Spinal cord injury is a severe neurological condition with limited neuronal regeneration and functional recovery.Currently,no effective treatments exist to improve spinal cord injury prognosis.Neuronal guidance protei...Spinal cord injury is a severe neurological condition with limited neuronal regeneration and functional recovery.Currently,no effective treatments exist to improve spinal cord injury prognosis.Neuronal guidance proteins are a diverse group of molecules that play crucial roles in axon and dendrite growth during nervous system development.Increasing evidence highlights their regulatory functions in spinal cord injury.This review provides a brief overview of the modulation patterns of key neuronal guidance proteins in neuronal axon growth during nervous system formation and subsequently focuses on their roles in neuronal regeneration and functional recovery following spinal cord injury.Neuronal guidance proteins include,but are not limited to,semaphorins and their receptors,plexins;netrins and their receptors,deleted in colorectal cancer and UNC5;Eph receptors and their ligands,ephrins;Slit and its receptor,Robo;repulsive guidance molecules and their receptor,neogenin;Wnt proteins and their receptor,Frizzled;and protocadherins.Localized Netrin-1 at the injury site inhibits motor axon regeneration after adult spinal cord injury while promoting oligodendrocyte growth.Slit2 enhances synapse formation in the injured spinal cord of rats.EphA7 regulates acute apoptosis in the early pathophysiological stages of spinal cord injury,while ephrinA1 plays a role in the nervous system’s injury response,with its reduced expression leading to impaired motor function in rats.EphA3 is upregulated following spinal cord injury,promoting an inhibitory environment for axonal regeneration.After spinal cord injury,bidirectional activation of ephrinB2 and EphB2 in astrocytes and fibroblasts results in the formation of a dense astrocyte-meningeal fibroblast scar.EphB1/ephrinB1 signaling mediates pain processing in spinal cord injury by regulating calpain-1 and caspase-3 in neurons.EphB3 expression increases in white matter after spinal cord injury,further inhibiting axon regeneration.Sema3A,expressed by neurons and fibroblasts in the scar surrounding the injury,inhibits motor neuron and sensory nerve growth after spinal cord injury.Sema4D suppresses neuronal axon myelination and axon regeneration,while its inhibition significantly enhances axon regeneration and motor recovery.Sema7A is involved in glial scar formation and may influence serotonin channel remodeling,thereby affecting motor coordination.Given these findings,the local or systemic application of neuronal guidance proteins represents a promising avenue for spinal cord injury treatment.展开更多
Neuronal plasticity,the brain's ability to adapt structurally and functionally,is essential for learning,memory,and recovery from injuries.In neurodegenerative diseases such as Alzheimer's disease and Parkinso...Neuronal plasticity,the brain's ability to adapt structurally and functionally,is essential for learning,memory,and recovery from injuries.In neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease,this plasticity is disrupted,leading to cognitive and motor deficits.This review explores the mechanisms of neuronal plasticity and its effect on Alzheimer's disease and Parkinson's disease.Alzheimer's disease features amyloid-beta plaques and tau tangles that impair synaptic function,while Parkinson's disease involves the loss of dopaminergic neurons affecting motor control.Enhancing neuronal plasticity offers therapeutic potential for these diseases.A systematic literature review was conducted using databases such as PubMed,Scopus,and Google Scholar,focusing on studies of neuronal plasticity in Alzheimer's disease and Parkinson's disease.Data synthesis identified key themes such as synaptic mechanisms,neurogenesis,and therapeutic strategies,linking molecular insights to clinical applications.Results highlight that targeting synaptic plasticity mechanisms,such as long-term potentiation and long-term depression,shows promise.Neurotrophic factors,advanced imaging techniques,and molecular tools(e.g.,clustered regularly interspaced short palindromic repeats and optogenetics)are crucial in understanding and enhancing plasticity.Current therapies,including dopamine replacement,deep brain stimulation,and lifestyle interventions,demonstrate the potential to alleviate symptoms and improve outcomes.In conclusion,enhancing neuronal plasticity through targeted therapies holds significant promise for treating neurodegenerative diseases.Future research should integrate multidisciplinary approaches to fully harness the therapeutic potential of neuronal plasticity in Alzheimer's disease and Parkinson's disease.展开更多
Indicaxanthin is a betalain that is abundant in Opuntia ficus-indica orange fruit and has antioxidative and anti-inflammatory effects. Nevertheless, very little is known about the neuroprotective potential of indicaxa...Indicaxanthin is a betalain that is abundant in Opuntia ficus-indica orange fruit and has antioxidative and anti-inflammatory effects. Nevertheless, very little is known about the neuroprotective potential of indicaxanthin. This study investigated the impact of indicaxanthin on neuronal damage and gut microbiota dysbiosis induced by a high-fat diet in mice. The mice were divided into three groups according to different diets: the negative control group was fed a standard diet;the high-fat diet group was fed a high-fat diet;and the high-fat diet + indicaxanthin group was fed a high-fat diet and received indicaxanthin orally(0.86 mg/kg per day) for 4 weeks. Brain apoptosis, redox status, inflammation, and the gut microbiota composition were compared among the different animal groups. The results demonstrated that indicaxanthin treatment reduced neuronal apoptosis by downregulating the expression of proapoptotic genes and increasing the expression of antiapoptotic genes. Indicaxanthin also markedly decreased the expression of neuroinflammatory proteins and genes and inhibited high-fat diet–induced neuronal oxidative stress by reducing reactive oxygen and nitrogen species, malondialdehyde, and nitric oxide levels. In addition, indicaxanthin treatment improved the microflora composition by increasing the abundance of healthy bacterial genera, known as producers of short-chain fatty acids(Lachnospiraceae, Alloprovetella, and Lactobacillus), and by reducing bacteria related to unhealthy profiles(Blautia, Faecalibaculum, Romboutsia and Bilophila). In conclusion, indicaxanthin has a positive effect on high-fat diet–induced neuronal damage and on the gut microbiota composition in obese mice.展开更多
Spinal cord injury(SCI) often results in permanent dysfunction of locomotion,sensation,and autonomic regulation,imposing a substantial burden on both individuals and society(Anjum et al.,2020).SCI has a complex pathop...Spinal cord injury(SCI) often results in permanent dysfunction of locomotion,sensation,and autonomic regulation,imposing a substantial burden on both individuals and society(Anjum et al.,2020).SCI has a complex pathophysiology:an initial primary injury(mechanical trauma,axonal disruption,and hemorrhage) is followed by a progressive secondary injury cascade that involves ischemia,neuronal loss,and inflammation.Given the challenges in achieving regeneration of the injured spinal cord,neuroprotection has been at the forefront of clinical research.展开更多
Aging is considered the main risk factor for the development of several diseases,including the leading neurodegenerative disorders.While the cellular features of aging are complex and multifaceted,neuronal senescence ...Aging is considered the main risk factor for the development of several diseases,including the leading neurodegenerative disorders.While the cellular features of aging are complex and multifaceted,neuronal senescence has emerged as a major contributor and driver of this process in the mammalian cell.Cellular senescence is a programmed response to stress and irreparable damage,which drives the cell into an apoptosis-resistant,non-proliferative state.Senescent cells can also deleteriously affect neighboring,non-senescent cells.Senescence is a complex and multifaceted process associated with a wide range of cellular events,including the secretion of pro-inflammatory molecules and the arrest of the cell cycle.展开更多
Phosphatidylethanolamine is a major phospholipid class abundant in the brain,particularly in the inner leaflet of the plasma and mitochondrial membranes.Although it is primarily synthesized from phosphatidylserine via...Phosphatidylethanolamine is a major phospholipid class abundant in the brain,particularly in the inner leaflet of the plasma and mitochondrial membranes.Although it is primarily synthesized from phosphatidylserine via decarboxylation in mitochondria or from ethanolamine via the cytidine diphosphate-ethanolamine pathway in the endoplasmic reticulum,phosphatidylethanolamine that resides in mitochondria is preferentially produced locally and is distinct and separate from the pool of phosphatidylethanolamine made in the endoplasmic reticulum.Mitochondria-derived phosphatidylethanolamine is not only essential for mitochondrial integrity but also is exported to other organelles to fulfill diverse cellular functions.Neurons are highly enriched with phosphatidylethanolamine,and the importance of phosphatidylethanolamine metabolism in neuronal health has recently been recognized following its reported links to Alzheimer’s disease,Parkinson’s disease,and hereditary spastic paraplegia,among other neurological disorders.Indeed,disturbances in mitochondrial function and phosphatidylethanolamine metabolism and the resulting neuronal dysfunction are the common features of individuals suffering from these diseases,highlighting the great importance of maintaining proper phosphatidylethanolamine homeostasis in neurons.In this review,we summarize the current knowledge of phosphatidylethanolamine metabolism and its role in neuronal function with a special emphasis on the phosphatidylethanolamine biosynthetic pathway in mitochondria.We then review findings on how phosphatidylethanolamine biosynthesis is affected in major neurodegenerative diseases.Finally,we highlight promising future research areas that will help advance the understanding of neuronal phosphatidylethanolamine mechanisms and identify phosphatidylethanolamine-targeted therapeutic strategies for combating such brain diseases.展开更多
Neurodegenerative diseases,which are characterized by progressive neuronal loss and the lack of disease-modifying therapies,are becoming a major global health challenge.The existing neuromodulation techniques,such as ...Neurodegenerative diseases,which are characterized by progressive neuronal loss and the lack of disease-modifying therapies,are becoming a major global health challenge.The existing neuromodulation techniques,such as deep brain stimulation and transcranial magnetic stimulation,show limitations such as invasiveness,restricted cortical targeting,and irreversible tissue effects.In this context,low-intensity transcranial ultrasound has emerged as a promising noninvasive alternative that can penetrate deep into the brain and modulate neuroplasticity.This review comprehensively assesses the therapeutic mechanisms,efficacy,and translational potential of low-intensity transcranial ultrasound in treating neurodegenerative diseases,with emphasis on its role in promoting neuronal regeneration,modulating neuroinflammation,and enhancing functional recovery.We summarize the findings of previous studies and systematically illustrate the potential of low-intensity transcranial ultrasound in regulating cell death mechanisms,enhancing neural repair and regeneration,and alleviating symptoms associated with neurodegenerative diseases.Preclinical findings indicate that low-intensity transcranial ultrasound can enhance the release of neurotrophic factors(e.g.,brain-derived neurotrophic factor),promote autophagy to clear protein aggregates,modulate microglial activation,and temporarily open the blood-brain barrier to facilitate targeted drug delivery.Existing clinical trial data show that low-intensity transcranial ultrasound can reduce amyloid-βplaques,improve motor and cognitive deficits,and promote remyelination in various disease models.Early clinical trials suggest that low-intensity transcranial ultrasound may enhance cognitive scores in Alzheimer’s disease and alleviate motor symptoms in Parkinson’s disease,all while demonstrating a favorable safety profile.Past studies support the notion that by integrating safety,precision,and reversibility,low-intensity transcranial ultrasound can transform the treatment landscape for neurodegenerative disease.However,more advancements are necessary for future clinical application of low-intensity transcranial ultrasound,including optimizing parameters such as frequency,intensity,and duty cycle;considering individual anatomical differences;and confirming long-term efficacy.We believe establishing standardized protocols,conducting larger trials,and investigating the underlying mechanisms to clarify dose-response relationships and refine personalized application strategies are essential in this regard.Future research should focus on translating preclinical findings into clinical practice,addressing technical challenges,and exploring combination therapies with pharmacological or gene interventions.展开更多
Oligodendrocyte precursor cells(OPCs)tile the central nervous system ubiquitously,accounting for about 5%of the total cell population in the central nervous system.Beyond their role in myelination,OPCs actively shape ...Oligodendrocyte precursor cells(OPCs)tile the central nervous system ubiquitously,accounting for about 5%of the total cell population in the central nervous system.Beyond their role in myelination,OPCs actively shape neural circuits(Fang and Bai,2023),by releasing neuromodulators,pruning synapses,maintaining the homeostasis of extracellular potassium concentration,and interacting with endothelial cells.展开更多
Stroke,particularly ischemic stroke,is the leading cause of long-term disability and mortality worldwide.It occurs due to the occlusion of the cerebral arteries,which significantly reduces the delivery of blood,oxygen...Stroke,particularly ischemic stroke,is the leading cause of long-term disability and mortality worldwide.It occurs due to the occlusion of the cerebral arteries,which significantly reduces the delivery of blood,oxygen,and essential nutrients to brain tissues.This deprivation triggers a cascade of cellular events that ultimately leads to neuronal death.Recent studies have clarified the multifactorial pathogenesis of ischemic stroke,highlighting the roles of energy failure,excitotoxicity,oxidative stress,neuroinflammation,and apoptosis.This review aimed to provide a comprehensive insight into the fundamental mechanisms driving neuronal death triggered by ischemia and to examine the progress of neuroprotective therapeutic approaches designed to mitigate neuronal loss and promote neurological recovery after a stroke.Additionally,we explored widely accepted findings regarding the potential pathways implicated in neuronal death during ischemic stroke,including the interplay of apoptosis,autophagy,pyroptosis,ferroptosis,and necrosis,which collectively influence neuronal fate.We also discussed advancements in neuroprotective therapeutics,encompassing a range of interventions from pharmacological modulation to stem cell-based therapies,aimed at reducing neuronal injury and enhancing functional recovery following ischemic stroke.Despite these advancements,challenges remain in translating mechanistic insights into effective clinical therapies.Although neuroprotective strategies have shown promise in preclinical models,their efficacy in human trials has been inconsistent,often due to the complex pathology of ischemic stroke and the timing of interventions.In conclusion,this review synthesizes mechanistic insights into the intricate interplay of molecular and cellular pathways driving neuronal death post-ischemia.It sheds light on cutting-edge advancements in potential neuroprotective therapeutics,underscores the promise of regenerative medicine,and offers a forward-looking perspective on potential clinical breakthroughs.The ongoing evolution of precision-targeted interventions is expected to significantly enhance preventative strategies and improve clinical outcomes.展开更多
Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage.Neuronal ferroptosis in particular plays an important role in...Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage.Neuronal ferroptosis in particular plays an important role in early brain injury.Bromodomain-containing protein 4,a member of the bromo and extraterminal domain family of proteins,participated in multiple cell death pathways,but the mechanisms by which it regulates ferroptosis remain unclear.The primary aim of this study was to investigate how bromodomain-containing protein 4 affects neuronal ferroptosis following subarachnoid hemorrhage in vivo and in vitro.Our findings revealed that endogenous bromodomain-containing protein 4 co-localized with neurons,and its expression was decreased 48 hours after subarachnoid hemorrhage of the cerebral cortex in vivo.In addition,ferroptosis-related pathways were activated in vivo and in vitro after subarachnoid hemorrhage.Targeted inhibition of bromodomain-containing protein 4 in neurons increased lipid peroxidation and intracellular ferrous iron accumulation via ferritinophagy and ultimately led to neuronal ferroptosis.Using cleavage under targets and tagmentation analysis,we found that bromodomain-containing protein 4 enrichment in the Raf-1 promoter region decreased following oxyhemoglobin stimulation in vitro.Furthermore,treating bromodomain-containing protein 4-knockdown HT-22 cell lines with GW5074,a Raf-1 inhibitor,exacerbated neuronal ferroptosis by suppressing the Raf-1/ERK1/2 signaling pathway.Moreover,targeted inhibition of neuronal bromodomain-containing protein 4 exacerbated early and long-term neurological function deficits after subarachnoid hemorrhage.Our findings suggest that bromodomain-containing protein 4 may have neuroprotective effects after subarachnoid hemorrhage,and that inhibiting ferroptosis could help treat subarachnoid hemorrhage.展开更多
Cmyc,a proto-oncogene,is expressed at extremely low levels in mature neurons and is traditionally thought to have no function in these cells.However,recent studies suggest that Cmyc may play a crucial role in maintain...Cmyc,a proto-oncogene,is expressed at extremely low levels in mature neurons and is traditionally thought to have no function in these cells.However,recent studies suggest that Cmyc may play a crucial role in maintaining the health and function of mature dopaminergic neurons.This study assessed the role of Cmyc in dopaminergic neurons and its significance in Parkinson’s disease.We used a conditional knockout approach to specifically delete Cmyc in substantia nigra dopaminergic neurons of adult mice.Our findings showed that Cmyc deletion led to progressive neuron loss,Parkinson’s disease-like symptoms,downregulation of Klotho,and upregulation of senescence-associated inflammatory factors,along with enhanced oxidative stress and nitrated alpha-synuclein accumulation,ultimately causing neuronal death.In vitro experiments confirmed increased senescence in C-MYC knockout cells,which was partially reversible by KLOTHO overexpression.We conclude that low-level Cmyc expression is essential for maintaining the health of mature dopaminergic neurons and preventing neurodegeneration,and suggest the c-Myc/Klotho axis as a potential therapeutic target for age-related neurodegenerative diseases,including Parkinson’s disease.Our study introduces a novel mouse model for Parkinson’s disease that replicates a condition associated with normal aging,offering a valuable tool for future research into disease mechanisms and therapeutic strategies.展开更多
The process of neurite outgrowth and branching is a crucial aspect of neuronal development and regeneration.Axons and dendrites,sometimes referred to as neurites,are extensions of a neuron's cellular body that are...The process of neurite outgrowth and branching is a crucial aspect of neuronal development and regeneration.Axons and dendrites,sometimes referred to as neurites,are extensions of a neuron's cellular body that are used to start networks.Here we explored the effects of diethyl(3,4-dihydroxyphenethylamino)(quinolin-4-yl)methylphosphonate(DDQ)on neurite developmental features in HT22 neuronal cells.In this work,we examined the protective effects of DDQ on neuronal processes and synaptic outgrowth in differentiated HT22cells expressing mutant Tau(mTau)cDNA.To investigate DDQ chara cteristics,cell viability,biochemical,molecular,western blotting,and immunocytochemistry were used.Neurite outgrowth is evaluated through the segmentation and measurement of neural processes.These neural processes can be seen and measured with a fluorescence microscope by manually tracing and measuring the length of the neurite growth.These neuronal processes can be observed and quantified with a fluorescent microscope by manually tracing and measuring the length of the neuronal HT22.DDQ-treated mTau-HT22 cells(HT22 cells transfected with cDNA mutant Tau)were seen to display increased levels of synaptophysin,MAP-2,andβ-tubulin.Additionally,we confirmed and noted reduced levels of both total and p-Tau,as well as elevated levels of microtubule-associated protein 2,β-tubulin,synaptophysin,vesicular acetylcholine transporter,and the mitochondrial biogenesis protein-pe roxisome prolife rator-activated receptor-gamma coactivator-1α.In mTa u-expressed HT22 neurons,we observed DDQ enhanced the neurite characteristics and improved neurite development through increased synaptic outgrowth.Our findings conclude that mTa u-HT22(Alzheimer's disease)cells treated with DDQ have functional neurite developmental chara cteristics.The key finding is that,in mTa u-HT22 cells,DDQ preserves neuronal structure and may even enhance nerve development function with mTa u inhibition.展开更多
Animals exhibit complex responses to external and internal stimuli.The information is computed by interconnected neurons that express numerous ion channels,which modulate the neuronal membrane potential.How can neuron...Animals exhibit complex responses to external and internal stimuli.The information is computed by interconnected neurons that express numerous ion channels,which modulate the neuronal membrane potential.How can neuronal activity orchestrate complex motor patterns or allow learning from previous experience?To answer such questions,we need the ability not only to record,but also to modulate neuronal activity in both space(e.g.,neuronal subsets)and time.展开更多
Sex-specific neurons play pivotal roles in regulating sexually dimorphic behaviors.In insects,the sex determination gene doublesex(dsx)establishes major sexual dimorphism of the nervous system,in which male-specific d...Sex-specific neurons play pivotal roles in regulating sexually dimorphic behaviors.In insects,the sex determination gene doublesex(dsx)establishes major sexual dimorphism of the nervous system,in which male-specific dsx^(M)promotes neuronal development,while female-specific dsx^(F)inhibits neuronal development by promoting neuronal apoptosis.In this study,we find that dsx regulates the number of dsx-expressing central neurons in Drosophila in cell-specific manners.Although dsx^(M)overall promotes an increase in the number of dsx neurons,it inhibits the emergence of specific pC1 neurons.dsx^(F)reduces the number of different pC1/pC2 subtypes,but promotes the formation of pC1d.We also find that dsx^(M)and dsx^(F)barely affect the number of some pC2 neurons.Changes in the number of pC1/pC2 neurons alter their roles in regulating different behaviors,including courtship,aggression,and locomotion.Our results illustrate the multifaceted functions of dsx in sexually dimorphic neuronal development and behaviors.展开更多
Humans and animals have a fundamental ability to use experiences and environmental information to organize behavior.It often happens that humans and animals make decisions and prepare actions under uncertain situation...Humans and animals have a fundamental ability to use experiences and environmental information to organize behavior.It often happens that humans and animals make decisions and prepare actions under uncertain situations.Uncertainty would significantly affect the state of animals’minds,but may not be reflected in behavior.How to“read animals’mind state”under different situations is a challenge.Here,we report that neuronal activity in the medial prefrontal cortex(mPFC)of rats can reflect the environmental uncertainty when the task situation changes from certain to uncertain.Rats were trained to perform behavioral tasks under certain and uncertain situations.Under certain situations,rats were required to simply repeat two nose-poking actions that each triggered short auditory tone feedback(single-task situation).Whereas under the uncertain situation,the feedback could randomly be either the previous tone or a short musical rhythm.No additional action was required upon the music feedback,and the same secondary nose-poking action was required upon the tone feedback(dual-task situation);therefore,the coming task was uncertain before action initiation.We recorded single-unit activity from the mPFC when the rats were performing the tasks.We found that in the dual task,when uncertainty was introduced,many mPFC neurons were actively engaged in dealing with the uncertainty before the task initiation,suggesting that the rats could be aware of the task situation change and encode the information in the mPFC before the action of task initiation.展开更多
BACKGROUND Spinal cord injury(SCI)often results in irreversible neurological deficits;therefore,effective treatment is urgently needed.Neural stem cells(NSCs)have excellent differentiation potential.However,the role o...BACKGROUND Spinal cord injury(SCI)often results in irreversible neurological deficits;therefore,effective treatment is urgently needed.Neural stem cells(NSCs)have excellent differentiation potential.However,the role of the long noncoding RNA X inactive-specific transcript(XIST)in NSCs and SCI remains unclear.AIM To explore the role of XIST in enhancing NSC function and its therapeutic potential in SCI.METHODS We used in vitro and in vivo models to examine the effects of XIST on NSCs.XIST was overexpressed in NSCs,and its impact on mitochondrial function,neuronal differentiation,and the insulin-like growth factor 2 mRNA binding protein 2(IGF2BP2)/carnitine palmitoyl transferase 1A(CPT1A)pathway was assessed using a series of biochemical assays,quantitative PCR,and Seahorse XF24 analysis.A mouse model of SCI was used to evaluate the therapeutic effects of XIST in vivo.RESULTS Overexpression of XIST in NSCs significantly increased mitochondrial membrane potential,ATP production,and oxygen consumption rate.XIST also promoted NSC proliferation and neuronal differentiation while inhibiting astrocytic differentiation.Mechanistically,XIST regulated CPT1A expression post-transcriptionally by interacting with IGF2BP2.In vivo XIST-treated mice exhibited improved motor scores and reduced proinflammatory cytokine expression following SCI.CONCLUSIONThese findings suggested that XIST modulated mitochondrial function and neural differentiation in NSCs throughthe IGF2BP2/CPT1A pathway. While preliminary in vivo results are encouraging, further studies are needed todetermine the long-term therapeutic relevance and underlying mechanisms of XIST in SCI recovery.展开更多
Alzheimer’s disease(AD)is a neurodegenerative disease causing the most frequent form of dementia in old age.AD etiology is still uncertain and deposition of abnormal proteins in the brain along with chronic neuroinfl...Alzheimer’s disease(AD)is a neurodegenerative disease causing the most frequent form of dementia in old age.AD etiology is still uncertain and deposition of abnormal proteins in the brain along with chronic neuroinflammation have been suggested as pathogenic mechanisms of neuronal death.Infections by exogenous neurotropic virus,endogenous retrovirus reactivation,infections by other microbes,and air pollutants may either induce neurodegeneration or activate brain inflammation.Up to 8%of the human genome has a retroviral origin.These ancient retroviruses,also called human endogenous retroviruses,are associated with a clinical history of several neurodegenerative diseases.Under persistent stress,such as chronic infections and inflammation,neurons,and microglia cells may enter a state of division inactivation called cell senescence.Senescent cells are resistant to apoptosis and can release pro-inflammatory molecules promoting the functional decline of tissues and organs and also activate silent viruses.Infections andmutations induced by pollutants can lead to the expression of different endogenous retroviruses,which may contribute to several different diseases,including AD-associated neurodegeneration.Here I discuss that infection by exogenous pathogen,activation of endogenous retrovirus or retrotransposons and pollutants might induce neuronal senescence and cause persistent brain neurodegeneration.Therefore,cell senescence appears to be an emerging mechanism that might contribute to AD neurodegeneration.Finally,treatment of AD patients with senolytic drugs,e.g.,compounds able to kill senescent cells,might show a positive effect on AD progression.展开更多
A traditional Chinese medicine(TCM)monomer is a bioactive compound extracted from Chinese herbal medicines possessing determined biological activity and pharmacological effects,and has gained much attention for treati...A traditional Chinese medicine(TCM)monomer is a bioactive compound extracted from Chinese herbal medicines possessing determined biological activity and pharmacological effects,and has gained much attention for treating neuronal diseases.However,the application of TCM monomers is limited by their low solubility and poor ability to cross the blood-brain barrier(BBB).Exosomes are small extracellular vesicles(EVs)ranging in size from 30 to 150 nm in diameter and can be used as drug delivery carriers that directly target cells or tissues with unique advantages,including low toxicity,low immunogenicity,high stability in blood,and the ability to cross the BBB.This review discusses the biogenesis,components,stability,surface modification,isolation technology,advantages,and disadvantages of exosomes as drug carriers and compares exosomes and other similar drug delivery systems.Furthermore,exosome-encapsulated TCM monomers exert neuroprotective roles,such as anti-inflammation,anti-apoptosis,anti-mitophagy,and anti-oxidation,in various neuronal diseases,including Alzheimer's disease(AD),Parkinson's disease(PD),multiple sclerosis(MS),and cerebral ischemia and reperfusion(CI/R)injury,as well as anti-drug resistance,anti-tumorigenesis,anti-angiogenesis,and promotion of apoptosis in brain tumors,providing more inspiration to promote the development of an exosome-based delivery tool in targeted therapy for neuronal diseases.展开更多
BACKGROUND Spinal cord injury(SCI)is a severe and permanent trauma that often leads to significant motor,sensory,and autonomic dysfunction.Neuronal apoptosis is a major pathomechanism underlying secondary injury in SC...BACKGROUND Spinal cord injury(SCI)is a severe and permanent trauma that often leads to significant motor,sensory,and autonomic dysfunction.Neuronal apoptosis is a major pathomechanism underlying secondary injury in SCI.Long non-coding RNAs(lncRNAs)have emerged as key regulators of gene expression and cellular processes,including apoptosis.However,the role of lncRNA growth arrest-specific transcript 5(GAS5)in SCI-induced neuronal apoptosis remains unclear.AIM To investigate the role of lncRNA GAS5 in SCI-induced neuronal apoptosis via its interaction with microRNA(miR)-21 and the phosphatase and tensin homolog(PTEN)/AKT pathway.METHODS SCI rat models and hypoxic neuronal cell models were established.Motor function was assessed using the Basso-Beattie-Bresnahan score.Expression levels of GAS5,miR-21,PTEN,caspase 3,B-cell lymphoma 2(Bcl-2),Bcl-2-associated X protein(Bax),and AKT were measured using quantitative PCR or Western blot analysis.Neuronal apoptosis was determined by TUNEL staining.Dual-luciferase reporter assays validated GAS5-miR-21 binding.Knockdown and overexpression experiments explored the functional effects of the GAS5/miR-21 axis.RESULTS GAS5 was significantly upregulated in the spinal cord following SCI,coinciding with increased neuronal apoptosis and decreased AKT activation.In vitro experiments demonstrated that GAS5 acted as a molecular sponge for miR-21,leading to increased PTEN expression and inhibition of the AKT signaling pathway,thereby promoting apoptosis.In vivo,GAS5 knockdown attenuated neuronal apoptosis,enhanced AKT activation,and improved motor function recovery in SCI rats.CONCLUSION GAS5 promotes neuronal apoptosis in SCI by binding to miR-21 and upregulating PTEN expression,inhibiting the AKT pathway.Targeting GAS5 may represent a novel therapeutic strategy for SCI.展开更多
Deep learning networks are increasingly exploited in the field of neuronal soma segmentation.However,annotating dataset is also an expensive and time-consuming task.Unsupervised domain adaptation is an effective metho...Deep learning networks are increasingly exploited in the field of neuronal soma segmentation.However,annotating dataset is also an expensive and time-consuming task.Unsupervised domain adaptation is an effective method to mitigate the problem,which is able to learn an adaptive segmentation model by transferring knowledge from a rich-labeled source domain.In this paper,we propose a multi-level distribution alignment-based unsupervised domain adaptation network(MDA-Net)for segmentation of 3D neuronal soma images.Distribution alignment is performed in both feature space and output space.In the feature space,features from different scales are adaptively fused to enhance the feature extraction capability for small target somata and con-strained to be domain invariant by adversarial adaptation strategy.In the output space,local discrepancy maps that can reveal the spatial structures of somata are constructed on the predicted segmentation results.Then thedistribution alignment is performed on the local discrepancies maps across domains to obtain a superior discrepancy map in the target domain,achieving refined segmentation performance of neuronal somata.Additionally,after a period of distribution align-ment procedure,a portion of target samples with high confident pseudo-labels are selected as training data,which assist in learning a more adaptive segmentation network.We verified the superiority of the proposed algorithm by comparing several domain adaptation networks on two 3D mouse brain neuronal somata datasets and one macaque brain neuronal soma dataset.展开更多
基金supported by Shenzhen University General Hospital Scientific Research Project,No.SUGH2019QD002Shenzhen Science and Technology Development Foundation,No.20220810173216001(both to ZS).
文摘Spinal cord injury is a severe neurological condition with limited neuronal regeneration and functional recovery.Currently,no effective treatments exist to improve spinal cord injury prognosis.Neuronal guidance proteins are a diverse group of molecules that play crucial roles in axon and dendrite growth during nervous system development.Increasing evidence highlights their regulatory functions in spinal cord injury.This review provides a brief overview of the modulation patterns of key neuronal guidance proteins in neuronal axon growth during nervous system formation and subsequently focuses on their roles in neuronal regeneration and functional recovery following spinal cord injury.Neuronal guidance proteins include,but are not limited to,semaphorins and their receptors,plexins;netrins and their receptors,deleted in colorectal cancer and UNC5;Eph receptors and their ligands,ephrins;Slit and its receptor,Robo;repulsive guidance molecules and their receptor,neogenin;Wnt proteins and their receptor,Frizzled;and protocadherins.Localized Netrin-1 at the injury site inhibits motor axon regeneration after adult spinal cord injury while promoting oligodendrocyte growth.Slit2 enhances synapse formation in the injured spinal cord of rats.EphA7 regulates acute apoptosis in the early pathophysiological stages of spinal cord injury,while ephrinA1 plays a role in the nervous system’s injury response,with its reduced expression leading to impaired motor function in rats.EphA3 is upregulated following spinal cord injury,promoting an inhibitory environment for axonal regeneration.After spinal cord injury,bidirectional activation of ephrinB2 and EphB2 in astrocytes and fibroblasts results in the formation of a dense astrocyte-meningeal fibroblast scar.EphB1/ephrinB1 signaling mediates pain processing in spinal cord injury by regulating calpain-1 and caspase-3 in neurons.EphB3 expression increases in white matter after spinal cord injury,further inhibiting axon regeneration.Sema3A,expressed by neurons and fibroblasts in the scar surrounding the injury,inhibits motor neuron and sensory nerve growth after spinal cord injury.Sema4D suppresses neuronal axon myelination and axon regeneration,while its inhibition significantly enhances axon regeneration and motor recovery.Sema7A is involved in glial scar formation and may influence serotonin channel remodeling,thereby affecting motor coordination.Given these findings,the local or systemic application of neuronal guidance proteins represents a promising avenue for spinal cord injury treatment.
基金financially supported by King Abdulaziz University,Deanship of Scientific Research(DSR)。
文摘Neuronal plasticity,the brain's ability to adapt structurally and functionally,is essential for learning,memory,and recovery from injuries.In neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease,this plasticity is disrupted,leading to cognitive and motor deficits.This review explores the mechanisms of neuronal plasticity and its effect on Alzheimer's disease and Parkinson's disease.Alzheimer's disease features amyloid-beta plaques and tau tangles that impair synaptic function,while Parkinson's disease involves the loss of dopaminergic neurons affecting motor control.Enhancing neuronal plasticity offers therapeutic potential for these diseases.A systematic literature review was conducted using databases such as PubMed,Scopus,and Google Scholar,focusing on studies of neuronal plasticity in Alzheimer's disease and Parkinson's disease.Data synthesis identified key themes such as synaptic mechanisms,neurogenesis,and therapeutic strategies,linking molecular insights to clinical applications.Results highlight that targeting synaptic plasticity mechanisms,such as long-term potentiation and long-term depression,shows promise.Neurotrophic factors,advanced imaging techniques,and molecular tools(e.g.,clustered regularly interspaced short palindromic repeats and optogenetics)are crucial in understanding and enhancing plasticity.Current therapies,including dopamine replacement,deep brain stimulation,and lifestyle interventions,demonstrate the potential to alleviate symptoms and improve outcomes.In conclusion,enhancing neuronal plasticity through targeted therapies holds significant promise for treating neurodegenerative diseases.Future research should integrate multidisciplinary approaches to fully harness the therapeutic potential of neuronal plasticity in Alzheimer's disease and Parkinson's disease.
基金funding from the European Union -NextGenerationEU through the Italian Ministry of University and Research under PRIN PNRR REG D.R.1718-2022– Project number PRJ-1575 INDICA。
文摘Indicaxanthin is a betalain that is abundant in Opuntia ficus-indica orange fruit and has antioxidative and anti-inflammatory effects. Nevertheless, very little is known about the neuroprotective potential of indicaxanthin. This study investigated the impact of indicaxanthin on neuronal damage and gut microbiota dysbiosis induced by a high-fat diet in mice. The mice were divided into three groups according to different diets: the negative control group was fed a standard diet;the high-fat diet group was fed a high-fat diet;and the high-fat diet + indicaxanthin group was fed a high-fat diet and received indicaxanthin orally(0.86 mg/kg per day) for 4 weeks. Brain apoptosis, redox status, inflammation, and the gut microbiota composition were compared among the different animal groups. The results demonstrated that indicaxanthin treatment reduced neuronal apoptosis by downregulating the expression of proapoptotic genes and increasing the expression of antiapoptotic genes. Indicaxanthin also markedly decreased the expression of neuroinflammatory proteins and genes and inhibited high-fat diet–induced neuronal oxidative stress by reducing reactive oxygen and nitrogen species, malondialdehyde, and nitric oxide levels. In addition, indicaxanthin treatment improved the microflora composition by increasing the abundance of healthy bacterial genera, known as producers of short-chain fatty acids(Lachnospiraceae, Alloprovetella, and Lactobacillus), and by reducing bacteria related to unhealthy profiles(Blautia, Faecalibaculum, Romboutsia and Bilophila). In conclusion, indicaxanthin has a positive effect on high-fat diet–induced neuronal damage and on the gut microbiota composition in obese mice.
文摘Spinal cord injury(SCI) often results in permanent dysfunction of locomotion,sensation,and autonomic regulation,imposing a substantial burden on both individuals and society(Anjum et al.,2020).SCI has a complex pathophysiology:an initial primary injury(mechanical trauma,axonal disruption,and hemorrhage) is followed by a progressive secondary injury cascade that involves ischemia,neuronal loss,and inflammation.Given the challenges in achieving regeneration of the injured spinal cord,neuroprotection has been at the forefront of clinical research.
文摘Aging is considered the main risk factor for the development of several diseases,including the leading neurodegenerative disorders.While the cellular features of aging are complex and multifaceted,neuronal senescence has emerged as a major contributor and driver of this process in the mammalian cell.Cellular senescence is a programmed response to stress and irreparable damage,which drives the cell into an apoptosis-resistant,non-proliferative state.Senescent cells can also deleteriously affect neighboring,non-senescent cells.Senescence is a complex and multifaceted process associated with a wide range of cellular events,including the secretion of pro-inflammatory molecules and the arrest of the cell cycle.
基金supported by the National Institutes of Health(grant numbers R01NS089737,RF1NS130881,and R21AG089974,to QC).
文摘Phosphatidylethanolamine is a major phospholipid class abundant in the brain,particularly in the inner leaflet of the plasma and mitochondrial membranes.Although it is primarily synthesized from phosphatidylserine via decarboxylation in mitochondria or from ethanolamine via the cytidine diphosphate-ethanolamine pathway in the endoplasmic reticulum,phosphatidylethanolamine that resides in mitochondria is preferentially produced locally and is distinct and separate from the pool of phosphatidylethanolamine made in the endoplasmic reticulum.Mitochondria-derived phosphatidylethanolamine is not only essential for mitochondrial integrity but also is exported to other organelles to fulfill diverse cellular functions.Neurons are highly enriched with phosphatidylethanolamine,and the importance of phosphatidylethanolamine metabolism in neuronal health has recently been recognized following its reported links to Alzheimer’s disease,Parkinson’s disease,and hereditary spastic paraplegia,among other neurological disorders.Indeed,disturbances in mitochondrial function and phosphatidylethanolamine metabolism and the resulting neuronal dysfunction are the common features of individuals suffering from these diseases,highlighting the great importance of maintaining proper phosphatidylethanolamine homeostasis in neurons.In this review,we summarize the current knowledge of phosphatidylethanolamine metabolism and its role in neuronal function with a special emphasis on the phosphatidylethanolamine biosynthetic pathway in mitochondria.We then review findings on how phosphatidylethanolamine biosynthesis is affected in major neurodegenerative diseases.Finally,we highlight promising future research areas that will help advance the understanding of neuronal phosphatidylethanolamine mechanisms and identify phosphatidylethanolamine-targeted therapeutic strategies for combating such brain diseases.
基金supported by STI2030-Major Project,No,2021ZD0204200(to LX).
文摘Neurodegenerative diseases,which are characterized by progressive neuronal loss and the lack of disease-modifying therapies,are becoming a major global health challenge.The existing neuromodulation techniques,such as deep brain stimulation and transcranial magnetic stimulation,show limitations such as invasiveness,restricted cortical targeting,and irreversible tissue effects.In this context,low-intensity transcranial ultrasound has emerged as a promising noninvasive alternative that can penetrate deep into the brain and modulate neuroplasticity.This review comprehensively assesses the therapeutic mechanisms,efficacy,and translational potential of low-intensity transcranial ultrasound in treating neurodegenerative diseases,with emphasis on its role in promoting neuronal regeneration,modulating neuroinflammation,and enhancing functional recovery.We summarize the findings of previous studies and systematically illustrate the potential of low-intensity transcranial ultrasound in regulating cell death mechanisms,enhancing neural repair and regeneration,and alleviating symptoms associated with neurodegenerative diseases.Preclinical findings indicate that low-intensity transcranial ultrasound can enhance the release of neurotrophic factors(e.g.,brain-derived neurotrophic factor),promote autophagy to clear protein aggregates,modulate microglial activation,and temporarily open the blood-brain barrier to facilitate targeted drug delivery.Existing clinical trial data show that low-intensity transcranial ultrasound can reduce amyloid-βplaques,improve motor and cognitive deficits,and promote remyelination in various disease models.Early clinical trials suggest that low-intensity transcranial ultrasound may enhance cognitive scores in Alzheimer’s disease and alleviate motor symptoms in Parkinson’s disease,all while demonstrating a favorable safety profile.Past studies support the notion that by integrating safety,precision,and reversibility,low-intensity transcranial ultrasound can transform the treatment landscape for neurodegenerative disease.However,more advancements are necessary for future clinical application of low-intensity transcranial ultrasound,including optimizing parameters such as frequency,intensity,and duty cycle;considering individual anatomical differences;and confirming long-term efficacy.We believe establishing standardized protocols,conducting larger trials,and investigating the underlying mechanisms to clarify dose-response relationships and refine personalized application strategies are essential in this regard.Future research should focus on translating preclinical findings into clinical practice,addressing technical challenges,and exploring combination therapies with pharmacological or gene interventions.
基金supported by DeutscheForschungsgemeinschaft(BA 8014/1-1 to XB)University of Saarland(NanoBioMed Young Investigatorgrant 2021 to XB,Anschubsfinanzierung2024to XB,HOMFORExzellenz2025 andAnschubsfinanzierung2025 to LPF)the ChinaPharmaceutical University(UndergraduateInternship Program to YZ).
文摘Oligodendrocyte precursor cells(OPCs)tile the central nervous system ubiquitously,accounting for about 5%of the total cell population in the central nervous system.Beyond their role in myelination,OPCs actively shape neural circuits(Fang and Bai,2023),by releasing neuromodulators,pruning synapses,maintaining the homeostasis of extracellular potassium concentration,and interacting with endothelial cells.
基金supported by the National Natural Science Foundation of China,Nos.82171387 and 31830111(both to SL).
文摘Stroke,particularly ischemic stroke,is the leading cause of long-term disability and mortality worldwide.It occurs due to the occlusion of the cerebral arteries,which significantly reduces the delivery of blood,oxygen,and essential nutrients to brain tissues.This deprivation triggers a cascade of cellular events that ultimately leads to neuronal death.Recent studies have clarified the multifactorial pathogenesis of ischemic stroke,highlighting the roles of energy failure,excitotoxicity,oxidative stress,neuroinflammation,and apoptosis.This review aimed to provide a comprehensive insight into the fundamental mechanisms driving neuronal death triggered by ischemia and to examine the progress of neuroprotective therapeutic approaches designed to mitigate neuronal loss and promote neurological recovery after a stroke.Additionally,we explored widely accepted findings regarding the potential pathways implicated in neuronal death during ischemic stroke,including the interplay of apoptosis,autophagy,pyroptosis,ferroptosis,and necrosis,which collectively influence neuronal fate.We also discussed advancements in neuroprotective therapeutics,encompassing a range of interventions from pharmacological modulation to stem cell-based therapies,aimed at reducing neuronal injury and enhancing functional recovery following ischemic stroke.Despite these advancements,challenges remain in translating mechanistic insights into effective clinical therapies.Although neuroprotective strategies have shown promise in preclinical models,their efficacy in human trials has been inconsistent,often due to the complex pathology of ischemic stroke and the timing of interventions.In conclusion,this review synthesizes mechanistic insights into the intricate interplay of molecular and cellular pathways driving neuronal death post-ischemia.It sheds light on cutting-edge advancements in potential neuroprotective therapeutics,underscores the promise of regenerative medicine,and offers a forward-looking perspective on potential clinical breakthroughs.The ongoing evolution of precision-targeted interventions is expected to significantly enhance preventative strategies and improve clinical outcomes.
基金supported by the National Natural Science Foundation of China,Nos.82371310(to YJ),82271306(to JP)the Sichuan Science and Technology Support Program,Nos.2023YFH0069(to JP),2023NSFSC0028(to YJ),2023NSFSC1559(to YJ),2022YFS0615(to JP),2022NSFSC1421(to JP)+1 种基金Scientific Research Project of Sichuan Provincial Health Commission,No.23LCYJ040(to YJ)Youth Foundation of Southwestern Medical University and Southwest Medical University Project,Nos.2020ZRQNA038(to JP),2021ZKZD013(to JP),2021LZXNYD-P01(to YJ),2023QN014(to JP).
文摘Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage.Neuronal ferroptosis in particular plays an important role in early brain injury.Bromodomain-containing protein 4,a member of the bromo and extraterminal domain family of proteins,participated in multiple cell death pathways,but the mechanisms by which it regulates ferroptosis remain unclear.The primary aim of this study was to investigate how bromodomain-containing protein 4 affects neuronal ferroptosis following subarachnoid hemorrhage in vivo and in vitro.Our findings revealed that endogenous bromodomain-containing protein 4 co-localized with neurons,and its expression was decreased 48 hours after subarachnoid hemorrhage of the cerebral cortex in vivo.In addition,ferroptosis-related pathways were activated in vivo and in vitro after subarachnoid hemorrhage.Targeted inhibition of bromodomain-containing protein 4 in neurons increased lipid peroxidation and intracellular ferrous iron accumulation via ferritinophagy and ultimately led to neuronal ferroptosis.Using cleavage under targets and tagmentation analysis,we found that bromodomain-containing protein 4 enrichment in the Raf-1 promoter region decreased following oxyhemoglobin stimulation in vitro.Furthermore,treating bromodomain-containing protein 4-knockdown HT-22 cell lines with GW5074,a Raf-1 inhibitor,exacerbated neuronal ferroptosis by suppressing the Raf-1/ERK1/2 signaling pathway.Moreover,targeted inhibition of neuronal bromodomain-containing protein 4 exacerbated early and long-term neurological function deficits after subarachnoid hemorrhage.Our findings suggest that bromodomain-containing protein 4 may have neuroprotective effects after subarachnoid hemorrhage,and that inhibiting ferroptosis could help treat subarachnoid hemorrhage.
基金supported by the National Natural Science Foundation of China,No.81671263(to XX)Scientific Research and Innovation Team,Education Department of Anhui Province,China,No.2023AH010072(to XX)+1 种基金the Natural Science Foundation of Anhui Province,No.2208085MH221(to XX)The Key Projects for National Science Research of Education Department of Anhui Province,No.KJ2021A0851(to YD).
文摘Cmyc,a proto-oncogene,is expressed at extremely low levels in mature neurons and is traditionally thought to have no function in these cells.However,recent studies suggest that Cmyc may play a crucial role in maintaining the health and function of mature dopaminergic neurons.This study assessed the role of Cmyc in dopaminergic neurons and its significance in Parkinson’s disease.We used a conditional knockout approach to specifically delete Cmyc in substantia nigra dopaminergic neurons of adult mice.Our findings showed that Cmyc deletion led to progressive neuron loss,Parkinson’s disease-like symptoms,downregulation of Klotho,and upregulation of senescence-associated inflammatory factors,along with enhanced oxidative stress and nitrated alpha-synuclein accumulation,ultimately causing neuronal death.In vitro experiments confirmed increased senescence in C-MYC knockout cells,which was partially reversible by KLOTHO overexpression.We conclude that low-level Cmyc expression is essential for maintaining the health of mature dopaminergic neurons and preventing neurodegeneration,and suggest the c-Myc/Klotho axis as a potential therapeutic target for age-related neurodegenerative diseases,including Parkinson’s disease.Our study introduces a novel mouse model for Parkinson’s disease that replicates a condition associated with normal aging,offering a valuable tool for future research into disease mechanisms and therapeutic strategies.
基金supported by NIH grants AG079264(to PHR)and AG071560(to APR)。
文摘The process of neurite outgrowth and branching is a crucial aspect of neuronal development and regeneration.Axons and dendrites,sometimes referred to as neurites,are extensions of a neuron's cellular body that are used to start networks.Here we explored the effects of diethyl(3,4-dihydroxyphenethylamino)(quinolin-4-yl)methylphosphonate(DDQ)on neurite developmental features in HT22 neuronal cells.In this work,we examined the protective effects of DDQ on neuronal processes and synaptic outgrowth in differentiated HT22cells expressing mutant Tau(mTau)cDNA.To investigate DDQ chara cteristics,cell viability,biochemical,molecular,western blotting,and immunocytochemistry were used.Neurite outgrowth is evaluated through the segmentation and measurement of neural processes.These neural processes can be seen and measured with a fluorescence microscope by manually tracing and measuring the length of the neurite growth.These neuronal processes can be observed and quantified with a fluorescent microscope by manually tracing and measuring the length of the neuronal HT22.DDQ-treated mTau-HT22 cells(HT22 cells transfected with cDNA mutant Tau)were seen to display increased levels of synaptophysin,MAP-2,andβ-tubulin.Additionally,we confirmed and noted reduced levels of both total and p-Tau,as well as elevated levels of microtubule-associated protein 2,β-tubulin,synaptophysin,vesicular acetylcholine transporter,and the mitochondrial biogenesis protein-pe roxisome prolife rator-activated receptor-gamma coactivator-1α.In mTa u-expressed HT22 neurons,we observed DDQ enhanced the neurite characteristics and improved neurite development through increased synaptic outgrowth.Our findings conclude that mTa u-HT22(Alzheimer's disease)cells treated with DDQ have functional neurite developmental chara cteristics.The key finding is that,in mTa u-HT22 cells,DDQ preserves neuronal structure and may even enhance nerve development function with mTa u inhibition.
文摘Animals exhibit complex responses to external and internal stimuli.The information is computed by interconnected neurons that express numerous ion channels,which modulate the neuronal membrane potential.How can neuronal activity orchestrate complex motor patterns or allow learning from previous experience?To answer such questions,we need the ability not only to record,but also to modulate neuronal activity in both space(e.g.,neuronal subsets)and time.
基金supported by the National Key R&D Program of China(2021YFA1101300)the National Natural Science Foundation of China(32371067 to Y.P.)+1 种基金the Natural Science Foundation from Jiangsu Province(BK20231418 to Q.P.)the Fundamental Research Funds for the Central Universities(2242023R40054 to Q.P.).
文摘Sex-specific neurons play pivotal roles in regulating sexually dimorphic behaviors.In insects,the sex determination gene doublesex(dsx)establishes major sexual dimorphism of the nervous system,in which male-specific dsx^(M)promotes neuronal development,while female-specific dsx^(F)inhibits neuronal development by promoting neuronal apoptosis.In this study,we find that dsx regulates the number of dsx-expressing central neurons in Drosophila in cell-specific manners.Although dsx^(M)overall promotes an increase in the number of dsx neurons,it inhibits the emergence of specific pC1 neurons.dsx^(F)reduces the number of different pC1/pC2 subtypes,but promotes the formation of pC1d.We also find that dsx^(M)and dsx^(F)barely affect the number of some pC2 neurons.Changes in the number of pC1/pC2 neurons alter their roles in regulating different behaviors,including courtship,aggression,and locomotion.Our results illustrate the multifaceted functions of dsx in sexually dimorphic neuronal development and behaviors.
基金supported by the National Natural Science Foundation of China(32060199,32360197,31971035,and 31771182)the Jiangxi Province Natural Science Foundation(20224ACB206016).
文摘Humans and animals have a fundamental ability to use experiences and environmental information to organize behavior.It often happens that humans and animals make decisions and prepare actions under uncertain situations.Uncertainty would significantly affect the state of animals’minds,but may not be reflected in behavior.How to“read animals’mind state”under different situations is a challenge.Here,we report that neuronal activity in the medial prefrontal cortex(mPFC)of rats can reflect the environmental uncertainty when the task situation changes from certain to uncertain.Rats were trained to perform behavioral tasks under certain and uncertain situations.Under certain situations,rats were required to simply repeat two nose-poking actions that each triggered short auditory tone feedback(single-task situation).Whereas under the uncertain situation,the feedback could randomly be either the previous tone or a short musical rhythm.No additional action was required upon the music feedback,and the same secondary nose-poking action was required upon the tone feedback(dual-task situation);therefore,the coming task was uncertain before action initiation.We recorded single-unit activity from the mPFC when the rats were performing the tasks.We found that in the dual task,when uncertainty was introduced,many mPFC neurons were actively engaged in dealing with the uncertainty before the task initiation,suggesting that the rats could be aware of the task situation change and encode the information in the mPFC before the action of task initiation.
文摘BACKGROUND Spinal cord injury(SCI)often results in irreversible neurological deficits;therefore,effective treatment is urgently needed.Neural stem cells(NSCs)have excellent differentiation potential.However,the role of the long noncoding RNA X inactive-specific transcript(XIST)in NSCs and SCI remains unclear.AIM To explore the role of XIST in enhancing NSC function and its therapeutic potential in SCI.METHODS We used in vitro and in vivo models to examine the effects of XIST on NSCs.XIST was overexpressed in NSCs,and its impact on mitochondrial function,neuronal differentiation,and the insulin-like growth factor 2 mRNA binding protein 2(IGF2BP2)/carnitine palmitoyl transferase 1A(CPT1A)pathway was assessed using a series of biochemical assays,quantitative PCR,and Seahorse XF24 analysis.A mouse model of SCI was used to evaluate the therapeutic effects of XIST in vivo.RESULTS Overexpression of XIST in NSCs significantly increased mitochondrial membrane potential,ATP production,and oxygen consumption rate.XIST also promoted NSC proliferation and neuronal differentiation while inhibiting astrocytic differentiation.Mechanistically,XIST regulated CPT1A expression post-transcriptionally by interacting with IGF2BP2.In vivo XIST-treated mice exhibited improved motor scores and reduced proinflammatory cytokine expression following SCI.CONCLUSIONThese findings suggested that XIST modulated mitochondrial function and neural differentiation in NSCs throughthe IGF2BP2/CPT1A pathway. While preliminary in vivo results are encouraging, further studies are needed todetermine the long-term therapeutic relevance and underlying mechanisms of XIST in SCI recovery.
文摘Alzheimer’s disease(AD)is a neurodegenerative disease causing the most frequent form of dementia in old age.AD etiology is still uncertain and deposition of abnormal proteins in the brain along with chronic neuroinflammation have been suggested as pathogenic mechanisms of neuronal death.Infections by exogenous neurotropic virus,endogenous retrovirus reactivation,infections by other microbes,and air pollutants may either induce neurodegeneration or activate brain inflammation.Up to 8%of the human genome has a retroviral origin.These ancient retroviruses,also called human endogenous retroviruses,are associated with a clinical history of several neurodegenerative diseases.Under persistent stress,such as chronic infections and inflammation,neurons,and microglia cells may enter a state of division inactivation called cell senescence.Senescent cells are resistant to apoptosis and can release pro-inflammatory molecules promoting the functional decline of tissues and organs and also activate silent viruses.Infections andmutations induced by pollutants can lead to the expression of different endogenous retroviruses,which may contribute to several different diseases,including AD-associated neurodegeneration.Here I discuss that infection by exogenous pathogen,activation of endogenous retrovirus or retrotransposons and pollutants might induce neuronal senescence and cause persistent brain neurodegeneration.Therefore,cell senescence appears to be an emerging mechanism that might contribute to AD neurodegeneration.Finally,treatment of AD patients with senolytic drugs,e.g.,compounds able to kill senescent cells,might show a positive effect on AD progression.
基金funded by the National Natural Science Foundation of China(Grant No.:31900694).
文摘A traditional Chinese medicine(TCM)monomer is a bioactive compound extracted from Chinese herbal medicines possessing determined biological activity and pharmacological effects,and has gained much attention for treating neuronal diseases.However,the application of TCM monomers is limited by their low solubility and poor ability to cross the blood-brain barrier(BBB).Exosomes are small extracellular vesicles(EVs)ranging in size from 30 to 150 nm in diameter and can be used as drug delivery carriers that directly target cells or tissues with unique advantages,including low toxicity,low immunogenicity,high stability in blood,and the ability to cross the BBB.This review discusses the biogenesis,components,stability,surface modification,isolation technology,advantages,and disadvantages of exosomes as drug carriers and compares exosomes and other similar drug delivery systems.Furthermore,exosome-encapsulated TCM monomers exert neuroprotective roles,such as anti-inflammation,anti-apoptosis,anti-mitophagy,and anti-oxidation,in various neuronal diseases,including Alzheimer's disease(AD),Parkinson's disease(PD),multiple sclerosis(MS),and cerebral ischemia and reperfusion(CI/R)injury,as well as anti-drug resistance,anti-tumorigenesis,anti-angiogenesis,and promotion of apoptosis in brain tumors,providing more inspiration to promote the development of an exosome-based delivery tool in targeted therapy for neuronal diseases.
基金Supported by the Major Research Plan from the Health Commission of Hongkou District,No.2001-03Academic Subject Boosting Plan in the Shanghai Fourth People’s Hospital affiliated to Tongji University School of Medicine Shanghai,No.SY-XKZT-2020-1003.
文摘BACKGROUND Spinal cord injury(SCI)is a severe and permanent trauma that often leads to significant motor,sensory,and autonomic dysfunction.Neuronal apoptosis is a major pathomechanism underlying secondary injury in SCI.Long non-coding RNAs(lncRNAs)have emerged as key regulators of gene expression and cellular processes,including apoptosis.However,the role of lncRNA growth arrest-specific transcript 5(GAS5)in SCI-induced neuronal apoptosis remains unclear.AIM To investigate the role of lncRNA GAS5 in SCI-induced neuronal apoptosis via its interaction with microRNA(miR)-21 and the phosphatase and tensin homolog(PTEN)/AKT pathway.METHODS SCI rat models and hypoxic neuronal cell models were established.Motor function was assessed using the Basso-Beattie-Bresnahan score.Expression levels of GAS5,miR-21,PTEN,caspase 3,B-cell lymphoma 2(Bcl-2),Bcl-2-associated X protein(Bax),and AKT were measured using quantitative PCR or Western blot analysis.Neuronal apoptosis was determined by TUNEL staining.Dual-luciferase reporter assays validated GAS5-miR-21 binding.Knockdown and overexpression experiments explored the functional effects of the GAS5/miR-21 axis.RESULTS GAS5 was significantly upregulated in the spinal cord following SCI,coinciding with increased neuronal apoptosis and decreased AKT activation.In vitro experiments demonstrated that GAS5 acted as a molecular sponge for miR-21,leading to increased PTEN expression and inhibition of the AKT signaling pathway,thereby promoting apoptosis.In vivo,GAS5 knockdown attenuated neuronal apoptosis,enhanced AKT activation,and improved motor function recovery in SCI rats.CONCLUSION GAS5 promotes neuronal apoptosis in SCI by binding to miR-21 and upregulating PTEN expression,inhibiting the AKT pathway.Targeting GAS5 may represent a novel therapeutic strategy for SCI.
基金supported by the Fund of Key Laboratory of Biomedical Engineering of Hainan Province(No.BME20240001)the STI2030-Major Projects(No.2021ZD0200104)the National Natural Science Foundations of China under Grant 61771437.
文摘Deep learning networks are increasingly exploited in the field of neuronal soma segmentation.However,annotating dataset is also an expensive and time-consuming task.Unsupervised domain adaptation is an effective method to mitigate the problem,which is able to learn an adaptive segmentation model by transferring knowledge from a rich-labeled source domain.In this paper,we propose a multi-level distribution alignment-based unsupervised domain adaptation network(MDA-Net)for segmentation of 3D neuronal soma images.Distribution alignment is performed in both feature space and output space.In the feature space,features from different scales are adaptively fused to enhance the feature extraction capability for small target somata and con-strained to be domain invariant by adversarial adaptation strategy.In the output space,local discrepancy maps that can reveal the spatial structures of somata are constructed on the predicted segmentation results.Then thedistribution alignment is performed on the local discrepancies maps across domains to obtain a superior discrepancy map in the target domain,achieving refined segmentation performance of neuronal somata.Additionally,after a period of distribution align-ment procedure,a portion of target samples with high confident pseudo-labels are selected as training data,which assist in learning a more adaptive segmentation network.We verified the superiority of the proposed algorithm by comparing several domain adaptation networks on two 3D mouse brain neuronal somata datasets and one macaque brain neuronal soma dataset.
