Mirror neuron system （MNS） represents one past decade, and it has been found to involve in multiple of the most important discoveries of cognitive neuroscience in the aspects of brain functions including action unde...Mirror neuron system （MNS） represents one past decade, and it has been found to involve in multiple of the most important discoveries of cognitive neuroscience in the aspects of brain functions including action understanding, imitation, language understanding, empathy, action prediction and speech evolution. This manuscript reviewed the function of MNS in action understanding as well as language evolution, and specifically assessed its roles as the bridge from body language to fluent speeches. Then we discussed the speech defects of autism patients due to the disruption of MNS. Finally, given that MNS is plastic in adult brain, we proposed MNS targeted therapy provides an efficient rehabilitation approach for brain damages conditions as well as autism patients.展开更多
The mirror neuron system （MNS） was first discovered in non-human primates; these neurons fire when a monkey performs an action or observes another monkey （or even some people） performing that same action. Recent f...The mirror neuron system （MNS） was first discovered in non-human primates; these neurons fire when a monkey performs an action or observes another monkey （or even some people） performing that same action. Recent findings have suggested that neural rehabilitation might be achieved through the activation of the MNS in patients after stroke. We propose two major mechanisms （one involving adult neurogenesis and another involving brain-derived neurotrophic factor） that may underlie the activation, modulation and experience-dependent plasticity in the MNS, for further study on promoting central nerve functional reconstruction and rehabilitation of patients with central nervous system injury.展开更多
Previous studies have demonstrated that hand shadows may activate the motor cortex associated with the mirror neuron system in human brain. However, there is no evidence of activity of the human mirror neuron system d...Previous studies have demonstrated that hand shadows may activate the motor cortex associated with the mirror neuron system in human brain. However, there is no evidence of activity of the human mirror neuron system during the observation of intransitive movements by shadows and line drawings of hands. This study examined the suppression of electroencephalography mu waves （8-13 Hz） induced by observation of stimuli in 18 healthy students. Three stimuli were used： real hand actions, hand shadow actions and actions made by line drawings of hands. The results showed significant desynchronization of the mu rhythm （＂mu suppression＂） across the sensodmotor cortex （recorded at C3, Cz and C4）, the frontal cortex （recorded at F3, Fz and F4） and the central and right posterior parietal cortex （recorded at Pz and P4） under all three conditions. Our experimental findings suggest that the observation of ＂impoverished hand actions＂, such as intransitive movements of shadows and line drawings of hands, is able to activate widespread cortical areas related to the putative human mirror neuron system.展开更多
With the rapid development of computer science and artificial intelligence technology, the complexity and intelligence of the neural network models constructed by people have been greatly improved. When the complex ne...With the rapid development of computer science and artificial intelligence technology, the complexity and intelligence of the neural network models constructed by people have been greatly improved. When the complex neuron system is subjected to the impact of ＂catastrophic＂, its original characteristics may be changed, and the consequences are difficult to predict. Catastrophe dynamics mainly studies the source of the sudden violent change of nature and human society and its evolution. The impact of the system can be divided into endogenous and exogenous shocks. In this article, catastrophe theory is used to study the neuron system. Based on the mean field model of Hurst and Sornette, introducing the weight parameters, mathematical models are constructed to study the response characteristics of the neuron system in face of exogenous shocks, endogenous shocks, and integrated shocks. The time characteristics of the shock response of the neuron system are discussed too, such as the instantaneous and long-term response of the system in face of shocks, the different response forms according to the weight or linear superposition, and the influence of adjusting parameters on the neuron system. The research result shows that the authoritarian coefficient and weight coefficient have a very important influence on the response of neuron system; By adjusting the two coefficients, the purpose of disaster prevention, self-healing protection and response reducing can be well achieved.展开更多
Using the model of Hindmarsh Rose neurons, we study the synchronous behavior of the firing patterns in an uncoupled cell system. In this work, the membrane current Iext is selected as a controllable parameter, whose i...Using the model of Hindmarsh Rose neurons, we study the synchronous behavior of the firing patterns in an uncoupled cell system. In this work, the membrane current Iext is selected as a controllable parameter, whose initial values for all N cells are set to be near one of the bifurcation points randomly. It is found that the system will show un-synchronous state when the external stimuli is absent, otherwise, full synchrony will appear, even though without any coupling connection among these N neurons, indicating the occurrence of uncoupled synchrony. Moreover, similar behavior could also be observed when these neurons are set to be near other bifurcation points. The synchronous error is calculated for discussing this uncoupled synehrony behavior. Finally, we find that such synchrony may have some inherent relevance with the decrease of phase difference between different cells. Our results suggest that biological neuron systems may achieve an effective response to external feeble stimulus by the mode of uncoupled synchrony instead of only by the coupled scheme.展开更多
Primary impairments of developmental coordination disorder (DCD) include impairments in motor skill, motor learning, and imitation. Such difficulties present challenges for individuals with DCD and may persist into ad...Primary impairments of developmental coordination disorder (DCD) include impairments in motor skill, motor learning, and imitation. Such difficulties present challenges for individuals with DCD and may persist into adulthood, negatively impacting daily life in school, work, and social domains. A better understanding of the neural correlates of motor and imitation impairments in DCD holds the potential for informing development of treatment approaches to address these impairments. Although the disorder is assumed to be of neurological origin, little is known of the brain-based etiology of DCD. In recent years the discovery of a fronto-parietal circuit—known as the mirror neuron system—has enabled researchers to better understand imitation, general motor functions, and aspects of social cognition. Given its involvement in imitation and other motor functions, we propose that dysfunction in the mirror neuron system may underlie the characteristic impairments of DCD. We review literature pertaining to the mirror neuron system and develop a theory of disordered mirror neuron functioning in DCD. Finally, we review the limited neuroimaging literature available on neural correlates of DCD and show that the findings from those investigations are congruent with a mirror neuron system theory of DCD. Future research in this population should be designed to investigate specifically mirror neuron regions in individuals with DCD during skilled motor tasks and imitation in particular.展开更多
The reliability of the AI systems to the harsh space radiation is of great concerns with the increasing application in aerospace.Because of its neuromorphic device architecture and operation mode,low-power neuron chip...The reliability of the AI systems to the harsh space radiation is of great concerns with the increasing application in aerospace.Because of its neuromorphic device architecture and operation mode,low-power neuron chips have enormous potentials in resistance of single event effect,which is one of the most important failures of spacecraft caused by space radiation.In this work,a mixed-signal spiking neuron chip,named PAVLOV^([1]),has been studied at circuit and chip level with respect to its response to single event errors.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
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
Short-chain fatty acids,metabolites produced by the fermentation of dietary fiber by gut microbiota,have garnered significant attention due to their correlation with neurodegenerative diseases,particularly Parkinson’...Short-chain fatty acids,metabolites produced by the fermentation of dietary fiber by gut microbiota,have garnered significant attention due to their correlation with neurodegenerative diseases,particularly Parkinson’s disease.In this review,we summarize the changes in short-chain fatty acid levels and the abundance of short-chain fatty acid-producing bacteria in various samples from patients with Parkinson’s disease,highlighting the critical role of gut homeostasis imbalance in the pathogenesis and progression of the disease.Focusing on the nervous system,we discuss the molecular mechanisms by which short-chain fatty acids influence the homeostasis of both the enteric nervous system and the central nervous system.We identify key processes,including the activation of G protein-coupled receptors and the inhibition of histone deacetylases by short-chain fatty acids.Importantly,structural or functional disruptions in the enteric nervous system mediated by these fatty acids may lead to abnormalα-synuclein expression and gastrointestinal dysmotility,which could serve as an initiating event in Parkinson’s disease.Furthermore,we propose that short-chain fatty acids help establish communication between the enteric nervous system and the central nervous system via the vagal nerve,immune circulation,and endocrine signaling.This communication may shed light on their potential role in the transmission ofα-synuclein from the gut to the brain.Finally,we elucidate novel treatment strategies for Parkinson’s disease that target short-chain fatty acids and examine the challenges associated with translating short-chain fatty acid-based therapies into clinical practice.In conclusion,this review emphasizes the pivotal role of short-chain fatty acids in regulating gut-brain axis integrity and their significance in the pathogenesis of Parkinson’s disease from the perspective of the nervous system.Moreover,it highlights the potential value of short-chain fatty acids in early intervention for Parkinson’s disease.Future research into the molecular mechanisms of short-chain fatty acids and their synergistic interactions with other gut metabolites is likely to advance the clinical translation of innovative short-chain fatty acid-based therapies for Parkinson’s disease.展开更多
Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsol...Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsolved issue in pain medicine.Our previous study,using protein kinase C gamma(PKCγ)-tdTomato mice,highlights the spinal feedforward inhibitory circuit involving PKCγ neurons in gating neuropathic allodynia.However,the regulatory mechanisms governing this circuit necessitate further elucidation.We used diverse transgenic mice and advanced techniques to uncover the regulatory role of the descending serotonin(5-HT)facilitation system on spinal PKCγ neurons.Our findings revealed that 5-HT neurons from the rostral ventromedial medulla hyperpolarize spinal inhibitory interneurons via 5-HT_(2C) receptors,disinhibiting the feedforward inhibitory circuit involving PKCγ neurons and exacerbating allodynia.Inhibiting spinal 5-HT_(2C) receptors restored the feedforward inhibitory circuit,effectively preventing neuropathic allodynia.These insights offer promising therapeutic targets for neuropathic allodynia management,emphasizing the potential of spinal 5-HT_(2C) receptors as a novel avenue for intervention.展开更多
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
Nonhuman primates are increasingly being used as animal models in neuroscience research.However,efficient neuronal tracing techniques for labeling motor neurons and primary sensory afferents in the monkey spinal cord ...Nonhuman primates are increasingly being used as animal models in neuroscience research.However,efficient neuronal tracing techniques for labeling motor neurons and primary sensory afferents in the monkey spinal cord are lacking.Here,by injecting the cholera toxin B subunit into the sciatic nerve of a rhesus monkey,we successfully labeled the motor neurons and primary sensory afferents in the lumbar and sacralspinal cord.Labeled alpha motor neurons were located in lamina IX of the L6–S1 segments,which innervate both flexors and extensors.The labeled primary sensory afferents were mainly myelinated Aβfibers that terminated mostly in laminae I and II of the L4–L7 segments.Together with the labeled proprioceptive afferents,the primary sensory afferents formed excitatory synapses with multiple types of spinal neurons.In summary,our methods successfully traced neuronal connections in the monkey spinal cord and can be used in spinal cord studies when nonhuman primates are used.展开更多
Unwarranted death of neurons is a major cause of neurodegenerative diseases.Since mature neurons are postmitotic and do not replicate,their death usually constitutes an irreversible step in pathology.A logical strateg...Unwarranted death of neurons is a major cause of neurodegenerative diseases.Since mature neurons are postmitotic and do not replicate,their death usually constitutes an irreversible step in pathology.A logical strategy to prevent neurodegeneration would then be to save all neurons that are still alive,i.e.protecting the ones that are still healthy as well as trying to rescue the ones that are damaged and in the process of dying.Regarding the latter,recent experiments have indicated that the possibility of reversing the cell death process and rescuing dying cells is more significant than previously anticipated.In many situations,the elimination of the cell death trigger alone enables dying cells to spontaneously repair their damage,recover,and survive.In this review,we explore the factors,which determine the fate of neurons engaged in the cell death process.A deeper insight into cell death mechanisms and the intrinsic capacity of cells to recover could pave the way for novel therapeutic approaches to neurodegenerative diseases.展开更多
Parkinson’s disease(PD)is the second most common neurodegenerative disorder.The progressive degeneration of dopamine(DA)producing neurons in the midbrain is the pathological hallmark,which leads to debilitating motor...Parkinson’s disease(PD)is the second most common neurodegenerative disorder.The progressive degeneration of dopamine(DA)producing neurons in the midbrain is the pathological hallmark,which leads to debilitating motor symptoms,including tremors,rigidity,and bradykinesia.Drug treatments,such as levodopa,provide symptomatic relief.However,they do not halt disease progression,and their effectiveness diminishes over time(reviewed in Poewe et al.,2017).展开更多
The generation of human induced pluripotent stem cell-derived motor neurons overcomes limited access to human tissues and offers an unprecedented approach to modeling motor neuron diseases such as dystonia and amyotro...The generation of human induced pluripotent stem cell-derived motor neurons overcomes limited access to human tissues and offers an unprecedented approach to modeling motor neuron diseases such as dystonia and amyotrophic lateral sclerosis.Motor neurons generated through different strategies may exhibit substantial differences in purity,maturation,characterization,and even neuronal identity,leading to variable outcomes in disease modeling and drug screening.However,very few comparative studies have been conducted to determine the similarities and differences among motor neurons prepared via different protocols.In this study,we prepared human induced pluripotent stem cell-derived motor neurons via lentiviral delivery of transcription factors and chemical induction and performed a systematic comparative analysis.We found that motor neurons generated by both approaches showed typical motor neuron morphology and robustly expressed motor neuron-specific markers,such as nuclear homeobox transcription factor 9 and choline acetyltransferase.The chemical induction protocol utilizes a combination of small molecules to induce motor neuron differentiation,offering a significantly faster maturation time of 35 days compared to 46 days with lentiviral delivery of transcription factors.Additionally,while lentiviral delivery of transcription factors are suitable for downstream biochemical analysis,chemical induction are more applicable for therapeutic approaches as they avoid the use of lentiviruses.Both approaches produce motor neurons with high purity(>95%)and yield.No significant differences were found between chemical induction and lentiviral delivery of transcription factors in terms of motor neuron markers and maturation markers.These robust methodologies offer researchers powerful tools for investigating motor neuron diseases and potential therapeutic strategies.展开更多
Motor neuron diseases are sporadic or inherited fatal neurodegenerative conditions.They selectively affect the upper and/or lower motor neurons in the brain and spinal cord and feature a slow onset and a subacute cour...Motor neuron diseases are sporadic or inherited fatal neurodegenerative conditions.They selectively affect the upper and/or lower motor neurons in the brain and spinal cord and feature a slow onset and a subacute course contingent upon the site of damage.The main types include amyotrophic lateral sclerosis,progressive muscular atrophy,primary lateral sclerosis,and progressive bulbar palsy,the pathological processes of which are largely identical,with the main disparity lying in the location of the lesions.Amyotrophic lateral sclerosis is the representative condition in this group of diseases,while other types are its variants.Hence,this article mainly focuses on the advancements and challenges in drug research for amyotrophic lateral sclerosis but also briefly addresses several other important degenerative motor neuron diseases.Although the precise pathogenesis remains elusive,recent advancements have shed light on various theories,including gene mutation,excitatory amino acid toxicity,autoimmunology,and neurotrophic factors.The US Food and Drug Administration has approved four drugs for use in delaying the progression of amyotrophic lateral sclerosis:riluzole,edaravone,AMX0035,and tofersen,with the latter being the most recent to receive approval.However,following several phaseⅢtrials that failed to yield favorable outcomes,AMX0035 has been voluntarily withdrawn from both the US and Canadian markets.This article presents a comprehensive summary of drug trials primarily completed between January 1,2023,and June 30,2024,based on data sourced from clinicaltrials.gov.Among these trials,five are currently in phaseⅠ,seventeen are in phaseⅡ,and eleven are undergoing phaseⅢevaluation.Notably,24 clinical trials are now investigating potential disease-modifying therapy drugs,accounting for the majority of the drugs included in this review.Some promising drugs being investigated in preclinical studies,such as ATH-1105,are included in our analysis,and another review in frontiers in gene therapy and immunotherapy has demonstrated their therapeutic potential for motor neuron diseases.This article was written to be an overview of research trends and treatment prospects related to motor neuron disease drugs,with the aim of highlighting the latest potentialities for clinical therapy.展开更多
DJ-1,also known as Parkinson’s disease protein 7(PARK7),is a multifunctional protein that plays an important role in oxidative stress regulation and neuroprotection.Previous studies have shown that DJ-1 affects early...DJ-1,also known as Parkinson’s disease protein 7(PARK7),is a multifunctional protein that plays an important role in oxidative stress regulation and neuroprotection.Previous studies have shown that DJ-1 affects early-onset Parkinson’s disease by regulating neuroinflammation,but its specific mechanism remains unclear.The study investigated the role of DJ-1 in mediating microglia-neuron communication to identify potential therapeutic targets for neuroinflammation in Parkinson’s disease.In this study,we observed a significant decrease in the levels of C-X3-C motif chemokine ligand 1(CX3CL1)in Park7 knockout mice and SH-SY5Y cells with Park7 knockdown.Protein microarray analysis and validation using GEO datasets confirmed that knockout of the Park7 gene led to downregulation of CX3CL1 and two other chemokines,namely monocyte chemoattractant protein-1 and interleukin-8.Further investigation revealed that Park7 deficiency reduced the processing of a disintegrin and metalloproteinase domain-containing protein 10(ADAM10)in the neuronal endoplasmic reticulum of both mice and SH-SY5Y cells,thereby decreasing CX3CL1 secretion.This subsequently led to abnormal microglial activation,with a shift toward the proinflammatory M1 phenotype,exacerbating neuroinflammatory responses.These effects were mitigated by exogenous CX3CL1 administration.Concurrently,exogenous CX3CL1 improved motor function in Parkinson’s disease model mice with the Park7 knockout,promoting survival of tyrosine hydroxylase-positive neurons in the substantia nigra and reducing Iba-1-positive microglial activation.These findings demonstrate that DJ-1 exerts neuroprotective effects on dopaminergic neurons by suppressing microglial activation through CX3CL1 regulation,suggesting that targeting the DJ-1/CX3CL1 axis may represent a novel therapeutic strategy for modulating neuroinflammation and protecting dopaminergic neurons.展开更多
The number and diversity of inhibitory neurons(INs)increased substantially during mammalian brain evolution.However,the generative mechanisms of the vast repertoire of human INs remain elusive.We performed spatial and...The number and diversity of inhibitory neurons(INs)increased substantially during mammalian brain evolution.However,the generative mechanisms of the vast repertoire of human INs remain elusive.We performed spatial and single-cell transcriptomics of human medial ganglionic eminence(hMGE),a pivotal source of cortical and subpallial INs,and built the trajectories of hMGE-derived cells during brain development.We identified spatiotemporally and molecularly segregated progenitor cell populations fated to produce distinct IN types.展开更多
基金Sci-ence Foundation of Ministry of Education of China (No.FBB011469)
文摘Mirror neuron system （MNS） represents one past decade, and it has been found to involve in multiple of the most important discoveries of cognitive neuroscience in the aspects of brain functions including action understanding, imitation, language understanding, empathy, action prediction and speech evolution. This manuscript reviewed the function of MNS in action understanding as well as language evolution, and specifically assessed its roles as the bridge from body language to fluent speeches. Then we discussed the speech defects of autism patients due to the disruption of MNS. Finally, given that MNS is plastic in adult brain, we proposed MNS targeted therapy provides an efficient rehabilitation approach for brain damages conditions as well as autism patients.
基金Science Foundation of Ministry of Education of China,No.FBB011469Hangzhou Municipal Natural Science Foundation, No.0737XP39Foundation of Hong Kong Special Administrative Region(RGC)
文摘The mirror neuron system （MNS） was first discovered in non-human primates; these neurons fire when a monkey performs an action or observes another monkey （or even some people） performing that same action. Recent findings have suggested that neural rehabilitation might be achieved through the activation of the MNS in patients after stroke. We propose two major mechanisms （one involving adult neurogenesis and another involving brain-derived neurotrophic factor） that may underlie the activation, modulation and experience-dependent plasticity in the MNS, for further study on promoting central nerve functional reconstruction and rehabilitation of patients with central nervous system injury.
基金supported by the grants from the National Natural Science Foundation of China,No.60775019,60970062 and 61173116the Research Fund for the Doctoral Program of Higher Education of China,No.201100702110014
文摘Previous studies have demonstrated that hand shadows may activate the motor cortex associated with the mirror neuron system in human brain. However, there is no evidence of activity of the human mirror neuron system during the observation of intransitive movements by shadows and line drawings of hands. This study examined the suppression of electroencephalography mu waves （8-13 Hz） induced by observation of stimuli in 18 healthy students. Three stimuli were used： real hand actions, hand shadow actions and actions made by line drawings of hands. The results showed significant desynchronization of the mu rhythm （＂mu suppression＂） across the sensodmotor cortex （recorded at C3, Cz and C4）, the frontal cortex （recorded at F3, Fz and F4） and the central and right posterior parietal cortex （recorded at Pz and P4） under all three conditions. Our experimental findings suggest that the observation of ＂impoverished hand actions＂, such as intransitive movements of shadows and line drawings of hands, is able to activate widespread cortical areas related to the putative human mirror neuron system.
基金Project(CX2016B142)supported by the Hunan Provincial Innovation Foundation for Postgraduate,China
文摘With the rapid development of computer science and artificial intelligence technology, the complexity and intelligence of the neural network models constructed by people have been greatly improved. When the complex neuron system is subjected to the impact of ＂catastrophic＂, its original characteristics may be changed, and the consequences are difficult to predict. Catastrophe dynamics mainly studies the source of the sudden violent change of nature and human society and its evolution. The impact of the system can be divided into endogenous and exogenous shocks. In this article, catastrophe theory is used to study the neuron system. Based on the mean field model of Hurst and Sornette, introducing the weight parameters, mathematical models are constructed to study the response characteristics of the neuron system in face of exogenous shocks, endogenous shocks, and integrated shocks. The time characteristics of the shock response of the neuron system are discussed too, such as the instantaneous and long-term response of the system in face of shocks, the different response forms according to the weight or linear superposition, and the influence of adjusting parameters on the neuron system. The research result shows that the authoritarian coefficient and weight coefficient have a very important influence on the response of neuron system; By adjusting the two coefficients, the purpose of disaster prevention, self-healing protection and response reducing can be well achieved.
基金Supported by the National Natural Science Foundation of China under Grant No 11047017the Natural Science Funds of Anhui Province under Grant No 1508085MA15
文摘Using the model of Hindmarsh Rose neurons, we study the synchronous behavior of the firing patterns in an uncoupled cell system. In this work, the membrane current Iext is selected as a controllable parameter, whose initial values for all N cells are set to be near one of the bifurcation points randomly. It is found that the system will show un-synchronous state when the external stimuli is absent, otherwise, full synchrony will appear, even though without any coupling connection among these N neurons, indicating the occurrence of uncoupled synchrony. Moreover, similar behavior could also be observed when these neurons are set to be near other bifurcation points. The synchronous error is calculated for discussing this uncoupled synehrony behavior. Finally, we find that such synchrony may have some inherent relevance with the decrease of phase difference between different cells. Our results suggest that biological neuron systems may achieve an effective response to external feeble stimulus by the mode of uncoupled synchrony instead of only by the coupled scheme.
文摘Primary impairments of developmental coordination disorder (DCD) include impairments in motor skill, motor learning, and imitation. Such difficulties present challenges for individuals with DCD and may persist into adulthood, negatively impacting daily life in school, work, and social domains. A better understanding of the neural correlates of motor and imitation impairments in DCD holds the potential for informing development of treatment approaches to address these impairments. Although the disorder is assumed to be of neurological origin, little is known of the brain-based etiology of DCD. In recent years the discovery of a fronto-parietal circuit—known as the mirror neuron system—has enabled researchers to better understand imitation, general motor functions, and aspects of social cognition. Given its involvement in imitation and other motor functions, we propose that dysfunction in the mirror neuron system may underlie the characteristic impairments of DCD. We review literature pertaining to the mirror neuron system and develop a theory of disordered mirror neuron functioning in DCD. Finally, we review the limited neuroimaging literature available on neural correlates of DCD and show that the findings from those investigations are congruent with a mirror neuron system theory of DCD. Future research in this population should be designed to investigate specifically mirror neuron regions in individuals with DCD during skilled motor tasks and imitation in particular.
文摘The reliability of the AI systems to the harsh space radiation is of great concerns with the increasing application in aerospace.Because of its neuromorphic device architecture and operation mode,low-power neuron chips have enormous potentials in resistance of single event effect,which is one of the most important failures of spacecraft caused by space radiation.In this work,a mixed-signal spiking neuron chip,named PAVLOV^([1]),has been studied at circuit and chip level with respect to its response to single event errors.
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 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 the National Key R&D Program of China,No.2021YFC2501200(to PC).
文摘Short-chain fatty acids,metabolites produced by the fermentation of dietary fiber by gut microbiota,have garnered significant attention due to their correlation with neurodegenerative diseases,particularly Parkinson’s disease.In this review,we summarize the changes in short-chain fatty acid levels and the abundance of short-chain fatty acid-producing bacteria in various samples from patients with Parkinson’s disease,highlighting the critical role of gut homeostasis imbalance in the pathogenesis and progression of the disease.Focusing on the nervous system,we discuss the molecular mechanisms by which short-chain fatty acids influence the homeostasis of both the enteric nervous system and the central nervous system.We identify key processes,including the activation of G protein-coupled receptors and the inhibition of histone deacetylases by short-chain fatty acids.Importantly,structural or functional disruptions in the enteric nervous system mediated by these fatty acids may lead to abnormalα-synuclein expression and gastrointestinal dysmotility,which could serve as an initiating event in Parkinson’s disease.Furthermore,we propose that short-chain fatty acids help establish communication between the enteric nervous system and the central nervous system via the vagal nerve,immune circulation,and endocrine signaling.This communication may shed light on their potential role in the transmission ofα-synuclein from the gut to the brain.Finally,we elucidate novel treatment strategies for Parkinson’s disease that target short-chain fatty acids and examine the challenges associated with translating short-chain fatty acid-based therapies into clinical practice.In conclusion,this review emphasizes the pivotal role of short-chain fatty acids in regulating gut-brain axis integrity and their significance in the pathogenesis of Parkinson’s disease from the perspective of the nervous system.Moreover,it highlights the potential value of short-chain fatty acids in early intervention for Parkinson’s disease.Future research into the molecular mechanisms of short-chain fatty acids and their synergistic interactions with other gut metabolites is likely to advance the clinical translation of innovative short-chain fatty acid-based therapies for Parkinson’s disease.
基金supported by the National Natural Science Foundation of China(81971058,82371226,82101295,82301398)the National Funded Postdoctoral Researcher Program(GZC20233585)The Boost Plan of Xijing Hospital(XJZT24QN25,XJZT25CX22).
文摘Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsolved issue in pain medicine.Our previous study,using protein kinase C gamma(PKCγ)-tdTomato mice,highlights the spinal feedforward inhibitory circuit involving PKCγ neurons in gating neuropathic allodynia.However,the regulatory mechanisms governing this circuit necessitate further elucidation.We used diverse transgenic mice and advanced techniques to uncover the regulatory role of the descending serotonin(5-HT)facilitation system on spinal PKCγ neurons.Our findings revealed that 5-HT neurons from the rostral ventromedial medulla hyperpolarize spinal inhibitory interneurons via 5-HT_(2C) receptors,disinhibiting the feedforward inhibitory circuit involving PKCγ neurons and exacerbating allodynia.Inhibiting spinal 5-HT_(2C) receptors restored the feedforward inhibitory circuit,effectively preventing neuropathic allodynia.These insights offer promising therapeutic targets for neuropathic allodynia management,emphasizing the potential of spinal 5-HT_(2C) receptors as a novel avenue for intervention.
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supported by a grant from Ministry of Science and Technology China,No.2022ZD0204704(to WW)the National Natural Science Foundation of China,No.82301572(to XZ)the China Postdoctoral Science Foundation,No.2023M731202(to XZ)。
文摘Nonhuman primates are increasingly being used as animal models in neuroscience research.However,efficient neuronal tracing techniques for labeling motor neurons and primary sensory afferents in the monkey spinal cord are lacking.Here,by injecting the cholera toxin B subunit into the sciatic nerve of a rhesus monkey,we successfully labeled the motor neurons and primary sensory afferents in the lumbar and sacralspinal cord.Labeled alpha motor neurons were located in lamina IX of the L6–S1 segments,which innervate both flexors and extensors.The labeled primary sensory afferents were mainly myelinated Aβfibers that terminated mostly in laminae I and II of the L4–L7 segments.Together with the labeled proprioceptive afferents,the primary sensory afferents formed excitatory synapses with multiple types of spinal neurons.In summary,our methods successfully traced neuronal connections in the monkey spinal cord and can be used in spinal cord studies when nonhuman primates are used.
基金supported by the following foundations:“Stichting Oogfonds Nederland(No.2023-26)”the“Landelijke Stichting voor Blinden en Slechtzienden(No.2023-24)”that contributed through UitZicht,ZonMw grant(No.435005020)a grant of the Chinese Scholarship Council(No.201809110169)(to TGMFG,CPMR,and WY).
文摘Unwarranted death of neurons is a major cause of neurodegenerative diseases.Since mature neurons are postmitotic and do not replicate,their death usually constitutes an irreversible step in pathology.A logical strategy to prevent neurodegeneration would then be to save all neurons that are still alive,i.e.protecting the ones that are still healthy as well as trying to rescue the ones that are damaged and in the process of dying.Regarding the latter,recent experiments have indicated that the possibility of reversing the cell death process and rescuing dying cells is more significant than previously anticipated.In many situations,the elimination of the cell death trigger alone enables dying cells to spontaneously repair their damage,recover,and survive.In this review,we explore the factors,which determine the fate of neurons engaged in the cell death process.A deeper insight into cell death mechanisms and the intrinsic capacity of cells to recover could pave the way for novel therapeutic approaches to neurodegenerative diseases.
基金supported by the DGIST start-up funds from the Ministry of Science and ICT(2024010330)a National Research Foundation of Korea(NRF)grant funded by the Korea Government(MSIT)(No.RS-2024-00351442)(to TWK).
文摘Parkinson’s disease(PD)is the second most common neurodegenerative disorder.The progressive degeneration of dopamine(DA)producing neurons in the midbrain is the pathological hallmark,which leads to debilitating motor symptoms,including tremors,rigidity,and bradykinesia.Drug treatments,such as levodopa,provide symptomatic relief.However,they do not halt disease progression,and their effectiveness diminishes over time(reviewed in Poewe et al.,2017).
基金National Institute of Health(NIH)National Institute of Neurological Disorders and Stroke(NINDS),Nos.NS112910,NS133252(to BD)Department of Defense(DoD)Peer Reviewed Medical Research Program(PRMRP)Discovery Award,No.W81XWH2010186(to BD).
文摘The generation of human induced pluripotent stem cell-derived motor neurons overcomes limited access to human tissues and offers an unprecedented approach to modeling motor neuron diseases such as dystonia and amyotrophic lateral sclerosis.Motor neurons generated through different strategies may exhibit substantial differences in purity,maturation,characterization,and even neuronal identity,leading to variable outcomes in disease modeling and drug screening.However,very few comparative studies have been conducted to determine the similarities and differences among motor neurons prepared via different protocols.In this study,we prepared human induced pluripotent stem cell-derived motor neurons via lentiviral delivery of transcription factors and chemical induction and performed a systematic comparative analysis.We found that motor neurons generated by both approaches showed typical motor neuron morphology and robustly expressed motor neuron-specific markers,such as nuclear homeobox transcription factor 9 and choline acetyltransferase.The chemical induction protocol utilizes a combination of small molecules to induce motor neuron differentiation,offering a significantly faster maturation time of 35 days compared to 46 days with lentiviral delivery of transcription factors.Additionally,while lentiviral delivery of transcription factors are suitable for downstream biochemical analysis,chemical induction are more applicable for therapeutic approaches as they avoid the use of lentiviruses.Both approaches produce motor neurons with high purity(>95%)and yield.No significant differences were found between chemical induction and lentiviral delivery of transcription factors in terms of motor neuron markers and maturation markers.These robust methodologies offer researchers powerful tools for investigating motor neuron diseases and potential therapeutic strategies.
基金supported by the National Key Research and Development Program of China,No.2022YFC2703101(to YC)the National Natural Science Fundation of China,No.82371422(to YC)+1 种基金the National Innovation and Entrepreneurship Training Program for College Students,No.202310611408(to XW)the 1·3·5 Project for Disciplines of Excellence Clinical Research Fund,West China Hospital,Sichuan University,No.2023HXFH032(to YC)。
文摘Motor neuron diseases are sporadic or inherited fatal neurodegenerative conditions.They selectively affect the upper and/or lower motor neurons in the brain and spinal cord and feature a slow onset and a subacute course contingent upon the site of damage.The main types include amyotrophic lateral sclerosis,progressive muscular atrophy,primary lateral sclerosis,and progressive bulbar palsy,the pathological processes of which are largely identical,with the main disparity lying in the location of the lesions.Amyotrophic lateral sclerosis is the representative condition in this group of diseases,while other types are its variants.Hence,this article mainly focuses on the advancements and challenges in drug research for amyotrophic lateral sclerosis but also briefly addresses several other important degenerative motor neuron diseases.Although the precise pathogenesis remains elusive,recent advancements have shed light on various theories,including gene mutation,excitatory amino acid toxicity,autoimmunology,and neurotrophic factors.The US Food and Drug Administration has approved four drugs for use in delaying the progression of amyotrophic lateral sclerosis:riluzole,edaravone,AMX0035,and tofersen,with the latter being the most recent to receive approval.However,following several phaseⅢtrials that failed to yield favorable outcomes,AMX0035 has been voluntarily withdrawn from both the US and Canadian markets.This article presents a comprehensive summary of drug trials primarily completed between January 1,2023,and June 30,2024,based on data sourced from clinicaltrials.gov.Among these trials,five are currently in phaseⅠ,seventeen are in phaseⅡ,and eleven are undergoing phaseⅢevaluation.Notably,24 clinical trials are now investigating potential disease-modifying therapy drugs,accounting for the majority of the drugs included in this review.Some promising drugs being investigated in preclinical studies,such as ATH-1105,are included in our analysis,and another review in frontiers in gene therapy and immunotherapy has demonstrated their therapeutic potential for motor neuron diseases.This article was written to be an overview of research trends and treatment prospects related to motor neuron disease drugs,with the aim of highlighting the latest potentialities for clinical therapy.
基金National Natural Science Foundation of China,Nos.82471264(to YL),82201392(to AZ),82071415(to JL)Shanghai Rising Stars of Medical Talents Youth Development Program,No.2023-62(to YL)+2 种基金the Shanghai Municipal Health Commission Clinical Research Special Fund for the Health Industry,No.20234Y0026(to YL)the Shanghai Sailing Program,No.22YF1425100(to AZ)Chinese Postdoctoral Science Foundation,No.2021M702169(to YJ).
文摘DJ-1,also known as Parkinson’s disease protein 7(PARK7),is a multifunctional protein that plays an important role in oxidative stress regulation and neuroprotection.Previous studies have shown that DJ-1 affects early-onset Parkinson’s disease by regulating neuroinflammation,but its specific mechanism remains unclear.The study investigated the role of DJ-1 in mediating microglia-neuron communication to identify potential therapeutic targets for neuroinflammation in Parkinson’s disease.In this study,we observed a significant decrease in the levels of C-X3-C motif chemokine ligand 1(CX3CL1)in Park7 knockout mice and SH-SY5Y cells with Park7 knockdown.Protein microarray analysis and validation using GEO datasets confirmed that knockout of the Park7 gene led to downregulation of CX3CL1 and two other chemokines,namely monocyte chemoattractant protein-1 and interleukin-8.Further investigation revealed that Park7 deficiency reduced the processing of a disintegrin and metalloproteinase domain-containing protein 10(ADAM10)in the neuronal endoplasmic reticulum of both mice and SH-SY5Y cells,thereby decreasing CX3CL1 secretion.This subsequently led to abnormal microglial activation,with a shift toward the proinflammatory M1 phenotype,exacerbating neuroinflammatory responses.These effects were mitigated by exogenous CX3CL1 administration.Concurrently,exogenous CX3CL1 improved motor function in Parkinson’s disease model mice with the Park7 knockout,promoting survival of tyrosine hydroxylase-positive neurons in the substantia nigra and reducing Iba-1-positive microglial activation.These findings demonstrate that DJ-1 exerts neuroprotective effects on dopaminergic neurons by suppressing microglial activation through CX3CL1 regulation,suggesting that targeting the DJ-1/CX3CL1 axis may represent a novel therapeutic strategy for modulating neuroinflammation and protecting dopaminergic neurons.
文摘The number and diversity of inhibitory neurons(INs)increased substantially during mammalian brain evolution.However,the generative mechanisms of the vast repertoire of human INs remain elusive.We performed spatial and single-cell transcriptomics of human medial ganglionic eminence(hMGE),a pivotal source of cortical and subpallial INs,and built the trajectories of hMGE-derived cells during brain development.We identified spatiotemporally and molecularly segregated progenitor cell populations fated to produce distinct IN types.
