Promoting synaptic plasticity and inducing functional reorganization of residual nerve fibers hold clinical significance for restoring motor function following spinal cord injury.Neuromagnetic stimulation targeting th...Promoting synaptic plasticity and inducing functional reorganization of residual nerve fibers hold clinical significance for restoring motor function following spinal cord injury.Neuromagnetic stimulation targeting the nerve roots has been shown to improve motor function by enhancing nerve conduction in the injured spinal cord and restoring the synaptic ultrastructure of both the sensory and motor cortex.However,our understanding of the neurophysiological mechanisms by which nerve root magnetic stimulation facilitates motor function recovery in the spinal cord is limited,and its role in neuroplasticity remains unclear.In this study,we established a model of spinal cord injury in adult male Sprague–Dawley rats by applying moderate compression at the T10 vertebra.We then performed magnetic stimulation on the L5 nerve root for 3 weeks,beginning on day 3 post-injury.At day 22 post-injury,we observed that nerve root magnetic stimulation downregulated the level of interleukin-6 in the injured spinal cord tissue of rats.Additionally,this treatment reduced neuronal damage and glial scar formation,and increased the number of neurons in the injured spinal cord.Furthermore,nerve root magnetic stimulation decreased the levels of acetylcholine,norepinephrine,and dopamine,and increased the expression of synaptic plasticity-related m RNA and proteins PSD95,GAP43,and Synapsin II.Taken together,these results showed that nerve root magnetic stimulation alleviated neuronal damage in the injured spinal cord,regulated synaptic plasticity,and suppressed inflammatory responses.These findings provide laboratory evidence for the clinical application of nerve root magnetic stimulation in the treatment of spinal cord injury.展开更多
Synaptic pruning is a crucial process in synaptic refinement,eliminating unstable synaptic connections in neural circuits.This process is triggered and regulated primarily by spontaneous neural activity and experience...Synaptic pruning is a crucial process in synaptic refinement,eliminating unstable synaptic connections in neural circuits.This process is triggered and regulated primarily by spontaneous neural activity and experience-dependent mechanisms.The pruning process involves multiple molecular signals and a series of regulatory activities governing the“eat me”and“don't eat me”states.Under physiological conditions,the interaction between glial cells and neurons results in the clearance of unnecessary synapses,maintaining normal neural circuit functionality via synaptic pruning.Alterations in genetic and environmental factors can lead to imbalanced synaptic pruning,thus promoting the occurrence and development of autism spectrum disorder,schizophrenia,Alzheimer's disease,and other neurological disorders.In this review,we investigated the molecular mechanisms responsible for synaptic pruning during neural development.We focus on how synaptic pruning can regulate neural circuits and its association with neurological disorders.Furthermore,we discuss the application of emerging optical and imaging technologies to observe synaptic structure and function,as well as their potential for clinical translation.Our aim was to enhance our understanding of synaptic pruning during neural development,including the molecular basis underlying the regulation of synaptic function and the dynamic changes in synaptic density,and to investigate the potential role of these mechanisms in the pathophysiology of neurological diseases,thus providing a theoretical foundation for the treatment of neurological disorders.展开更多
Alzheimer’s disease(AD)is the most common cause of dementia,characterized by progressive cognitive decline,and affects over 55 million people worldwide.AD is pathological featured by the aberrant accumulation of amyl...Alzheimer’s disease(AD)is the most common cause of dementia,characterized by progressive cognitive decline,and affects over 55 million people worldwide.AD is pathological featured by the aberrant accumulation of amyloid-βplaques,neurofibrillary tangles formed by hyperphosphorylated tau,synaptic loss,and dysfunction of neurotransmitter systems.Evidence from in vivo and autopsy studies has consistently shown that synaptic dysfunction and loss are strongly correlated with cognitive decline in AD,particularly in brain regions such as the hippocampus and cortex,which are critical for memory formation and processing.This perspective highlights recent histopathological findings related to synaptic dysfunction in AD,advancements in the development of imaging and fluid-based biomarkers for synaptic loss,and future studies.展开更多
Diabetic retinopathy is a prominent cause of blindness in adults,with early retinal ganglion cell loss contributing to visual dysfunction or blindness.In the brain,defects inγ-aminobutyric acid synaptic transmission ...Diabetic retinopathy is a prominent cause of blindness in adults,with early retinal ganglion cell loss contributing to visual dysfunction or blindness.In the brain,defects inγ-aminobutyric acid synaptic transmission are associated with pathophysiological and neurodegenerative disorders,whereas glucagon-like peptide-1 has demonstrated neuroprotective effects.However,it is not yet clear whether diabetes causes alterations in inhibitory input to retinal ganglion cells and whether and how glucagon-like peptide-1 protects against neurodegeneration in the diabetic retina through regulating inhibitory synaptic transmission to retinal ganglion cells.In the present study,we used the patch-clamp technique to recordγ-aminobutyric acid subtype A receptor-mediated miniature inhibitory postsynaptic currents in retinal ganglion cells from streptozotocin-induced diabetes model rats.We found that early diabetes(4 weeks of hyperglycemia)decreased the frequency of GABAergic miniature inhibitory postsynaptic currents in retinal ganglion cells without altering their amplitude,suggesting a reduction in the spontaneous release ofγ-aminobutyric acid to retinal ganglion cells.Topical administration of glucagon-like peptide-1 eyedrops over a period of 2 weeks effectively countered the hyperglycemia-induced downregulation of GABAergic mIPSC frequency,subsequently enhancing the survival of retinal ganglion cells.Concurrently,the protective effects of glucagon-like peptide-1 on retinal ganglion cells in diabetic rats were eliminated by topical administration of exendin-9-39,a specific glucagon-like peptide-1 receptor antagonist,or SR95531,a specific antagonist of theγ-aminobutyric acid subtype A receptor.Furthermore,extracellular perfusion of glucagon-like peptide-1 was found to elevate the frequencies of GABAergic miniature inhibitory postsynaptic currents in both ON-and OFF-type retinal ganglion cells.This elevation was shown to be mediated by activation of the phosphatidylinositol-phospholipase C/inositol 1,4,5-trisphosphate receptor/Ca2+/protein kinase C signaling pathway downstream of glucagon-like peptide-1 receptor activation.Moreover,multielectrode array recordings revealed that glucagon-like peptide-1 functionally augmented the photoresponses of ON-type retinal ganglion cells.Optomotor response tests demonstrated that diabetic rats exhibited reductions in visual acuity and contrast sensitivity that were significantly ameliorated by topical administration of glucagon-like peptide-1.These results suggest that glucagon-like peptide-1 facilitates the release ofγ-aminobutyric acid onto retinal ganglion cells through the activation of glucagon-like peptide-1 receptor,leading to the de-excitation of retinal ganglion cell circuits and the inhibition of excitotoxic processes associated with diabetic retinopathy.Collectively,our findings indicate that theγ-aminobutyric acid system has potential as a therapeutic target for mitigating early-stage diabetic retinopathy.Furthermore,the topical administration of glucagon-like peptide-1 eyedrops represents a non-invasive and effective treatment approach for managing early-stage diabetic retinopathy.展开更多
In recent years,research focusing on synaptic device based on phototransistors has provided a new method for asso-ciative learning and neuromorphic computing.A TiO_(2)/AlGaN/GaN heterostructure-based synaptic phototra...In recent years,research focusing on synaptic device based on phototransistors has provided a new method for asso-ciative learning and neuromorphic computing.A TiO_(2)/AlGaN/GaN heterostructure-based synaptic phototransistor is fabricated and measured,integrating a TiO_(2)nanolayer gate and a two-dimensional electron gas(2DEG)channel to mimic the synaptic weight and the synaptic cleft,respectively.The maximum drain to source current is 10 nA,while the device is driven at a reverse bias not exceeding-2.5 V.A excitatory postsynaptic current(EPSC)of 200 nA can be triggered by a 365 nm UVA light spike with the duration of 1 s at light intensity of 1.35μW·cm^(-2).Multiple synaptic neuromorphic functions,including EPSC,short-term/long-term plasticity(STP/LTP)and paried-pulse facilitation(PPF),are effectively mimicked by our GaN-based het-erostructure synaptic device.In the typical Pavlov’s dog experiment,we demonstrate that the device can achieve"retraining"process to extend memory time through enhancing the intensity of synaptic weight,which is similar to the working mecha-nism of human brain.展开更多
To address the increasing demand for massive data storage and processing,brain-inspired neuromorphic comput-ing systems based on artificial synaptic devices have been actively developed in recent years.Among the vario...To address the increasing demand for massive data storage and processing,brain-inspired neuromorphic comput-ing systems based on artificial synaptic devices have been actively developed in recent years.Among the various materials inves-tigated for the fabrication of synaptic devices,silicon carbide(SiC)has emerged as a preferred choices due to its high electron mobility,superior thermal conductivity,and excellent thermal stability,which exhibits promising potential for neuromorphic applications in harsh environments.In this review,the recent progress in SiC-based synaptic devices is summarized.Firstly,an in-depth discussion is conducted regarding the categories,working mechanisms,and structural designs of these devices.Subse-quently,several application scenarios for SiC-based synaptic devices are presented.Finally,a few perspectives and directions for their future development are outlined.展开更多
In this data explosion era,ensuring the secure storage,access,and transmission of information is imperative,encom-passing all aspects ranging from safeguarding personal devices to formulating national information secu...In this data explosion era,ensuring the secure storage,access,and transmission of information is imperative,encom-passing all aspects ranging from safeguarding personal devices to formulating national information security strategies.Leverag-ing the potential offered by dual-type carriers for transportation and employing optical modulation techniques to develop high reconfigurable ambipolar optoelectronic transistors enables effective implementation of information destruction after read-ing,thereby guaranteeing data security.In this study,a reconfigurable ambipolar optoelectronic synaptic transistor based on poly(3-hexylthiophene)(P3HT)and poly[[N,N-bis(2-octyldodecyl)-napthalene-1,4,5,8-bis(dicarboximide)-2,6-diyl]-alt-5,5′-(2,2′-bithiophene)](N2200)blend film was fabricated through solution-processed method.The resulting transistor exhib-ited a relatively large ON/OFF ratio of 10^(3) in both n-and p-type regions,and tunable photoconductivity after light illumination,particularly with green light.The photo-generated carriers could be effectively trapped under the gate bias,indicating its poten-tial application in mimicking synaptic behaviors.Furthermore,the synaptic plasticity,including volatile/non-volatile and excita-tory/inhibitory characteristics,could be finely modulated by electrical and optical stimuli.These optoelectronic reconfigurable properties enable the realization of information light assisted burn after reading.This study not only offers valuable insights for the advancement of high-performance ambipolar organic optoelectronic synaptic transistors but also presents innovative ideas for the future information security access systems.展开更多
The rapid growth of artificial intelligence has accelerated data generation,which increasingly exposes the limitations faced by traditional computational architectures,particularly in terms of energy consumption and d...The rapid growth of artificial intelligence has accelerated data generation,which increasingly exposes the limitations faced by traditional computational architectures,particularly in terms of energy consumption and data latency.In contrast,data-centric computing that integrates processing and storage has the potential of reducing latency and energy usage.Organic optoelectronic synaptic transistors have emerged as one type of promising devices to implement the data-centric com-puting paradigm owing to their superiority of flexibility,low cost,and large-area fabrication.However,sophisticated functions including vector-matrix multiplication that a single device can achieve are limited.Thus,the fabrication and utilization of organic optoelectronic synaptic transistor arrays(OOSTAs)are imperative.Here,we summarize the recent advances in OOSTAs.Various strategies for manufacturing OOSTAs are introduced,including coating and casting,physical vapor deposition,printing,and photolithography.Furthermore,innovative applications of the OOSTA system integration are discussed,including neuromor-phic visual systems and neuromorphic computing systems.At last,challenges and future perspectives of utilizing OOSTAs in real-world applications are discussed.展开更多
Alzheimer’s disease is a neurodegenerative disease resulting from deficits in synaptic transmission and homeostasis.The Alzheimer’s disease brain tends to be hyperexcitable and hypersynchronized,thereby causing neur...Alzheimer’s disease is a neurodegenerative disease resulting from deficits in synaptic transmission and homeostasis.The Alzheimer’s disease brain tends to be hyperexcitable and hypersynchronized,thereby causing neurodegeneration and ultimately disrupting the operational abilities in daily life,leaving patients incapacitated.Repetitive transcranial magnetic stimulation is a cost-effective,neuro-modulatory technique used for multiple neurological conditions.Over the past two decades,it has been widely used to predict cognitive decline;identify pathophysiological markers;promote neuroplasticity;and assess brain excitability,plasticity,and connectivity.It has also been applied to patients with dementia,because it can yield facilitatory effects on cognition and promote brain recovery after a neurological insult.However,its therapeutic effectiveness at the molecular and synaptic levels has not been elucidated because of a limited number of studies.This study aimed to characterize the neurobiological changes following repetitive transcranial magnetic stimulation treatment,evaluate its effects on synaptic plasticity,and identify the associated mechanisms.This review essentially focuses on changes in the pathology,amyloidogenesis,and clearance pathways,given that amyloid deposition is a major hypothesis in the pathogenesis of Alzheimer’s disease.Apoptotic mechanisms associated with repetitive transcranial magnetic stimulation procedures and different pathways mediating gene transcription,which are closely related to the neural regeneration process,are also highlighted.Finally,we discuss the outcomes of animal studies in which neuroplasticity is modulated and assessed at the structural and functional levels by using repetitive transcranial magnetic stimulation,with the aim to highlight future directions for better clinical translations.展开更多
Several experimental evidence suggests a link between brain Herpes simplex virus type-1 infection and the occurrence of Alzheimer’s disease.However,the molecular mechanisms underlying this association are not complet...Several experimental evidence suggests a link between brain Herpes simplex virus type-1 infection and the occurrence of Alzheimer’s disease.However,the molecular mechanisms underlying this association are not completely understood.Among the molecular mediators of synaptic and cognitive dysfunction occurring after Herpes simplex virus type-1 infection and reactivation in the brain neuroinflammatory cytokines seem to occupy a central role.Here,we specifically reviewed literature reports dealing with the impact of neuroinflammation on synaptic dysfunction observed after recurrent Herpes simplex virus type-1 reactivation in the brain,highlighting the role of interleukins and,in particular,interleukin 1βas a possible target against Herpes simplex virus type-1-induced neuronal dysfunctions.展开更多
With an increase in global aging,the number of people affected by cerebrovascular diseases is also increasing,and the incidence of vascular dementia-closely related to cerebrovascular risk-is increasing at an epidemic...With an increase in global aging,the number of people affected by cerebrovascular diseases is also increasing,and the incidence of vascular dementia-closely related to cerebrovascular risk-is increasing at an epidemic rate.However,few therapeutic options exist that can markedly improve the cognitive impairment and prognosis of vascular dementia patients.Similarly in Alzheimer’s disease and other neurological disorders,synaptic dysfunction is recognized as the main reason for cognitive decline.Nitric oxide is one of the ubiquitous gaseous cellular messengers involved in multiple physiological and pathological processes of the central nervous system.Recently,nitric oxide has been implicated in regulating synaptic plasticity and plays an important role in the pathogenesis of vascular dementia.This review introduces in detail the emerging role of nitric oxide in physiological and pathological states of vascular dementia and summarizes the diverse effects of nitric oxide on different aspects of synaptic dysfunction,neuroinflammation,oxidative stress,and blood-brain barrier dysfunction that underlie the progress of vascular dementia.Additionally,we propose that targeting the nitric oxide-sGC-cGMP pathway using certain specific approaches may provide a novel therapeutic strategy for vascular dementia.展开更多
Learning-associated functional plasticity at hippocampal synapses remains largely unexplored. Here, in a single session of reward-based trace conditioning, we examine learning-induced synaptic plasticity in the dorsal...Learning-associated functional plasticity at hippocampal synapses remains largely unexplored. Here, in a single session of reward-based trace conditioning, we examine learning-induced synaptic plasticity in the dorsal CA1 hippocampus (dCA1). Local field-potential recording combined with selective optogenetic inhibition first revealed an increase of dCA1 synaptic responses to the conditioned stimulus (CS) induced during conditioning at both Schaffer collaterals to the stratum radiatum (Rad) and temporoammonic input to the lacunosum moleculare (LMol). At these dCA1 inputs, synaptic potentiation of CS-responding excitatory synapses was further demonstrated by locally blocking NMDA receptors during conditioning and whole-cell recording sensory-evoked synaptic responses in dCA1 neurons from naive animals. An overall similar time course of the induction of synaptic potentiation was found in the Rad and LMol by multiple-site recording;this emerged later and saturated earlier than conditioned behavioral responses. Our experiments demonstrate a cued memory-associated dCA1 synaptic plasticity induced at both Schaffer collaterals and temporoammonic pathways.展开更多
Rapid development of artificial intelligence requires the implementation of hardware systems with bioinspired parallel information processing and presentation and energy efficiency.Electrolyte-gated organic transistor...Rapid development of artificial intelligence requires the implementation of hardware systems with bioinspired parallel information processing and presentation and energy efficiency.Electrolyte-gated organic transistors(EGOTs)offer significant advantages as neuromorphic devices due to their ultra-low operation voltages,minimal hardwired connectivity,and similar operation environment as electrophysiology.Meanwhile,ionic–electronic coupling and the relatively low elastic moduli of organic channel materials make EGOTs suitable for interfacing with biology.This review presents an overview of the device architectures based on organic electrochemical transistors and organic field-effect transistors.Furthermore,we review the requirements of low energy consumption and tunable synaptic plasticity of EGOTs in emulating biological synapses and how they are affected by the organic materials,electrolyte,architecture,and operation mechanism.In addition,we summarize the basic operation principle of biological sensory systems and the recent progress of EGOTs as a building block in artificial systems.Finally,the current challenges and future development of the organic neuromorphic devices are discussed.展开更多
Objective To reveal the effects and potential mechanisms by which synaptic vesicle glycoprotein 2A(SV2A)influences the distribution of amyloid precursor protein(APP)in the trans-Golgi network(TGN),endolysosomal system...Objective To reveal the effects and potential mechanisms by which synaptic vesicle glycoprotein 2A(SV2A)influences the distribution of amyloid precursor protein(APP)in the trans-Golgi network(TGN),endolysosomal system,and cell membranes and to reveal the effects of SV2A on APP amyloid degradation.Methods Colocalization analysis of APP with specific tagged proteins in the TGN,ensolysosomal system,and cell membrane was performed to explore the effects of SV2A on the intracellular transport of APP.APP,β-site amyloid precursor protein cleaving enzyme 1(BACE1)expressions,and APP cleavage products levels were investigated to observe the effects of SV2A on APP amyloidogenic processing.Results APP localization was reduced in the TGN,early endosomes,late endosomes,and lysosomes,whereas it was increased in the recycling endosomes and cell membrane of SV2A-overexpressed neurons.Moreover,Arl5b(ADP-ribosylation factor 5b),a protein responsible for transporting APP from the TGN to early endosomes,was upregulated by SV2A.SV2A overexpression also decreased APP transport from the cell membrane to early endosomes by downregulating APP endocytosis.In addition,products of APP amyloid degradation,including sAPPβ,Aβ1-42,and Aβ1-40,were decreased in SV2A-overexpressed cells.Conclusion These results demonstrated that SV2A promotes APP transport from the TGN to early endosomes by upregulating Arl5b and promoting APP transport from early endosomes to recycling endosomes-cell membrane pathway,which slows APP amyloid degradation.展开更多
Autism Spectrum Disorder(ASD)is marked by early-onset neurodevelopmental anomalies,yet the tem-poral dynamics of genetic contributions to these processes remain insufficiently understood.This study aimed to elu-cidate...Autism Spectrum Disorder(ASD)is marked by early-onset neurodevelopmental anomalies,yet the tem-poral dynamics of genetic contributions to these processes remain insufficiently understood.This study aimed to elu-cidate the role of the Shank3 gene,known to be associated with monogenic causes of autism,in early developmental processes to inform the timing and mechanisms for poten-tial interventions for ASD.Utilizing the Shank3B knockout(KO)mouse model,we examined Shank3 expression and its impact on neuronal maturation through Golgi staining for dendritic morphology and electrophysiological recordings to measure synaptic function in the anterior cingulate cortex(ACC)across different postnatal stages.Our longitudinal analysis revealed that,while Shank3B KO mice displayed normal neuronal morphology at one week postnatal,signifi-cant impairments in dendritic growth and synaptic activity emerged by two to three weeks.These findings highlight the critical developmental window during which Shank3 is essential for neuronal and synaptic maturation in the ACC.展开更多
Poly(vinylidene-trifluoroethylene) [P(VDF-TrFE)] copolymer films generally demonstrate limited compatibility with organic semiconductors. The material is frequently compromised by exposure to organic semiconductor sol...Poly(vinylidene-trifluoroethylene) [P(VDF-TrFE)] copolymer films generally demonstrate limited compatibility with organic semiconductors. The material is frequently compromised by exposure to organic semiconductor solutions and other fabrication processes utilized in the production of organic ferroelectric transistors. In this study, an organic ferroelectric field effect transistor(OFeFET) with the 6,13-Bis(triisopropylsilylethynyl) pentacene(TIPS-pentacene) channel is fabricated, in which the aluminum oxide(Al_(2)O_(3)) interlayer is used to improve compatibility. The device displays polymorphic memory and synaptic plasticity of long-term potentiation and depression. Furthermore, an artificial neural network constructed using our devices is simulated to succeed in recognizing the MNIST handwritten digit database with a high accuracy of 92.8%. This research offers a viable approach to enhance the compatibility of the organic ferroelectric polymer P(VDF-TrFE) with organic semiconductors.展开更多
Synaptic nano-devices have powerful capabilities in logic,memory and learning,making them essential compo-nents for constructing brain-like neuromorphic computing systems.Here,we have successfully developed and demons...Synaptic nano-devices have powerful capabilities in logic,memory and learning,making them essential compo-nents for constructing brain-like neuromorphic computing systems.Here,we have successfully developed and demonstrated a synaptic nano-device based on Ga_(2)O_(3) nanowires with low energy consumption.Under 255 nm light stimulation,the biomimetic synaptic nano-device can stimulate various functionalities of biological synapses,including pulse facilitation,peak time-dependent plasticity and memory learning ability.It is found that the artificial synaptic device based on Ga_(2)O_(3) nanowires can achieve an excellent"learning-forgetting-relearning"functionality.The transition from short-term memory to long-term memory and retention of the memory level after the stepwise learning can attribute to the great relearning functionality of Ga_(2)O_(3) nanowires.Furthermore,the energy consumption of the synaptic nano-device can be lower than 2.39×10^(-11) J for a synaptic event.Moreover,our device demonstrates exceptional stability in long-term stimulation and storage.In the applica-tion of neural morphological computation,the accuracy of digit recognition exceeds 90%after 12 training sessions,indicating the strong learning capability of the cognitive system composed of this synaptic nano-device.Therefore,our work paves an effective way for advancing hardware-based neural morphological computation and artificial intelligence systems requiring low power consumption.展开更多
Microglia are the main non-neuronal cells in the central nervous system that have important roles in brain development and functional connectivity of neural circuits.In brain physiology,highly dynamic microglial proce...Microglia are the main non-neuronal cells in the central nervous system that have important roles in brain development and functional connectivity of neural circuits.In brain physiology,highly dynamic microglial processes are facilitated to sense the surrounding environment and stimuli.Once the brain switches its functional states,microglia are recruited to specific sites to exert their immune functions,including the release of cytokines and phagocytosis of cellular debris.The crosstalk of microglia between neurons,neural stem cells,endothelial cells,oligodendrocytes,and astrocytes contributes to their functions in synapse pruning,neurogenesis,vascularization,myelination,and blood-brain barrier permeability.In this review,we highlight the neuron-derived“find-me,”“eat-me,”and“don't eat-me”molecular signals that drive microglia in response to changes in neuronal activity for synapse refinement during brain development.This review reveals the molecular mechanism of neuron-microglia interaction in synaptic pruning and presents novel ideas for the synaptic pruning of microglia in disease,thereby providing important clues for discovery of target drugs and development of nervous system disease treatment methods targeting synaptic dysfunction.展开更多
Emerging research suggests a potential association of progression of Alzheimer's disease(AD)with alterations in synaptic currents and mitochondrial dynamics.However,the specific associations between these patholog...Emerging research suggests a potential association of progression of Alzheimer's disease(AD)with alterations in synaptic currents and mitochondrial dynamics.However,the specific associations between these pathological changes remain unclear.In this study,we utilized Aβ42-induced AD rats and primary neural cells as in vivo and in vitro models.The investigations included behavioural tests,brain magnetic resonance imaging(MRI),liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)analysis,Nissl staining,thioflavin-S staining,enzyme-linked immunosorbent assay,Golgi-Cox staining,transmission electron microscopy(TEM),immunofluorescence staining,proteomics,adenosine triphosphate(ATP)detection,mitochondrial membrane potential(MMP)and reactive oxygen species(ROS)assessment,mitochondrial morphology analysis,electrophysiological studies,Western blotting,and molecular docking.The results revealed changes in synaptic currents,mitophagy,and mitochondrial dynamics in the AD models.Remarkably,intervention with Dengzhan Shengmai(DZSM)capsules emerged as a pivotal element in this investigation.Aβ42-induced synaptic dysfunction was significantly mitigated by DZSM intervention,which notably amplified the frequency and amplitude of synaptic transmission.The cognitive impairment observed in AD rats was ameliorated and accompanied by robust protection against structural damage in key brain regions,including the hippocampal CA3,primary cingular cortex,prelimbic system,and dysgranular insular cortex.DZSM intervention led to increased IDE levels,augmented long-term potential(LTP)amplitude,and enhanced dendritic spine density and length.Moreover,DZSM intervention led to favourable changes in mitochondrial parameters,including ROS expression,MMP and ATP contents,and mitochondrial morphology.In conclusion,our findings delved into the realm of altered synaptic currents,mitophagy,and mitochondrial dynamics in AD,concurrently highlighting the therapeutic potential of DZSM intervention.展开更多
Parkinson's disease is characterized by the selective degeneration of dopamine neurons in the nigrostriatal pathway and dopamine deficiency in the striatum.The precise reasons behind the specific degeneration of t...Parkinson's disease is characterized by the selective degeneration of dopamine neurons in the nigrostriatal pathway and dopamine deficiency in the striatum.The precise reasons behind the specific degeneration of these dopamine neurons remain largely elusive.Genetic investigations have identified over 20 causative PARK genes and 90 genomic risk loci associated with both familial and sporadic Parkinson's disease.Notably,several of these genes are linked to the synaptic vesicle recycling process,particularly the clathrinmediated endocytosis pathway.This suggests that impaired synaptic vesicle recycling might represent an early feature of Parkinson's disease,followed by axonal degeneration and the eventual loss of dopamine cell bodies in the midbrain via a"dying back"mechanism.Recently,several new animal and cellular models with Parkinson's disease-linked mutations affecting the endocytic pathway have been created and extensively characterized.These models faithfully recapitulate certain Parkinson's disease-like features at the animal,circuit,and cellular levels,and exhibit defects in synaptic membrane trafficking,further supporting the findings from human genetics and clinical studies.In this review,we will first summarize the cellular and molecular findings from the models of two Parkinson's disease-linked clathrin uncoating proteins:auxilin(DNAJC6/PARK19)and synaptojanin 1(SYNJ1/PARK20).The mouse models carrying these two PARK gene mutations phenocopy each other with specific dopamine terminal pathology and display a potent synergistic effect.Subsequently,we will delve into the involvement of several clathrin-mediated endocytosis-related proteins(GAK,endophilin A1,SAC2/INPP5 F,synaptotagmin-11),identified as Parkinson's disease risk factors through genome-wide association studies,in Parkinson's disease pathogenesis.We will also explore the direct or indirect roles of some common Parkinson's disease-linked proteins(alpha-synuclein(PARK1/4),Parkin(PARK2),and LRRK2(PARK8))in synaptic endocytic trafficking.Additionally,we will discuss the emerging novel functions of these endocytic proteins in downstream membrane traffic pathways,particularly autophagy.Given that synaptic dysfunction is considered as an early event in Parkinson's disease,a deeper understanding of the cellular mechanisms underlying synaptic vesicle endocytic trafficking may unveil novel to rgets for early diagnosis and the development of interventional therapies for Parkinson's disease.Future research should aim to elucidate why generalized synaptic endocytic dysfunction leads to the selective degeneration of nigrostriatal dopamine neurons in Parkinson's disease.展开更多
基金supported by the National Natural Science Foundation of China,Nos.81772453(to DX),81974358(to DX),81973157(to JZ),82173646(to JZ),82302866(to YZ)。
文摘Promoting synaptic plasticity and inducing functional reorganization of residual nerve fibers hold clinical significance for restoring motor function following spinal cord injury.Neuromagnetic stimulation targeting the nerve roots has been shown to improve motor function by enhancing nerve conduction in the injured spinal cord and restoring the synaptic ultrastructure of both the sensory and motor cortex.However,our understanding of the neurophysiological mechanisms by which nerve root magnetic stimulation facilitates motor function recovery in the spinal cord is limited,and its role in neuroplasticity remains unclear.In this study,we established a model of spinal cord injury in adult male Sprague–Dawley rats by applying moderate compression at the T10 vertebra.We then performed magnetic stimulation on the L5 nerve root for 3 weeks,beginning on day 3 post-injury.At day 22 post-injury,we observed that nerve root magnetic stimulation downregulated the level of interleukin-6 in the injured spinal cord tissue of rats.Additionally,this treatment reduced neuronal damage and glial scar formation,and increased the number of neurons in the injured spinal cord.Furthermore,nerve root magnetic stimulation decreased the levels of acetylcholine,norepinephrine,and dopamine,and increased the expression of synaptic plasticity-related m RNA and proteins PSD95,GAP43,and Synapsin II.Taken together,these results showed that nerve root magnetic stimulation alleviated neuronal damage in the injured spinal cord,regulated synaptic plasticity,and suppressed inflammatory responses.These findings provide laboratory evidence for the clinical application of nerve root magnetic stimulation in the treatment of spinal cord injury.
基金supported by the National Natural Science Foundation of China,No.31760290,82160688the Key Development Areas Project of Ganzhou Science and Technology,No.2022B-SF9554(all to XL)。
文摘Synaptic pruning is a crucial process in synaptic refinement,eliminating unstable synaptic connections in neural circuits.This process is triggered and regulated primarily by spontaneous neural activity and experience-dependent mechanisms.The pruning process involves multiple molecular signals and a series of regulatory activities governing the“eat me”and“don't eat me”states.Under physiological conditions,the interaction between glial cells and neurons results in the clearance of unnecessary synapses,maintaining normal neural circuit functionality via synaptic pruning.Alterations in genetic and environmental factors can lead to imbalanced synaptic pruning,thus promoting the occurrence and development of autism spectrum disorder,schizophrenia,Alzheimer's disease,and other neurological disorders.In this review,we investigated the molecular mechanisms responsible for synaptic pruning during neural development.We focus on how synaptic pruning can regulate neural circuits and its association with neurological disorders.Furthermore,we discuss the application of emerging optical and imaging technologies to observe synaptic structure and function,as well as their potential for clinical translation.Our aim was to enhance our understanding of synaptic pruning during neural development,including the molecular basis underlying the regulation of synaptic function and the dynamic changes in synaptic density,and to investigate the potential role of these mechanisms in the pathophysiology of neurological diseases,thus providing a theoretical foundation for the treatment of neurological disorders.
基金supported by Swiss Center for Applied Human Toxicology(SCAHT AP22-01)(to RN).
文摘Alzheimer’s disease(AD)is the most common cause of dementia,characterized by progressive cognitive decline,and affects over 55 million people worldwide.AD is pathological featured by the aberrant accumulation of amyloid-βplaques,neurofibrillary tangles formed by hyperphosphorylated tau,synaptic loss,and dysfunction of neurotransmitter systems.Evidence from in vivo and autopsy studies has consistently shown that synaptic dysfunction and loss are strongly correlated with cognitive decline in AD,particularly in brain regions such as the hippocampus and cortex,which are critical for memory formation and processing.This perspective highlights recent histopathological findings related to synaptic dysfunction in AD,advancements in the development of imaging and fluid-based biomarkers for synaptic loss,and future studies.
基金supported by the National Natural Science Foundation of China,Nos.32070989(to YMZ),31872766(to YMZ),81790640(to XLY),and 82070993(to SJW)the grant from Sanming Project of Medicine in Shenzhen,No.SZSM202011015(to XLY)。
文摘Diabetic retinopathy is a prominent cause of blindness in adults,with early retinal ganglion cell loss contributing to visual dysfunction or blindness.In the brain,defects inγ-aminobutyric acid synaptic transmission are associated with pathophysiological and neurodegenerative disorders,whereas glucagon-like peptide-1 has demonstrated neuroprotective effects.However,it is not yet clear whether diabetes causes alterations in inhibitory input to retinal ganglion cells and whether and how glucagon-like peptide-1 protects against neurodegeneration in the diabetic retina through regulating inhibitory synaptic transmission to retinal ganglion cells.In the present study,we used the patch-clamp technique to recordγ-aminobutyric acid subtype A receptor-mediated miniature inhibitory postsynaptic currents in retinal ganglion cells from streptozotocin-induced diabetes model rats.We found that early diabetes(4 weeks of hyperglycemia)decreased the frequency of GABAergic miniature inhibitory postsynaptic currents in retinal ganglion cells without altering their amplitude,suggesting a reduction in the spontaneous release ofγ-aminobutyric acid to retinal ganglion cells.Topical administration of glucagon-like peptide-1 eyedrops over a period of 2 weeks effectively countered the hyperglycemia-induced downregulation of GABAergic mIPSC frequency,subsequently enhancing the survival of retinal ganglion cells.Concurrently,the protective effects of glucagon-like peptide-1 on retinal ganglion cells in diabetic rats were eliminated by topical administration of exendin-9-39,a specific glucagon-like peptide-1 receptor antagonist,or SR95531,a specific antagonist of theγ-aminobutyric acid subtype A receptor.Furthermore,extracellular perfusion of glucagon-like peptide-1 was found to elevate the frequencies of GABAergic miniature inhibitory postsynaptic currents in both ON-and OFF-type retinal ganglion cells.This elevation was shown to be mediated by activation of the phosphatidylinositol-phospholipase C/inositol 1,4,5-trisphosphate receptor/Ca2+/protein kinase C signaling pathway downstream of glucagon-like peptide-1 receptor activation.Moreover,multielectrode array recordings revealed that glucagon-like peptide-1 functionally augmented the photoresponses of ON-type retinal ganglion cells.Optomotor response tests demonstrated that diabetic rats exhibited reductions in visual acuity and contrast sensitivity that were significantly ameliorated by topical administration of glucagon-like peptide-1.These results suggest that glucagon-like peptide-1 facilitates the release ofγ-aminobutyric acid onto retinal ganglion cells through the activation of glucagon-like peptide-1 receptor,leading to the de-excitation of retinal ganglion cell circuits and the inhibition of excitotoxic processes associated with diabetic retinopathy.Collectively,our findings indicate that theγ-aminobutyric acid system has potential as a therapeutic target for mitigating early-stage diabetic retinopathy.Furthermore,the topical administration of glucagon-like peptide-1 eyedrops represents a non-invasive and effective treatment approach for managing early-stage diabetic retinopathy.
基金supported by the National Key R&D Program of China(2021YFB3601000,2021YFB3601004)the National Key R&D Program of China(2022YFB3604702)the Chinese Academy of Sciences.
文摘In recent years,research focusing on synaptic device based on phototransistors has provided a new method for asso-ciative learning and neuromorphic computing.A TiO_(2)/AlGaN/GaN heterostructure-based synaptic phototransistor is fabricated and measured,integrating a TiO_(2)nanolayer gate and a two-dimensional electron gas(2DEG)channel to mimic the synaptic weight and the synaptic cleft,respectively.The maximum drain to source current is 10 nA,while the device is driven at a reverse bias not exceeding-2.5 V.A excitatory postsynaptic current(EPSC)of 200 nA can be triggered by a 365 nm UVA light spike with the duration of 1 s at light intensity of 1.35μW·cm^(-2).Multiple synaptic neuromorphic functions,including EPSC,short-term/long-term plasticity(STP/LTP)and paried-pulse facilitation(PPF),are effectively mimicked by our GaN-based het-erostructure synaptic device.In the typical Pavlov’s dog experiment,we demonstrate that the device can achieve"retraining"process to extend memory time through enhancing the intensity of synaptic weight,which is similar to the working mecha-nism of human brain.
基金supported by the Natural Science Foundation of Zhejiang Province(Grant No.LQ24F040007)the National Natural Science Foundation of China(Grant No.U22A2075)the Opening Project of State Key Laboratory of Polymer Materials Engineering(Sichuan University)(Grant No.sklpme2024-1-21).
文摘To address the increasing demand for massive data storage and processing,brain-inspired neuromorphic comput-ing systems based on artificial synaptic devices have been actively developed in recent years.Among the various materials inves-tigated for the fabrication of synaptic devices,silicon carbide(SiC)has emerged as a preferred choices due to its high electron mobility,superior thermal conductivity,and excellent thermal stability,which exhibits promising potential for neuromorphic applications in harsh environments.In this review,the recent progress in SiC-based synaptic devices is summarized.Firstly,an in-depth discussion is conducted regarding the categories,working mechanisms,and structural designs of these devices.Subse-quently,several application scenarios for SiC-based synaptic devices are presented.Finally,a few perspectives and directions for their future development are outlined.
基金the National Natural-Science Foundation of China(Grant No.62304137)Guangdong Basic and Applied Basic Research Foundation(Grant Nos.2023A1515012479,2024A1515011737,and 2024A1515010006)+4 种基金the Science and Technology Innovation Commission of Shenzhen(Grant No.JCYJ20220818100206013)RSC Researcher Collaborations Grant(Grant No.C23-2422436283)State Key Laboratory of Radio Frequency Heterogeneous Integration(Independent Scientific Research Program No.2024010)the Project on Frontier and Interdisciplinary Research Assessment,Academic Divisions of the Chinese Academy of Sciences(Grant No.XK2023XXA002)NTUT-SZU Joint Research Program.
文摘In this data explosion era,ensuring the secure storage,access,and transmission of information is imperative,encom-passing all aspects ranging from safeguarding personal devices to formulating national information security strategies.Leverag-ing the potential offered by dual-type carriers for transportation and employing optical modulation techniques to develop high reconfigurable ambipolar optoelectronic transistors enables effective implementation of information destruction after read-ing,thereby guaranteeing data security.In this study,a reconfigurable ambipolar optoelectronic synaptic transistor based on poly(3-hexylthiophene)(P3HT)and poly[[N,N-bis(2-octyldodecyl)-napthalene-1,4,5,8-bis(dicarboximide)-2,6-diyl]-alt-5,5′-(2,2′-bithiophene)](N2200)blend film was fabricated through solution-processed method.The resulting transistor exhib-ited a relatively large ON/OFF ratio of 10^(3) in both n-and p-type regions,and tunable photoconductivity after light illumination,particularly with green light.The photo-generated carriers could be effectively trapped under the gate bias,indicating its poten-tial application in mimicking synaptic behaviors.Furthermore,the synaptic plasticity,including volatile/non-volatile and excita-tory/inhibitory characteristics,could be finely modulated by electrical and optical stimuli.These optoelectronic reconfigurable properties enable the realization of information light assisted burn after reading.This study not only offers valuable insights for the advancement of high-performance ambipolar organic optoelectronic synaptic transistors but also presents innovative ideas for the future information security access systems.
基金supported by the National Key Research and Development Program of China(2021YFA1101303)the National Natural Science Foundation of China(62374115)the Innovation Program of Shanghai Municipal Education Commission(2021-01-07-00-07-E00096).
文摘The rapid growth of artificial intelligence has accelerated data generation,which increasingly exposes the limitations faced by traditional computational architectures,particularly in terms of energy consumption and data latency.In contrast,data-centric computing that integrates processing and storage has the potential of reducing latency and energy usage.Organic optoelectronic synaptic transistors have emerged as one type of promising devices to implement the data-centric com-puting paradigm owing to their superiority of flexibility,low cost,and large-area fabrication.However,sophisticated functions including vector-matrix multiplication that a single device can achieve are limited.Thus,the fabrication and utilization of organic optoelectronic synaptic transistor arrays(OOSTAs)are imperative.Here,we summarize the recent advances in OOSTAs.Various strategies for manufacturing OOSTAs are introduced,including coating and casting,physical vapor deposition,printing,and photolithography.Furthermore,innovative applications of the OOSTA system integration are discussed,including neuromor-phic visual systems and neuromorphic computing systems.At last,challenges and future perspectives of utilizing OOSTAs in real-world applications are discussed.
基金supported by the Hefei Comprehensive National Science Center Hefei Brain Project(to KW)the National Natural Science Foundation of China,Nos.31970979(to KW),82101498(to XW)the STI2030-Major Projects,No.2021ZD0201800(to PH).
文摘Alzheimer’s disease is a neurodegenerative disease resulting from deficits in synaptic transmission and homeostasis.The Alzheimer’s disease brain tends to be hyperexcitable and hypersynchronized,thereby causing neurodegeneration and ultimately disrupting the operational abilities in daily life,leaving patients incapacitated.Repetitive transcranial magnetic stimulation is a cost-effective,neuro-modulatory technique used for multiple neurological conditions.Over the past two decades,it has been widely used to predict cognitive decline;identify pathophysiological markers;promote neuroplasticity;and assess brain excitability,plasticity,and connectivity.It has also been applied to patients with dementia,because it can yield facilitatory effects on cognition and promote brain recovery after a neurological insult.However,its therapeutic effectiveness at the molecular and synaptic levels has not been elucidated because of a limited number of studies.This study aimed to characterize the neurobiological changes following repetitive transcranial magnetic stimulation treatment,evaluate its effects on synaptic plasticity,and identify the associated mechanisms.This review essentially focuses on changes in the pathology,amyloidogenesis,and clearance pathways,given that amyloid deposition is a major hypothesis in the pathogenesis of Alzheimer’s disease.Apoptotic mechanisms associated with repetitive transcranial magnetic stimulation procedures and different pathways mediating gene transcription,which are closely related to the neural regeneration process,are also highlighted.Finally,we discuss the outcomes of animal studies in which neuroplasticity is modulated and assessed at the structural and functional levels by using repetitive transcranial magnetic stimulation,with the aim to highlight future directions for better clinical translations.
基金supported by UniversitàCattolica(D1 intramural funds to RP)Italian Ministry of University and Research(PRIN 2022ZYLB7B,P2022YW7BP funds to CG).
文摘Several experimental evidence suggests a link between brain Herpes simplex virus type-1 infection and the occurrence of Alzheimer’s disease.However,the molecular mechanisms underlying this association are not completely understood.Among the molecular mediators of synaptic and cognitive dysfunction occurring after Herpes simplex virus type-1 infection and reactivation in the brain neuroinflammatory cytokines seem to occupy a central role.Here,we specifically reviewed literature reports dealing with the impact of neuroinflammation on synaptic dysfunction observed after recurrent Herpes simplex virus type-1 reactivation in the brain,highlighting the role of interleukins and,in particular,interleukin 1βas a possible target against Herpes simplex virus type-1-induced neuronal dysfunctions.
基金supported by the National Key R&D Program of China,No.2019YFE0121200(to LQZ)the National Natural Science Foundation of China,Nos.82325017(to LQZ),82030032(to LQZ),82261138555(to DL)+2 种基金the Natural Science Foundation of Hubei Province,No.2022CFA004(to LQZ)the Natural Science Foundation of Jiangxi Province,No.20224BAB206040(to XZ)Research Project of Cognitive Science and Transdisciplinary Studies Center of Jiangxi Province,No.RZYB202201(to XZ).
文摘With an increase in global aging,the number of people affected by cerebrovascular diseases is also increasing,and the incidence of vascular dementia-closely related to cerebrovascular risk-is increasing at an epidemic rate.However,few therapeutic options exist that can markedly improve the cognitive impairment and prognosis of vascular dementia patients.Similarly in Alzheimer’s disease and other neurological disorders,synaptic dysfunction is recognized as the main reason for cognitive decline.Nitric oxide is one of the ubiquitous gaseous cellular messengers involved in multiple physiological and pathological processes of the central nervous system.Recently,nitric oxide has been implicated in regulating synaptic plasticity and plays an important role in the pathogenesis of vascular dementia.This review introduces in detail the emerging role of nitric oxide in physiological and pathological states of vascular dementia and summarizes the diverse effects of nitric oxide on different aspects of synaptic dysfunction,neuroinflammation,oxidative stress,and blood-brain barrier dysfunction that underlie the progress of vascular dementia.Additionally,we propose that targeting the nitric oxide-sGC-cGMP pathway using certain specific approaches may provide a novel therapeutic strategy for vascular dementia.
基金supported by grants from the National Natural Science Foundation of China(31970957 and 31471078)the Shanghai Science and Technology Commission(19ZR1416600)a 2021-JCJQ-JJ-1089 fund.
文摘Learning-associated functional plasticity at hippocampal synapses remains largely unexplored. Here, in a single session of reward-based trace conditioning, we examine learning-induced synaptic plasticity in the dorsal CA1 hippocampus (dCA1). Local field-potential recording combined with selective optogenetic inhibition first revealed an increase of dCA1 synaptic responses to the conditioned stimulus (CS) induced during conditioning at both Schaffer collaterals to the stratum radiatum (Rad) and temporoammonic input to the lacunosum moleculare (LMol). At these dCA1 inputs, synaptic potentiation of CS-responding excitatory synapses was further demonstrated by locally blocking NMDA receptors during conditioning and whole-cell recording sensory-evoked synaptic responses in dCA1 neurons from naive animals. An overall similar time course of the induction of synaptic potentiation was found in the Rad and LMol by multiple-site recording;this emerged later and saturated earlier than conditioned behavioral responses. Our experiments demonstrate a cued memory-associated dCA1 synaptic plasticity induced at both Schaffer collaterals and temporoammonic pathways.
基金financial support by the self-supporting project of Pazhou Lab(No.PZL2023ZZ0011)by National Key R&D Program of China(No.2019YFA0904801).
文摘Rapid development of artificial intelligence requires the implementation of hardware systems with bioinspired parallel information processing and presentation and energy efficiency.Electrolyte-gated organic transistors(EGOTs)offer significant advantages as neuromorphic devices due to their ultra-low operation voltages,minimal hardwired connectivity,and similar operation environment as electrophysiology.Meanwhile,ionic–electronic coupling and the relatively low elastic moduli of organic channel materials make EGOTs suitable for interfacing with biology.This review presents an overview of the device architectures based on organic electrochemical transistors and organic field-effect transistors.Furthermore,we review the requirements of low energy consumption and tunable synaptic plasticity of EGOTs in emulating biological synapses and how they are affected by the organic materials,electrolyte,architecture,and operation mechanism.In addition,we summarize the basic operation principle of biological sensory systems and the recent progress of EGOTs as a building block in artificial systems.Finally,the current challenges and future development of the organic neuromorphic devices are discussed.
基金supported by grants from the State Key Program of the National Natural Science Foundation of China(grant number 82030064)Beijing Hospital Authority Youth Program(grant number QML20230812)+2 种基金Research and Development Foundation of Capital Medical University(grant number PYZ23052)National Natural Science Youth Cultivation Project of Xuanwu Hospital,Capital Medical University(grant number QNPY202317)Capital Medical University Research and Cultivation Fund(grant number PYZ23049).
文摘Objective To reveal the effects and potential mechanisms by which synaptic vesicle glycoprotein 2A(SV2A)influences the distribution of amyloid precursor protein(APP)in the trans-Golgi network(TGN),endolysosomal system,and cell membranes and to reveal the effects of SV2A on APP amyloid degradation.Methods Colocalization analysis of APP with specific tagged proteins in the TGN,ensolysosomal system,and cell membrane was performed to explore the effects of SV2A on the intracellular transport of APP.APP,β-site amyloid precursor protein cleaving enzyme 1(BACE1)expressions,and APP cleavage products levels were investigated to observe the effects of SV2A on APP amyloidogenic processing.Results APP localization was reduced in the TGN,early endosomes,late endosomes,and lysosomes,whereas it was increased in the recycling endosomes and cell membrane of SV2A-overexpressed neurons.Moreover,Arl5b(ADP-ribosylation factor 5b),a protein responsible for transporting APP from the TGN to early endosomes,was upregulated by SV2A.SV2A overexpression also decreased APP transport from the cell membrane to early endosomes by downregulating APP endocytosis.In addition,products of APP amyloid degradation,including sAPPβ,Aβ1-42,and Aβ1-40,were decreased in SV2A-overexpressed cells.Conclusion These results demonstrated that SV2A promotes APP transport from the TGN to early endosomes by upregulating Arl5b and promoting APP transport from early endosomes to recycling endosomes-cell membrane pathway,which slows APP amyloid degradation.
基金supported by the Natural Science Foundation of China(32394032,82201699,and 82221001)the Natural Science Foundation of Zhejiang Province(LTGD24H250001)+1 种基金the Kay R&D Program of Shaanxi Province(2023-YBSF-093),the Young Talent Fund of University Association for Science and Technology in Shaanxi(20220306)the Joint Founding Project of Innovation Research Institute,Xijing Hospital(LHJJ24JH02).
文摘Autism Spectrum Disorder(ASD)is marked by early-onset neurodevelopmental anomalies,yet the tem-poral dynamics of genetic contributions to these processes remain insufficiently understood.This study aimed to elu-cidate the role of the Shank3 gene,known to be associated with monogenic causes of autism,in early developmental processes to inform the timing and mechanisms for poten-tial interventions for ASD.Utilizing the Shank3B knockout(KO)mouse model,we examined Shank3 expression and its impact on neuronal maturation through Golgi staining for dendritic morphology and electrophysiological recordings to measure synaptic function in the anterior cingulate cortex(ACC)across different postnatal stages.Our longitudinal analysis revealed that,while Shank3B KO mice displayed normal neuronal morphology at one week postnatal,signifi-cant impairments in dendritic growth and synaptic activity emerged by two to three weeks.These findings highlight the critical developmental window during which Shank3 is essential for neuronal and synaptic maturation in the ACC.
基金supported by the National Key Research and Development program of China (Nos. 2024YFA1410700 and 2021YFA1200700)the National Natural Science Foundation of China (Nos. T2222025, 62174053, 62474065 and 52372120)+3 种基金the Natural Science Foundation of Chongqing (CSTB2024NSCQ-JQX0005)the Shanghai Science and Technology Innovation Action Plan (Nos. 24QA2702300 and 24YF2710400)the National Postdoctoral Program (GZB20240225)the Fundamental Research Funds for the Central Universities。
文摘Poly(vinylidene-trifluoroethylene) [P(VDF-TrFE)] copolymer films generally demonstrate limited compatibility with organic semiconductors. The material is frequently compromised by exposure to organic semiconductor solutions and other fabrication processes utilized in the production of organic ferroelectric transistors. In this study, an organic ferroelectric field effect transistor(OFeFET) with the 6,13-Bis(triisopropylsilylethynyl) pentacene(TIPS-pentacene) channel is fabricated, in which the aluminum oxide(Al_(2)O_(3)) interlayer is used to improve compatibility. The device displays polymorphic memory and synaptic plasticity of long-term potentiation and depression. Furthermore, an artificial neural network constructed using our devices is simulated to succeed in recognizing the MNIST handwritten digit database with a high accuracy of 92.8%. This research offers a viable approach to enhance the compatibility of the organic ferroelectric polymer P(VDF-TrFE) with organic semiconductors.
基金financially supported by the Key Research Program of Frontier Sciences,CAS (No. ZDBS-LYJSC034)National Natural Science Foundation of China (No.62174172)+2 种基金China Postdoctoral Science Foundation (Nos.2023TQ0238 and 2023M742560)Basic Research Pilot Project of Suzhou (No. SSD2024003)Jiangsu Key Disciplines of the Fourteenth Five-Year Plan (No. 2021135)
文摘Synaptic nano-devices have powerful capabilities in logic,memory and learning,making them essential compo-nents for constructing brain-like neuromorphic computing systems.Here,we have successfully developed and demonstrated a synaptic nano-device based on Ga_(2)O_(3) nanowires with low energy consumption.Under 255 nm light stimulation,the biomimetic synaptic nano-device can stimulate various functionalities of biological synapses,including pulse facilitation,peak time-dependent plasticity and memory learning ability.It is found that the artificial synaptic device based on Ga_(2)O_(3) nanowires can achieve an excellent"learning-forgetting-relearning"functionality.The transition from short-term memory to long-term memory and retention of the memory level after the stepwise learning can attribute to the great relearning functionality of Ga_(2)O_(3) nanowires.Furthermore,the energy consumption of the synaptic nano-device can be lower than 2.39×10^(-11) J for a synaptic event.Moreover,our device demonstrates exceptional stability in long-term stimulation and storage.In the applica-tion of neural morphological computation,the accuracy of digit recognition exceeds 90%after 12 training sessions,indicating the strong learning capability of the cognitive system composed of this synaptic nano-device.Therefore,our work paves an effective way for advancing hardware-based neural morphological computation and artificial intelligence systems requiring low power consumption.
基金supported by the National Natural Science Foundation of ChinaNo.32200778(to QC)+5 种基金the Natural Science Foundation of Jiangsu ProvinceNo.BK20220494(to QC)Suzhou Medical and Health Technology Innovation ProjectNo.SKY2022107(to QC)a grant from the Clinical Research Center of Neurological Disease in The Second Affiliated Hospital of Soochow UniversityNos.ND2022A04(to QC)and ND2023B06(to JS)。
文摘Microglia are the main non-neuronal cells in the central nervous system that have important roles in brain development and functional connectivity of neural circuits.In brain physiology,highly dynamic microglial processes are facilitated to sense the surrounding environment and stimuli.Once the brain switches its functional states,microglia are recruited to specific sites to exert their immune functions,including the release of cytokines and phagocytosis of cellular debris.The crosstalk of microglia between neurons,neural stem cells,endothelial cells,oligodendrocytes,and astrocytes contributes to their functions in synapse pruning,neurogenesis,vascularization,myelination,and blood-brain barrier permeability.In this review,we highlight the neuron-derived“find-me,”“eat-me,”and“don't eat-me”molecular signals that drive microglia in response to changes in neuronal activity for synapse refinement during brain development.This review reveals the molecular mechanism of neuron-microglia interaction in synaptic pruning and presents novel ideas for the synaptic pruning of microglia in disease,thereby providing important clues for discovery of target drugs and development of nervous system disease treatment methods targeting synaptic dysfunction.
基金National Natural Science Foundation of China(Grant No.:82374317)State Key Program of National Natural Science of China(Grant Nos.:82130119 and 82130118)+4 种基金Postdoctoral Research Foundation of China(Grant No.:2021M690450)Traditional Chinese Medicine Research Project of Health Commission of Hubei Province(Grant No.:ZY2021M017)Hubei University of Chinese Medicine Funds for Distinguished Young Scholars(Grant No.:2022ZZXJ004)National Natural Science Foundation of China(Grant No.:82174210)Fundamental Research Funds for the Central Public Welfare Research Institutes(Grant No.:ZZ14-FL-005).
文摘Emerging research suggests a potential association of progression of Alzheimer's disease(AD)with alterations in synaptic currents and mitochondrial dynamics.However,the specific associations between these pathological changes remain unclear.In this study,we utilized Aβ42-induced AD rats and primary neural cells as in vivo and in vitro models.The investigations included behavioural tests,brain magnetic resonance imaging(MRI),liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)analysis,Nissl staining,thioflavin-S staining,enzyme-linked immunosorbent assay,Golgi-Cox staining,transmission electron microscopy(TEM),immunofluorescence staining,proteomics,adenosine triphosphate(ATP)detection,mitochondrial membrane potential(MMP)and reactive oxygen species(ROS)assessment,mitochondrial morphology analysis,electrophysiological studies,Western blotting,and molecular docking.The results revealed changes in synaptic currents,mitophagy,and mitochondrial dynamics in the AD models.Remarkably,intervention with Dengzhan Shengmai(DZSM)capsules emerged as a pivotal element in this investigation.Aβ42-induced synaptic dysfunction was significantly mitigated by DZSM intervention,which notably amplified the frequency and amplitude of synaptic transmission.The cognitive impairment observed in AD rats was ameliorated and accompanied by robust protection against structural damage in key brain regions,including the hippocampal CA3,primary cingular cortex,prelimbic system,and dysgranular insular cortex.DZSM intervention led to increased IDE levels,augmented long-term potential(LTP)amplitude,and enhanced dendritic spine density and length.Moreover,DZSM intervention led to favourable changes in mitochondrial parameters,including ROS expression,MMP and ATP contents,and mitochondrial morphology.In conclusion,our findings delved into the realm of altered synaptic currents,mitophagy,and mitochondrial dynamics in AD,concurrently highlighting the therapeutic potential of DZSM intervention.
文摘Parkinson's disease is characterized by the selective degeneration of dopamine neurons in the nigrostriatal pathway and dopamine deficiency in the striatum.The precise reasons behind the specific degeneration of these dopamine neurons remain largely elusive.Genetic investigations have identified over 20 causative PARK genes and 90 genomic risk loci associated with both familial and sporadic Parkinson's disease.Notably,several of these genes are linked to the synaptic vesicle recycling process,particularly the clathrinmediated endocytosis pathway.This suggests that impaired synaptic vesicle recycling might represent an early feature of Parkinson's disease,followed by axonal degeneration and the eventual loss of dopamine cell bodies in the midbrain via a"dying back"mechanism.Recently,several new animal and cellular models with Parkinson's disease-linked mutations affecting the endocytic pathway have been created and extensively characterized.These models faithfully recapitulate certain Parkinson's disease-like features at the animal,circuit,and cellular levels,and exhibit defects in synaptic membrane trafficking,further supporting the findings from human genetics and clinical studies.In this review,we will first summarize the cellular and molecular findings from the models of two Parkinson's disease-linked clathrin uncoating proteins:auxilin(DNAJC6/PARK19)and synaptojanin 1(SYNJ1/PARK20).The mouse models carrying these two PARK gene mutations phenocopy each other with specific dopamine terminal pathology and display a potent synergistic effect.Subsequently,we will delve into the involvement of several clathrin-mediated endocytosis-related proteins(GAK,endophilin A1,SAC2/INPP5 F,synaptotagmin-11),identified as Parkinson's disease risk factors through genome-wide association studies,in Parkinson's disease pathogenesis.We will also explore the direct or indirect roles of some common Parkinson's disease-linked proteins(alpha-synuclein(PARK1/4),Parkin(PARK2),and LRRK2(PARK8))in synaptic endocytic trafficking.Additionally,we will discuss the emerging novel functions of these endocytic proteins in downstream membrane traffic pathways,particularly autophagy.Given that synaptic dysfunction is considered as an early event in Parkinson's disease,a deeper understanding of the cellular mechanisms underlying synaptic vesicle endocytic trafficking may unveil novel to rgets for early diagnosis and the development of interventional therapies for Parkinson's disease.Future research should aim to elucidate why generalized synaptic endocytic dysfunction leads to the selective degeneration of nigrostriatal dopamine neurons in Parkinson's disease.
