerve fibers.In neuronal diseases such as multiple sclerosis,the conduction properties of axons are disturbed by the removal of the myelin sheath,leaving nerve cells at a higher risk of degenerating.In some cases,the protective myelin sheath of axons can be rebuilt by remyelination through oligodendroglial cells.In any case,however,changes in the ion channel organization occur and may help to restore impulse conduction after demyelination.On the other hand,changes in ion channel distribution may increase the energy demand of axons,thereby increasing the probability of axonal degeneration.Many attempts have been made or discussed in recent years to increase remyelination of affected axons in demyelinating diseases such as multiple sclerosis.These approaches range from pharmacological treatments that reduce inflammatory processes or block ion channels to the modulation of neuronal activity through electrical cortical stimulation.However,these treatments either affect the entire organism(pharmacological)or exert a very local effect(electrodes).Current results show that neuronal activity is a strong regulator of oligodendroglial development.To bridge the gap between global and very local treatments,non-invasive transcranial magnetic stimulation could be considered.Transcranial magnetic stimulation is externally applied to brain areas and experiments with repetitive transcranial magnetic stimulation show that the neuronal activity can be modulated depending on the stimulation parameters in both humans and animals.In this review,we discuss the possibilities of influencing ion channel distribution and increasing neuronal activity by transcranial magnetic stimulation as well as the effect of this modulation on oligodendroglial cells and their capacity to remyelinate previously demyelinated axons.Although the physiological mechanisms underlying the effects of transcranial magnetic stimulation clearly need further investigations,repetitive transcranial magnetic stimulation may be a promising approach for non-invasive neuronal modulation aiming at enhancing remyelination and thus reducing neurodegeneration.展开更多
Rosmarinic acid,a common ester extracted from Rosemary,Perilla frutescens,and Salvia miltiorrhiza Bunge,has been shown to have protective effects against various diseases.This is an investigation into whether rosmarin...Rosmarinic acid,a common ester extracted from Rosemary,Perilla frutescens,and Salvia miltiorrhiza Bunge,has been shown to have protective effects against various diseases.This is an investigation into whether rosmarinic acid can also affect the changes of white matter fibers and cognitive deficits caused by hypoxic injury.The right common carotid artery of 3-day-old rats was ligated for 2 hours.The rats were then prewarmed in a plastic container with holes in the lid,which was placed in 37°C water bath for 30 minutes.Afterwards,the rats were exposed to an atmosphere with 8% O2 and 92% N2 for 30 minutes to establish the perinatal hypoxia/ischemia injury models.The rat models were intraperitoneally injected with rosmarinic acid 20 mg/kg for 5 consecutive days.At 22 days after birth,rosmarinic acid was found to improve motor,anxiety,learning and spatial memory impairments induced by hypoxia/ischemia injury.Furthermore,rosmarinic acid promoted the proliferation of oligodendrocyte progenitor cells in the subventricular zone.After hypoxia/ischemia injury,rosmarinic acid reversed to some extent the downregulation of myelin basic protein and the loss of myelin sheath in the corpus callosum of white matter structure.Rosmarinic acid partially slowed down the expression of oligodendrocyte marker Olig2 and myelin basic protein and the increase of oligodendrocyte apoptosis marker inhibitors of DNA binding 2.These data indicate that rosmarinic acid ameliorated the cognitive dysfunction after perinatal hypoxia/ischemia injury by improving remyelination in corpus callosum.This study was approved by the Animal Experimental Ethics Committee of Xuzhou Medical University,China (approval No.20161636721) on September 16,2017.展开更多
The APPSwe/PSEN1 dE9(APP/PS1) transgenic mouse model is an Alzheimer's disease mouse model exhibiting symptoms of dementia, and is commonly used to explore pathological changes in the development of Alzheimer's di...The APPSwe/PSEN1 dE9(APP/PS1) transgenic mouse model is an Alzheimer's disease mouse model exhibiting symptoms of dementia, and is commonly used to explore pathological changes in the development of Alzheimer's disease. Previous clinical autopsy and imaging studies suggest that Alzheimer's disease patients have white matter and oligodendrocyte damage, but the underlying mechanisms of these have not been revealed. Therefore, the present study used APP/PS1 mice to assess cognitive change, myelin loss, and corresponding changes in oligodendrocytes, and to explore the underlying mechanisms. Morris water maze tests were performed to evaluate cognitive change in APP/PS1 mice and normal C57 BL/6 mice aged 3 and 6 months. Luxol fast blue staining of the corpus callosum and quantitative reverse transcription-polymerase chain reaction(q RT-PCR) for myelin basic protein(MBP) mRNA were carried out to quantify myelin damage. Immunohistochemistry staining for NG2 and qRT-PCR for monocarboxylic acid transporter 1(MCT1) mRNA were conducted to assess corresponding changes in oligodendrocytes. Our results demonstrate that compared with C57 BL/6 mice, there was a downregulation of MBP mRNA in APP/PS1 mice aged 3 months. This became more obvious in APP/PS1 mice aged 6 months accompanied by other abnormalities such as prolonged escape latency in the Morris water maze test, shrinkage of the corpus callosum, upregulation of NG2-immunoreactive cells, and downregulation of MCT1 mRNA. These findings indicate that the involvement of early demyelination at 3 months and the oligodendrocyte dysfunction at 6 months in APP/PS1 mice are in association with Alzheimer's disease pathogenesis.展开更多
AIM: To investigate the role of tumor necrosis factoralpha (TNF-α) in zebrafish retinal development and myelination. METHODS: Morpholino oligonucleotides (MO), which are complementary to the translation start...AIM: To investigate the role of tumor necrosis factoralpha (TNF-α) in zebrafish retinal development and myelination. METHODS: Morpholino oligonucleotides (MO), which are complementary to the translation start site of the wild-type embryonic zebrafish TNF-α mRNA sequence, were synthesized and injected into one to four-cell embryos. The translation blocking specificity was verified by Western blotting using an anti-TNF-α antibody, whole-mount in sltuhybridization using a hepatocytespecific mRNA probe ceruloplasmin (cp), and coinjection of TNF-α MO and TNF-α mRNA. An atonel homolog 7 (atoh7) mRNA probe was used to detect neurogenesis onset. The retinal neurodifferentiation was analyzed by immunohistochemistry using antibodies Zn12, Zprl, and Zpr3 to label ganglion cells, cones, and rods, respectively. Myelin basic protein (mbp)was used as a marker to track and observe the myelination using whole-mount in situ hybridization. RESULTS: Targeted knockdown of TNF-α resulted in specific suppression of TNF-α expression and a severely underdeveloped liver. The co-injection of TNF-α MO and mRNA rescued the liver development. Retinal neurogenesis in TNF-cc morphants was initiated on time. The retina was fully laminated, while ganglion cells, cones, and rods were well differentiated at 72 hours post-fertilization (hpf). mbp was expressed in Schwann cells in the lateral line nerves and cranial nerves from 3 days post -fertilization (dpf) as well as in oligodendrocytes linearly along the hindbrain bundles and the spinal cord from 4 dpf, which closely resembled its endogenous profile. CONCLUSION: TNF-α is not an essential regulator for retinal neurogenesis and optic myelination.展开更多
BACKGROUND: Acupuncture treatment on injured cerebral axons has shown to provide efficacy in clinical practice. It is unknown whether acupuncture produces therapeutic effects by protecting injured cerebral myelin in ...BACKGROUND: Acupuncture treatment on injured cerebral axons has shown to provide efficacy in clinical practice. It is unknown whether acupuncture produces therapeutic effects by protecting injured cerebral myelin in ischemic stroke. OBJECTIVE: To test whether acupuncture provides protection for injured cerebral myelin, based on quantitative data from cerebral ischemia-reperfusion rats, and to compare the effects of early and late acupuncture on serum myelin basic protein (MBP) content and remyelination of the ischemic internal capsule.DESIGN, TIME AND SETTING: A randomized, controlled experiment was performed at the Neurobiological Laboratory, Sichuan University from March 2005 to March 2006. MATERIALS: "Hua Tuo" Brand filiform needles were produced by the Medical Instrument Factory of Suzhou, China.METHODS: A total of 52 adult, healthy, male, Sprague Dawley rats were randomly assigned to four groups: control (n = 4), model (n = 16), early acupuncture (n = 16), and late acupuncture (n = 16). The focal cerebral ischemia-reperfusion model was established by middle cerebral artery occlusion in the right hemisphere using the modified thread embolism method in the latter three groups. Early and late acupuncture groups underwent acupuncture after ischemia for 30 minutes and 2 hours using the Xingnaokaiqiao needling method, respectively. Acupoints were "Neiguarf' (PC 6) and "Sanyinjiao" (SP 6) on the bilateral sides, as well as "Shuigou' (DU 26) and "Baihui" (DU 20) with stimulation for 1 minute at each acupoint. Acupuncture at all acupoints was performed two or three times while the needle was retained, once per day. No special handling was administered to the control clroup.MAIN OUTCOME MEASURES: For each group, remyelination of the internal capsule was observed by Pal-Weigert's myelin staining and serum MBP content was detected using enzyme-linked immunosorbent assay method on days 1,3, 5, and 7 following ischemia-reperfusion injury.RESULTS: Compared with the control group, massive demyelination of the internal capsule occurred, and serum MBP content increased in the model group (P 〈 0.05). Compared with the model group, the extent of demyelination in the internal capsule was less distinct and serum MBP content was significantly less in the early and late acupuncture group (P 〈 0.01 ). Compared with the late acupuncture group, serum MBP content reached a peak later and the peak value was less in the early acupuncture group. CONCLUSION: Results suggest that acupuncture exerts a protective effect on injured cerebral myelin in ischemia-reperfusion rats by reducing serum MBP content and promoting remyelination. The study also suggests that the effect of early acupuncture is superior to late acupuncture.展开更多
Myelination of Schwann cells in the peripheral nervous system is an intricate process involving myelin protein trafficking. Recently, the role and mechanism of the endosomal/lysosomal system in myelin formation were e...Myelination of Schwann cells in the peripheral nervous system is an intricate process involving myelin protein trafficking. Recently, the role and mechanism of the endosomal/lysosomal system in myelin formation were emphasized. Our previous results demonstrated that a small GTPase Rab27a regulates lysosomal exocytosis and myelin protein trafficking in Schwann cells. In this present study, we established a dorsal root ganglion (DRG) neuron and Schwann cell co-culture model to identify the signals associated with Rab27a during myelination. First, Slp2-a, as the Rab27a effector, was endogenously expressed in Schwann cells. Second, Rab27a expression significantly increased during Schwann cell myelination. Finally, Rab27a and Slp2-a silencing in Schwann cells not only reduced myelin protein expression, but also impaired formation of myelin-like membranes in DRG neuron and Schwann cell co-cultures. Our findings suggest that the Rab27a/ Slp2-a complex affects Schwann cell myelination in vitro.展开更多
Differential expression of mi RNAs occurs in injured proximal nerve stumps and includes mi RNAs that are firstly down-regulated and then gradually up-regulated following nerve injury.These mi RNAs might be related to ...Differential expression of mi RNAs occurs in injured proximal nerve stumps and includes mi RNAs that are firstly down-regulated and then gradually up-regulated following nerve injury.These mi RNAs might be related to a Schwann cell phenotypic switch.mi R-30 c,as a member of this group,was further investigated in the current study.Sprague-Dawley rats underwent sciatic nerve transection and proximal nerve stumps were collected at 1,4,7,14,21,and 28 days post injury for analysis.Following sciatic nerve injury,mi R-30 c was down-regulated,reaching a minimum on day 4,and was then upregulated to normal levels.Schwann cells were isolated from neonatal rat sciatic nerve stumps,then transfected with mi R-30 c agomir and co-cultured in vitro with dorsal root ganglia.The enhanced expression of mi R-30 c robustly increased the amount of myelin-associated protein in the co-cultured dorsal root ganglia and Schwann cells.We then modeled sciatic nerve crush injury in vivo in Sprague-Dawley rats and tested the effect of perineural injection of mi R-30 c agomir on myelin sheath regeneration.Fourteen days after surgery,sciatic nerve stumps were harvested and subjected to immunohistochemistry,western blot analysis,and transmission electron microscopy.The direct injection of mi R-30 c stimulated the formation of myelin sheath,thus contributing to peripheral nerve regeneration.Overall,our findings indicate that mi R-30 c can promote Schwann cell myelination following peripheral nerve injury.The functional study of mi R-30 c will benefit the discovery of new therapeutic targets and the development of new treatment strategies for peripheral nerve regeneration.展开更多
Remyelination plays a key role in functional recovery of axons after spinal cord injury.Glial cells are the most abundant cells in the central nervous system.When spinal cord injury occurs,many glial cells at the lesi...Remyelination plays a key role in functional recovery of axons after spinal cord injury.Glial cells are the most abundant cells in the central nervous system.When spinal cord injury occurs,many glial cells at the lesion site are immediately activated,and different cells differentially affect inflammatory reactions after injury.In this review,we aim to discuss the core role of oligodendrocyte precursor cells and crosstalk with the rest of glia and their subcategories in the remyelination process.Activated astrocytes influence proliferation,differentiation,and maturation of oligodendrocyte precursor cells,while activated microglia alter remyelination by regulating the inflammatory reaction after spinal cord injury.Understanding the interaction between oligodendrocyte precursor cells and the rest of glia is necessary when designing a therapeutic plan of remyelination after spinal cord injury.展开更多
Myelin plays important roles in vertebrates,ensuring the rapid propagation of action potentials and the long-term integrity of axons,but the molecular mechanisms of myelin formation remain poorly understood.Recent stu...Myelin plays important roles in vertebrates,ensuring the rapid propagation of action potentials and the long-term integrity of axons,but the molecular mechanisms of myelin formation remain poorly understood.Recent studies have demonstrated that myelination is regulated by the TYRO3,AXL(also known as UFO)and MERTK.展开更多
Adverse life experience induces permanent phenotypic changes in cognitive functions associated with the prefrontal cortex(PFC).However,the underlying mechanisms remain unclear.In this work,we use neonatal maternal sep...Adverse life experience induces permanent phenotypic changes in cognitive functions associated with the prefrontal cortex(PFC).However,the underlying mechanisms remain unclear.In this work,we use neonatal maternal separation(NMS)and chronic social defeat(CSD)rat models to address how adverse life experience affects PFC-dependent cognitive functions.Our results show that normal myelination of the medial PFC(mPFC)is necessary for mPFC-dependent behaviors,as experimental blockade of oligodendrocyte differentiation or lysolecithin-induced demyelination impairs mPFC-dependent behaviors.NMS or CSD produces severe deficits in mPFC myelination,while other brain regions,such as the hippocampusa and basal ganglia,remain intact.In parallel,rats with NMS or CSD exhibit anxiety-like behaviors and demonstrate poor performance on mPFC-dependent tasks.Further experiments demonstrate that,histone deacetylases 1/2(HDAC1/2)are reduced in the mPFC of NMS and CSD rats.Inhibition of HDAC1/2 promotes activation of Wnt signalling,which negatively regulates oligodendrocyte development.Conversely,selective inhibition of Wnt signaling rescues the myelination arrestment and behavioral deficiency induced by NMS or CSD.These findings indicate that NMS or CSD impairs mPFC cognitive functions via regulation of oligodendrogenesis and myelination.展开更多
基金financially supported by the National Natural Science Foundation of China,Nos.82172104(to CX),81873767(to HZ)a grant from Jiangsu Provincial Research Hospital,Nos.YJXYY202204(to HZ),YJXYY202204-ZD04(to HZ)+5 种基金a grant from Jiangsu Provincial Key Medical CenterJiangsu Provincial Medical Innovation Center,No.CXZX202212Jiangsu Provincial Medical Key Discipline,No.ZDXK202240the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)Technology Project of Nantong,No.MS22022008(to HZ)Postgraduate Research&Practice Innovation Program of Jiangsu Province,No.SJCX21_1457(to WW)。
文摘Demyelination and remyelination have been major focal points in the study of peripheral nerve regeneration following peripheral nerve injury.Notably,the gene regulatory network of regenerated myelin differs from that of native myelin.Silencing of enhancer of zeste homolog 2(EZH2)hinders the differentiation,maturation,and myelination of Schwann cells in vitro.To further determine the role of EZH2 in myelination and recovery post-peripheral nerve injury,conditional knockout mice lacking Ezh2 in Schwann cells(Ezh2^(fl/fl);Dhh-Cre and Ezh2^(fl/fl);Mpz-Cre)were generated.Our results show that a significant proportion of axons in the sciatic nerve of Ezh2-depleted mice remain unmyelinated.This highlights the crucial role of Ezh2 in initiating Schwann cell myelination.Furthermore,we observed that 21 days after inducing a sciatic nerve crush injury in these mice,most axons had remyelinated at the injury site in the control nerve,while Ezh2^(fl/fl);Mpz-Cre mice had significantly fewer remyelinated axons compared with their wild-type littermates.This suggests that the absence of Ezh2 in Schwann cells impairs myelin formation and remyelination.In conclusion,EZH2 has emerged as a pivotal regulatory factor in the process of demyelination and myelin regeneration following peripheral nerve injury.Modulating EZH2 activity during these processes may offer a promising therapeutic target for the treatment of peripheral nerve injuries.
基金supported by the Heart and Stroke Foundation and Ontario Institute of Regenerative Medicine (New Ideas Grant)Canada First Research Excellence Fund(Medicine by Design)+2 种基金the National Sciences and Engineering Research Councilthe Jurgen Manchot Foundationthe Christiane and Claudia Hempel Foundation for Clinical Stem Cell Research and the James and Elisabeth Cloppenburg,Peek and Cloppenburg Düsseldorf Stiftung (to PK)
文摘Astrocytes are indispensable for central nervous system development and homeostasis.In response to injury and disease,astrocytes are integral to the immunological-and the,albeit limited,repair response.In this review,we will examine some of the functions reactive astrocytes play in the context of multiple sclerosis and related animal models.We will consider the heterogeneity or plasticity of astrocytes and the mechanisms by which they promote or mitigate demyelination.Finally,we will discuss a set of biomedical strategies that can stimulate astrocytes in their promyelinating response.
基金supported by a grant from Aston University,Birmingham,UK (to DM)。
文摘Myelin is the protective sheath surrounding nerve fibers, and its damage(demyelination) occurs in many central nervous system(CNS) diseases, including multiple sclerosis(MS), traumatic injury, neurodegenerative diseases such as Alzheimer's disease, and mental disorders such as schizophrenia(Barateiro et al., 2016). Repair of damaged myelin sheaths(remyelination) often fails in MS, leading to neuronal loss and irreversible functional deficits.
基金funded by the General Research Fund(GRF)of the Research Grants Council of Hong Kong,China(11103721,11102820,and 11100018)the National Natural Science Foundation of China(NSFC)and RGC Joint Research Scheme(3171101014,N_CityU114/17)+3 种基金the Innovation and Technology Fund Hong Kong,China(CityU 9445909)(all to YL)supported by a grant from City University of Hong Kong Neuroscience Research Infrastructure(9610211)a grant from Center for BiosystemsNeuroscience,and Nanotechnology(9360148)(both to YL)。
文摘Introduction:Astrocytes,the predominant glial cell in the brain,play a vital role in a plethora of central nervous system functions.They are the major storage site of glycogen in the central nervous system.They produce L-lactate by glycogenolysis and glycolysis which is then transported to neurons(Magistretti and Allaman,2018).Multiple evidence using diverse behavioral paradigms,such as fear conditioning,conditioned place avoidance,rat gambling task(RGT),and flavor-place paired associate(PA)learning suggest that L-lactate has a beneficial effect on various aspects of cognition(Wang et al.,2017;Akter et al.,2023b).While the molecular mechanisms underlying the cognitive benefits of L-lactate are still emerging,it is well-established that astrocytic L-lactate can be used as an energy substrate by neurons and can induce N-methyl-D-aspartate receptor-dependent plasticity-driven gene expression during cognition(Magistretti and Allaman,2018).Additionally,recent evidence has revealed more roles of L-lactate which include myelination,neuronal mitochondrial biogenesis,and antioxidant defense(Sanchez-Abarca et al.,2001;Ichihara et al.,2017;Akter et al.,2023a,b).Myelin in the central nervous system is a specialized lipid-rich membrane formed by oligodendrocytes.
基金supported by the National Natural Science Foundation of China,Nos.81772094(to ZBC),81974289(to ZBC)the Key Research and Development Program of Hubei Province,No.2020BCB031(to ZBC)Natural Science Foundation of Hubei Province,No.2020CFB433(to YTL).
文摘Circular RNAs(circRNAs)play a vital role in diabetic peripheral neuropathy.However,their expression and function in Schwann cells in individuals with diabetic peripheral neuropathy remain poorly understood.Here,we performed protein profiling and circRNA sequencing of sural nerves in patients with diabetic peripheral neuropathy and controls.Protein profiling revealed 265 differentially expressed proteins in the diabetic peripheral neuropathy group.Gene Ontology indicated that differentially expressed proteins were mainly enriched in myelination and mitochondrial oxidative phosphorylation.A real-time polymerase chain reaction assay performed to validate the circRNA sequencing results yielded 11 differentially expressed circRNAs.circ_0002538 was markedly downregulated in patients with diabetic peripheral neuropathy.Further in vitro experiments showed that overexpression of circ_0002538 promoted the migration of Schwann cells by upregulating plasmolipin(PLLP)expression.Moreover,overexpression of circ_0002538 in the sciatic nerve in a streptozotocin-induced mouse model of diabetic peripheral neuropathy alleviated demyelination and improved sciatic nerve function.The results of a mechanistic experiment showed that circ_0002538 promotes PLLP expression by sponging miR-138-5p,while a lack of circ_0002538 led to a PLLP deficiency that further suppressed Schwann cell migration.These findings suggest that the circ_0002538/miR-138-5p/PLLP axis can promote the migration of Schwann cells in diabetic peripheral neuropathy patients,improving myelin sheath structure and nerve function.Thus,this axis is a potential target for therapeutic treatment of diabetic peripheral neuropathy.
基金supported in part by funding from the Veterans Administration (1IOBX001262, 1I01 BX004269)South Carolina State Spinal Cord Injury Research Fund (SCIRF-2015P-01, SCIRF-2015P-04, SCIRF-2015-I-01, SCIRF#2016 I-03, and SCIRF#2018 I-01)(to AH)+1 种基金supported in part by funding from the National Institutes of Health (1R21NS118393-01)(to AH)a Research Career Scientist award (#IK6BX005964) from the Department of veterans Affairs。
文摘Spinal cord injuries affect nearly five to ten individuals per million every year. Spinal cord injury causes damage to the nerves, muscles, and the tissue surrounding the spinal cord. Depending on the severity, spinal injuries are linked to degeneration of axons and myelin, resulting in neuronal impairment and skeletal muscle weakness and atrophy. The protection of neurons and promotion of myelin regeneration during spinal cord injury is important for recovery of function following spinal cord injury. Current treatments have little to no effect on spinal cord injury and neurogenic muscle loss. Clemastine, an Food and Drug Administration-approved antihistamine drug, reduces inflammation, protects cells, promotes remyelination, and preserves myelin integrity. Recent clinical evidence suggests that clemastine can decrease the loss of axons after spinal cord injury, stimulating the differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes that are capable of myelination. While clemastine can aid not only in the remyelination and preservation of myelin sheath integrity, it also protects neurons. However, its role in neurogenic muscle loss remains unclear. This review discusses the pathophysiology of spinal cord injury, and the role of clemastine in the protection of neurons, myelin, and axons as well as attenuation of skeletal muscle loss following spinal cord injury.
基金supported by the National Natural Science Foundation of China,Nos.81901193(to HLZ)and 81901267(to YY)。
文摘Piezo1 is a mechanically-gated calcium channel.Recent studies have shown that Piezo1,a mechanically-gated calcium channel,can attenuate both psychosineand lipopolysaccharide-induced demyelination.Because oligodendrocyte damage and demyelination occur in intracerebral hemorrhage,in this study,we investigated the role of Piezo1 in intracerebral hemorrhage.We established a mouse model of cerebral hemorrhage by injecting autologous blood into the right basal ganglia and found that Piezo1 was largely expressed soon(within 48 hours)after intracerebral hemorrhage,primarily in oligodendrocytes.Intraperitoneal injection of Dooku1 to inhibit Piezo1 resulted in marked alleviation of brain edema,myelin sheath loss,and degeneration in injured tissue,a substantial reduction in oligodendrocyte apoptosis,and a significant improvement in neurological function.In addition,we found that Dooku1-mediated Piezo1 suppression reduced intracellular endoplasmic reticulum stress and cell apoptosis through the PERK-ATF4-CHOP and inositol-requiring enzyme 1 signaling pathway.These findings suggest that Piezo1 is a potential therapeutic target for intracerebral hemorrhage,as its suppression reduces intracellular endoplasmic reticulum stress and cell apoptosis and protects the myelin sheath,thereby improving neuronal function after intracerebral hemorrhage.
基金supported by the US Department of Defense Grant WH-X81160715Department of Health and Human Services I National Institutes of Health/National Eye Institute Grants EY-027257and EY-14801 (to SKB)an unrestricted grant to the University of Miami from Research to Prevent Blindness。
文摘Remyelination and need to access it:A range of diseases such as Guillain-Barre syndrome,Pelizaeus Merzbacher disease,relapsing-remitting and secondary progressive multiple sclerosis is associated with various degrees of nerve demyelination.These diseases present with various degrees of demyelination and differentclinical manifestations.
基金supported by the Australian National Health and Medical Research Council
文摘In this review, we outline the major neural plasticity mechanisms that have been identified in the adult central nervous system (CNS), and offer a perspective on how they regulate CNS function. In particular we examine how myelin plasticity can operate alongside neurogenesis and synaptic plasticity to influence information processing and transfer in the mature CNS.
基金funded by the National Basic Research Program of China(973 Program),No.2014CB542201the National High Technology Research and Development Program of China(863 Program),No.SS2015AA020501the National Natural Science Foundation of China(General Program),No.31571235,31771322,31671248,31571236,31271284,31171150,81171146,31471144,30971526,31100860,31040043,31371210,and 81372044
文摘Delay of axon regeneration after peripheral nerve injury usually leads to progressive muscle atrophy and poor functional recovery. The Wnt/β-catenin signaling pathway is considered to be one of the main molecular mechanisms that lead to skeletal muscle atrophy in the elderly. We hold the hypothesis that the innervation of target muscle can be promoted by accelerating axon regeneration and decelerating muscle cell degeneration so as to improve functional recovery of skeletal muscle following peripheral nerve injury. This process may be associated with the Wnt/β-catenin signaling pathway. Our study designed in vitro cell models to simulate myelin regeneration and muscle atrophy. We investigated the effects of SB216763, a glycogen synthase kinase 3 beta inhibitor, on the two major murine cell lines RSC96 and C2C12 derived from Schwann cells and muscle satellite cells. The results showed that SB216763 stimulated the Schwann cell migra- tion and myotube contraction. Quantitative polymerase chain reaction results demonstrated that myelin related genes, myelin associated glycoprotein and cyclin-D1, muscle related gene myogenin and endplate-associated gene nicotinic acetylcholine receptors levels were stimulated by SB216763. Immunocytochemical staining revealed that the expressions of ^-catenin in the RSC96 and C2C12 cytosolic and nuclear compartments were increased in the SB216763-treated cells. These findings confirm that the glycogen synthase kinase 3 beta in- hibitor, SB216763, promoted the myelination and myotube differentiation through the Wnt/β-catenin signaling pathway and contributed to nerve remyelination and reduced denervated muscle atrophy after peripheral nerve injury.
基金supported by the DFG BE 6048/2-1(to AB)and DFG PF574/5-1(to FP)。
文摘Fast and efficient transmission of electrical signals in the nervous system is mediated through myelinated nerve fibers.In neuronal diseases such as multiple sclerosis,the conduction properties of axons are disturbed by the removal of the myelin sheath,leaving nerve cells at a higher risk of degenerating.In some cases,the protective myelin sheath of axons can be rebuilt by remyelination through oligodendroglial cells.In any case,however,changes in the ion channel organization occur and may help to restore impulse conduction after demyelination.On the other hand,changes in ion channel distribution may increase the energy demand of axons,thereby increasing the probability of axonal degeneration.Many attempts have been made or discussed in recent years to increase remyelination of affected axons in demyelinating diseases such as multiple sclerosis.These approaches range from pharmacological treatments that reduce inflammatory processes or block ion channels to the modulation of neuronal activity through electrical cortical stimulation.However,these treatments either affect the entire organism(pharmacological)or exert a very local effect(electrodes).Current results show that neuronal activity is a strong regulator of oligodendroglial development.To bridge the gap between global and very local treatments,non-invasive transcranial magnetic stimulation could be considered.Transcranial magnetic stimulation is externally applied to brain areas and experiments with repetitive transcranial magnetic stimulation show that the neuronal activity can be modulated depending on the stimulation parameters in both humans and animals.In this review,we discuss the possibilities of influencing ion channel distribution and increasing neuronal activity by transcranial magnetic stimulation as well as the effect of this modulation on oligodendroglial cells and their capacity to remyelinate previously demyelinated axons.Although the physiological mechanisms underlying the effects of transcranial magnetic stimulation clearly need further investigations,repetitive transcranial magnetic stimulation may be a promising approach for non-invasive neuronal modulation aiming at enhancing remyelination and thus reducing neurodegeneration.
基金supported by the Natural Science Foundation of Jiangsu Province of China,No.BK20171180(to XRW)
文摘Rosmarinic acid,a common ester extracted from Rosemary,Perilla frutescens,and Salvia miltiorrhiza Bunge,has been shown to have protective effects against various diseases.This is an investigation into whether rosmarinic acid can also affect the changes of white matter fibers and cognitive deficits caused by hypoxic injury.The right common carotid artery of 3-day-old rats was ligated for 2 hours.The rats were then prewarmed in a plastic container with holes in the lid,which was placed in 37°C water bath for 30 minutes.Afterwards,the rats were exposed to an atmosphere with 8% O2 and 92% N2 for 30 minutes to establish the perinatal hypoxia/ischemia injury models.The rat models were intraperitoneally injected with rosmarinic acid 20 mg/kg for 5 consecutive days.At 22 days after birth,rosmarinic acid was found to improve motor,anxiety,learning and spatial memory impairments induced by hypoxia/ischemia injury.Furthermore,rosmarinic acid promoted the proliferation of oligodendrocyte progenitor cells in the subventricular zone.After hypoxia/ischemia injury,rosmarinic acid reversed to some extent the downregulation of myelin basic protein and the loss of myelin sheath in the corpus callosum of white matter structure.Rosmarinic acid partially slowed down the expression of oligodendrocyte marker Olig2 and myelin basic protein and the increase of oligodendrocyte apoptosis marker inhibitors of DNA binding 2.These data indicate that rosmarinic acid ameliorated the cognitive dysfunction after perinatal hypoxia/ischemia injury by improving remyelination in corpus callosum.This study was approved by the Animal Experimental Ethics Committee of Xuzhou Medical University,China (approval No.20161636721) on September 16,2017.
基金supported by the National Natural Science Foundation of China,No.81371395the Liaoning Scientific and Technological Preferential Finance for Returned Overseas 2015 of China,No.[2015]125+2 种基金the Natural Science Foundation of Liaoning Province of China,No.20170541021,2015020547a grant from the Shenyang Science Technology Project,No.F16-206-9-12the China Post-doctoral Science Foundation,No.2015M581375
文摘The APPSwe/PSEN1 dE9(APP/PS1) transgenic mouse model is an Alzheimer's disease mouse model exhibiting symptoms of dementia, and is commonly used to explore pathological changes in the development of Alzheimer's disease. Previous clinical autopsy and imaging studies suggest that Alzheimer's disease patients have white matter and oligodendrocyte damage, but the underlying mechanisms of these have not been revealed. Therefore, the present study used APP/PS1 mice to assess cognitive change, myelin loss, and corresponding changes in oligodendrocytes, and to explore the underlying mechanisms. Morris water maze tests were performed to evaluate cognitive change in APP/PS1 mice and normal C57 BL/6 mice aged 3 and 6 months. Luxol fast blue staining of the corpus callosum and quantitative reverse transcription-polymerase chain reaction(q RT-PCR) for myelin basic protein(MBP) mRNA were carried out to quantify myelin damage. Immunohistochemistry staining for NG2 and qRT-PCR for monocarboxylic acid transporter 1(MCT1) mRNA were conducted to assess corresponding changes in oligodendrocytes. Our results demonstrate that compared with C57 BL/6 mice, there was a downregulation of MBP mRNA in APP/PS1 mice aged 3 months. This became more obvious in APP/PS1 mice aged 6 months accompanied by other abnormalities such as prolonged escape latency in the Morris water maze test, shrinkage of the corpus callosum, upregulation of NG2-immunoreactive cells, and downregulation of MCT1 mRNA. These findings indicate that the involvement of early demyelination at 3 months and the oligodendrocyte dysfunction at 6 months in APP/PS1 mice are in association with Alzheimer's disease pathogenesis.
基金Supported by the National Natural Science Foundation of China (No.81301080)the Tianjin Natural Science Foundation (No.15JCYBJC24400, No.15JCQNJC10900)the Scientific Research Foundation for the Returned Overseas Chinese Scholars (No.2012-1707)
文摘AIM: To investigate the role of tumor necrosis factoralpha (TNF-α) in zebrafish retinal development and myelination. METHODS: Morpholino oligonucleotides (MO), which are complementary to the translation start site of the wild-type embryonic zebrafish TNF-α mRNA sequence, were synthesized and injected into one to four-cell embryos. The translation blocking specificity was verified by Western blotting using an anti-TNF-α antibody, whole-mount in sltuhybridization using a hepatocytespecific mRNA probe ceruloplasmin (cp), and coinjection of TNF-α MO and TNF-α mRNA. An atonel homolog 7 (atoh7) mRNA probe was used to detect neurogenesis onset. The retinal neurodifferentiation was analyzed by immunohistochemistry using antibodies Zn12, Zprl, and Zpr3 to label ganglion cells, cones, and rods, respectively. Myelin basic protein (mbp)was used as a marker to track and observe the myelination using whole-mount in situ hybridization. RESULTS: Targeted knockdown of TNF-α resulted in specific suppression of TNF-α expression and a severely underdeveloped liver. The co-injection of TNF-α MO and mRNA rescued the liver development. Retinal neurogenesis in TNF-cc morphants was initiated on time. The retina was fully laminated, while ganglion cells, cones, and rods were well differentiated at 72 hours post-fertilization (hpf). mbp was expressed in Schwann cells in the lateral line nerves and cranial nerves from 3 days post -fertilization (dpf) as well as in oligodendrocytes linearly along the hindbrain bundles and the spinal cord from 4 dpf, which closely resembled its endogenous profile. CONCLUSION: TNF-α is not an essential regulator for retinal neurogenesis and optic myelination.
文摘BACKGROUND: Acupuncture treatment on injured cerebral axons has shown to provide efficacy in clinical practice. It is unknown whether acupuncture produces therapeutic effects by protecting injured cerebral myelin in ischemic stroke. OBJECTIVE: To test whether acupuncture provides protection for injured cerebral myelin, based on quantitative data from cerebral ischemia-reperfusion rats, and to compare the effects of early and late acupuncture on serum myelin basic protein (MBP) content and remyelination of the ischemic internal capsule.DESIGN, TIME AND SETTING: A randomized, controlled experiment was performed at the Neurobiological Laboratory, Sichuan University from March 2005 to March 2006. MATERIALS: "Hua Tuo" Brand filiform needles were produced by the Medical Instrument Factory of Suzhou, China.METHODS: A total of 52 adult, healthy, male, Sprague Dawley rats were randomly assigned to four groups: control (n = 4), model (n = 16), early acupuncture (n = 16), and late acupuncture (n = 16). The focal cerebral ischemia-reperfusion model was established by middle cerebral artery occlusion in the right hemisphere using the modified thread embolism method in the latter three groups. Early and late acupuncture groups underwent acupuncture after ischemia for 30 minutes and 2 hours using the Xingnaokaiqiao needling method, respectively. Acupoints were "Neiguarf' (PC 6) and "Sanyinjiao" (SP 6) on the bilateral sides, as well as "Shuigou' (DU 26) and "Baihui" (DU 20) with stimulation for 1 minute at each acupoint. Acupuncture at all acupoints was performed two or three times while the needle was retained, once per day. No special handling was administered to the control clroup.MAIN OUTCOME MEASURES: For each group, remyelination of the internal capsule was observed by Pal-Weigert's myelin staining and serum MBP content was detected using enzyme-linked immunosorbent assay method on days 1,3, 5, and 7 following ischemia-reperfusion injury.RESULTS: Compared with the control group, massive demyelination of the internal capsule occurred, and serum MBP content increased in the model group (P 〈 0.05). Compared with the model group, the extent of demyelination in the internal capsule was less distinct and serum MBP content was significantly less in the early and late acupuncture group (P 〈 0.01 ). Compared with the late acupuncture group, serum MBP content reached a peak later and the peak value was less in the early acupuncture group. CONCLUSION: Results suggest that acupuncture exerts a protective effect on injured cerebral myelin in ischemia-reperfusion rats by reducing serum MBP content and promoting remyelination. The study also suggests that the effect of early acupuncture is superior to late acupuncture.
基金supported by the National Natural Science Foundation of China,No.31071251,81471255,and 81471259a grant from the Ministry of Science and Technology of China(973 Program),No.2014CB542202+2 种基金a grant from the Basic Research Program of Education Department of Jiangsu Province,China,No.14KJA310004a grant from the Natural Science Research Project of Nantong Science and Technology Bureau,China,No.HS2013014a grant from the Natural Science Research Project of Nantong University,China,No.13Z008
文摘Myelination of Schwann cells in the peripheral nervous system is an intricate process involving myelin protein trafficking. Recently, the role and mechanism of the endosomal/lysosomal system in myelin formation were emphasized. Our previous results demonstrated that a small GTPase Rab27a regulates lysosomal exocytosis and myelin protein trafficking in Schwann cells. In this present study, we established a dorsal root ganglion (DRG) neuron and Schwann cell co-culture model to identify the signals associated with Rab27a during myelination. First, Slp2-a, as the Rab27a effector, was endogenously expressed in Schwann cells. Second, Rab27a expression significantly increased during Schwann cell myelination. Finally, Rab27a and Slp2-a silencing in Schwann cells not only reduced myelin protein expression, but also impaired formation of myelin-like membranes in DRG neuron and Schwann cell co-cultures. Our findings suggest that the Rab27a/ Slp2-a complex affects Schwann cell myelination in vitro.
基金supported by the Natural Science Foundation of Jiangsu Province,China,No.BK20150409the Natural Science Foundation of Jiangsu Higher Education Institutions of China,No.15KJB180013+3 种基金the Natural Science Foundation of Nantong of Jiangsu Province,No.MS12015043Postdoctoral Science Foundation of China,No.2016M600435Postdoctoral Science Foundation of Jiangsu Province of China,No.1601056AProject Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions
文摘Differential expression of mi RNAs occurs in injured proximal nerve stumps and includes mi RNAs that are firstly down-regulated and then gradually up-regulated following nerve injury.These mi RNAs might be related to a Schwann cell phenotypic switch.mi R-30 c,as a member of this group,was further investigated in the current study.Sprague-Dawley rats underwent sciatic nerve transection and proximal nerve stumps were collected at 1,4,7,14,21,and 28 days post injury for analysis.Following sciatic nerve injury,mi R-30 c was down-regulated,reaching a minimum on day 4,and was then upregulated to normal levels.Schwann cells were isolated from neonatal rat sciatic nerve stumps,then transfected with mi R-30 c agomir and co-cultured in vitro with dorsal root ganglia.The enhanced expression of mi R-30 c robustly increased the amount of myelin-associated protein in the co-cultured dorsal root ganglia and Schwann cells.We then modeled sciatic nerve crush injury in vivo in Sprague-Dawley rats and tested the effect of perineural injection of mi R-30 c agomir on myelin sheath regeneration.Fourteen days after surgery,sciatic nerve stumps were harvested and subjected to immunohistochemistry,western blot analysis,and transmission electron microscopy.The direct injection of mi R-30 c stimulated the formation of myelin sheath,thus contributing to peripheral nerve regeneration.Overall,our findings indicate that mi R-30 c can promote Schwann cell myelination following peripheral nerve injury.The functional study of mi R-30 c will benefit the discovery of new therapeutic targets and the development of new treatment strategies for peripheral nerve regeneration.
基金supported by the National Natural Science Foundation of China,No.81601957
文摘Remyelination plays a key role in functional recovery of axons after spinal cord injury.Glial cells are the most abundant cells in the central nervous system.When spinal cord injury occurs,many glial cells at the lesion site are immediately activated,and different cells differentially affect inflammatory reactions after injury.In this review,we aim to discuss the core role of oligodendrocyte precursor cells and crosstalk with the rest of glia and their subcategories in the remyelination process.Activated astrocytes influence proliferation,differentiation,and maturation of oligodendrocyte precursor cells,while activated microglia alter remyelination by regulating the inflammatory reaction after spinal cord injury.Understanding the interaction between oligodendrocyte precursor cells and the rest of glia is necessary when designing a therapeutic plan of remyelination after spinal cord injury.
基金supported by Grants-in-Aid from the Japanese MEXT and MHLWsupported by the Innovative Areas’ Scientific Research(Glial Assembly)the Takeda Science Foundation
文摘Myelin plays important roles in vertebrates,ensuring the rapid propagation of action potentials and the long-term integrity of axons,but the molecular mechanisms of myelin formation remain poorly understood.Recent studies have demonstrated that myelination is regulated by the TYRO3,AXL(also known as UFO)and MERTK.
文摘Adverse life experience induces permanent phenotypic changes in cognitive functions associated with the prefrontal cortex(PFC).However,the underlying mechanisms remain unclear.In this work,we use neonatal maternal separation(NMS)and chronic social defeat(CSD)rat models to address how adverse life experience affects PFC-dependent cognitive functions.Our results show that normal myelination of the medial PFC(mPFC)is necessary for mPFC-dependent behaviors,as experimental blockade of oligodendrocyte differentiation or lysolecithin-induced demyelination impairs mPFC-dependent behaviors.NMS or CSD produces severe deficits in mPFC myelination,while other brain regions,such as the hippocampusa and basal ganglia,remain intact.In parallel,rats with NMS or CSD exhibit anxiety-like behaviors and demonstrate poor performance on mPFC-dependent tasks.Further experiments demonstrate that,histone deacetylases 1/2(HDAC1/2)are reduced in the mPFC of NMS and CSD rats.Inhibition of HDAC1/2 promotes activation of Wnt signalling,which negatively regulates oligodendrocyte development.Conversely,selective inhibition of Wnt signaling rescues the myelination arrestment and behavioral deficiency induced by NMS or CSD.These findings indicate that NMS or CSD impairs mPFC cognitive functions via regulation of oligodendrogenesis and myelination.