Spiking neural network(SNN),widely known as the third-generation neural network,has been frequently investigated due to its excellent spatiotemporal information processing capability,high biological plausibility,and l...Spiking neural network(SNN),widely known as the third-generation neural network,has been frequently investigated due to its excellent spatiotemporal information processing capability,high biological plausibility,and low energy consumption characteristics.Analogous to the working mechanism of human brain,the SNN system transmits information through the spiking action of neurons.Therefore,artificial neurons are critical building blocks for constructing SNN in hardware.Memristors are drawing growing attention due to low consumption,high speed,and nonlinearity characteristics,which are recently introduced to mimic the functions of biological neurons.Researchers have proposed multifarious memristive materials including organic materials,inorganic materials,or even two-dimensional materials.Taking advantage of the unique electrical behavior of these materials,several neuron models are successfully implemented,such as Hodgkin–Huxley model,leaky integrate-and-fire model and integrate-and-fire model.In this review,the recent reports of artificial neurons based on memristive devices are discussed.In addition,we highlight the models and applications through combining artificial neuronal devices with sensors or other electronic devices.Finally,the future challenges and outlooks of memristor-based artificial neurons are discussed,and the development of hardware implementation of brain-like intelligence system based on SNN is also prospected.展开更多
Dynamical modeling of neural systems plays an important role in explaining and predicting some features of biophysical mechanisms.The electrophysiological environment inside and outside of the nerve cell is different....Dynamical modeling of neural systems plays an important role in explaining and predicting some features of biophysical mechanisms.The electrophysiological environment inside and outside of the nerve cell is different.Due to the continuous and periodical properties of electromagnetic fields in the cell during its operation,electronic components involving two capacitors and a memristor are effective in mimicking these physical features.In this paper,a neural circuit is reconstructed by two capacitors connected by a memristor with periodical mem-conductance.It is found that the memristive neural circuit can present abundant firing patterns without stimulus.The Hamilton energy function is deduced using the Helmholtz theorem.Further,a neuronal network consisting of memristive neurons is proposed by introducing energy coupling.The controllability and flexibility of parameters give the model the ability to describe the dynamics and synchronization behavior of the system.展开更多
Rare neurological diseases,while individually are rare,collectively impact millions globally,leading to diverse and often severe neurological symptoms.Often attributed to genetic mutations that disrupt protein functio...Rare neurological diseases,while individually are rare,collectively impact millions globally,leading to diverse and often severe neurological symptoms.Often attributed to genetic mutations that disrupt protein function or structure,understanding their genetic basis is crucial for accurate diagnosis and targeted therapies.To investigate the underlying pathogenesis of these conditions,researchers often use non-mammalian model organisms,such as Drosophila(fruit flies),which is valued for their genetic manipulability,cost-efficiency,and preservation of genes and biological functions across evolutionary time.Genetic tools available in Drosophila,including CRISPR-Cas9,offer a means to manipulate gene expression,allowing for a deep exploration of the genetic underpinnings of rare neurological diseases.Drosophila boasts a versatile genetic toolkit,rapid generation turnover,and ease of large-scale experimentation,making it an invaluable resource for identifying potential drug candidates.Researchers can expose flies carrying disease-associated mutations to various compounds,rapidly pinpointing promising therapeutic agents for further investigation in mammalian models and,ultimately,clinical trials.In this comprehensive review,we explore rare neurological diseases where fly research has significantly contributed to our understanding of their genetic basis,pathophysiology,and potential therapeutic implications.We discuss rare diseases associated with both neuron-expressed and glial-expressed genes.Specific cases include mutations in CDK19 resulting in epilepsy and developmental delay,mutations in TIAM1 leading to a neurodevelopmental disorder with seizures and language delay,and mutations in IRF2BPL causing seizures,a neurodevelopmental disorder with regression,loss of speech,and abnormal movements.And we explore mutations in EMC1 related to cerebellar atrophy,visual impairment,psychomotor retardation,and gain-of-function mutations in ACOX1 causing Mitchell syndrome.Loss-of-function mutations in ACOX1 result in ACOX1 deficiency,characterized by very-long-chain fatty acid accumulation and glial degeneration.Notably,this review highlights how modeling these diseases in Drosophila has provided valuable insights into their pathophysiology,offering a platform for the rapid identification of potential therapeutic interventions.Rare neurological diseases involve a wide range of expression systems,and sometimes common phenotypes can be found among different genes that cause abnormalities in neurons or glia.Furthermore,mutations within the same gene may result in varying functional outcomes,such as complete loss of function,partial loss of function,or gain-of-function mutations.The phenotypes observed in patients can differ significantly,underscoring the complexity of these conditions.In conclusion,Drosophila represents an indispensable and cost-effective tool for investigating rare neurological diseases.By facilitating the modeling of these conditions,Drosophila contributes to a deeper understanding of their genetic basis,pathophysiology,and potential therapies.This approach accelerates the discovery of promising drug candidates,ultimately benefiting patients affected by these complex and understudied diseases.展开更多
Amyotrophic lateral sclerosis is a rare neurodegenerative disease characterized by the involvement of both upper and lower motor neurons.Early bilateral limb involvement significantly affects patients'daily lives ...Amyotrophic lateral sclerosis is a rare neurodegenerative disease characterized by the involvement of both upper and lower motor neurons.Early bilateral limb involvement significantly affects patients'daily lives and may lead them to be confined to bed.However,the effect of upper and lower motor neuron impairment and other risk factors on bilateral limb involvement is unclear.To address this issue,we retrospectively collected data from 586 amyotrophic lateral sclerosis patients with limb onset diagnosed at Peking University Third Hospital between January 2020 and May 2022.A univariate analysis revealed no significant differences in the time intervals of spread in different directions between individuals with upper motor neuron-dominant amyotrophic lateral sclerosis and those with classic amyotrophic lateral sclerosis.We used causal directed acyclic graphs for risk factor determination and Cox proportional hazards models to investigate the association between the duration of bilateral limb involvement and clinical baseline characteristics in amyotrophic lateral sclerosis patients.Multiple factor analyses revealed that higher upper motor neuron scores(hazard ratio[HR]=1.05,95%confidence interval[CI]=1.01–1.09,P=0.018),onset in the left limb(HR=0.72,95%CI=0.58–0.89,P=0.002),and a horizontal pattern of progression(HR=0.46,95%CI=0.37–0.58,P<0.001)were risk factors for a shorter interval until bilateral limb involvement.The results demonstrated that a greater degree of upper motor neuron involvement might cause contralateral limb involvement to progress more quickly in limb-onset amyotrophic lateral sclerosis patients.These findings may improve the management of amyotrophic lateral sclerosis patients with limb onset and the prediction of patient prognosis.展开更多
The minimal two-dimensional model of bursting neuronal dynamics is used to study the influence of time-delay on the properties of synchronization of bursting neurons. Generic properties of bursting and dependence of t...The minimal two-dimensional model of bursting neuronal dynamics is used to study the influence of time-delay on the properties of synchronization of bursting neurons. Generic properties of bursting and dependence of the stability of synchronization on the time-lag and the strength of coupling are described, and compared with the two common types of synaptical coupling, i.e., time-delayed chemical and electrical synapses.展开更多
Object:Early-life neglect has irreversible emotional effects on the central nervous system.In this work,we aimed to elucidate distinct functional neural changes in me-dial prefrontal cortex(mPFC)of model rats.Methods:...Object:Early-life neglect has irreversible emotional effects on the central nervous system.In this work,we aimed to elucidate distinct functional neural changes in me-dial prefrontal cortex(mPFC)of model rats.Methods:Maternal separation with early weaning was used as a rat model of early-life neglect.The excitation of glutamatergic and GABAergic neurons in rat mPFC was recorded and analyzed by whole-cell patch clamp.Results:Glutamatergic and GABAergic neurons of mPFC were distinguished by typi-cal electrophysiological properties.The excitation of mPFC glutamatergic neurons was significantly increased in male groups,while the excitation of mPFC GABAergic neurons was significant in both female and male groups,but mainly in terms of rest membrane potential and amplitude,respectively.Conclusions:Glutamatergic and GABAergic neurons in medial prefrontal cortex showed different excitability changes in a rat model of early-life neglect,which can contribute to distinct mechanisms for emotional and cognitive manifestations.展开更多
Traumatic brain injury (TBI) is a mechanical injury to brain tissue that leads to an impairment of function and a broad spectrum of symptoms and disabilities; often, it is followed by diffuse axonal injury, which ca...Traumatic brain injury (TBI) is a mechanical injury to brain tissue that leads to an impairment of function and a broad spectrum of symptoms and disabilities; often, it is followed by diffuse axonal injury, which causes denaturation of the white matter and axon retraction, leaving patients with severe brain damage or even in a persistent vegetative state.展开更多
The present study revealed the stimulatory effects of NMDA on intracellular ca 2+ concentration in rat dorsal root ganglion (DRG) neurons. Fura 3/AM, an intracellular calcium fluorescent indicator was used to monitor ...The present study revealed the stimulatory effects of NMDA on intracellular ca 2+ concentration in rat dorsal root ganglion (DRG) neurons. Fura 3/AM, an intracellular calcium fluorescent indicator was used to monitor the fluctuation of 〔ca 2+ 〕 i. Here we present the evidence that (1) Confocal microscopy resolved the cells of three different sizes, based on which a cell diameter distribution histogram was drawn. The fluorescence signals originated from the cells of different sizes, small size (diameter<30μm), medium size (diameter between 30 to 50μm),and large size (diameter>50μm); presumably intracellular Ca 2+ concentration was different in the cells of different sizes. (2) The time related variation of fluorescence intensity was observed. In particular, the fluorescence intensity in 0 Ca 2+ bath solution was affected by the application of high ca 2+ solution. (3) In 0 ca 2+ bath solution the intracellular Ca 2+ concentration nonlinear properties of distinct diameter cells was described. (4) A kind of SETAR model was fitted with a medium sized cell.(5)The residuals from the fitted model were tested to see whether they were plausibly Gaussian. These findings indicated that in distinct types of cells intracellular Ca 2+ concentration had different characteristics in different DRG neurons, and contributed to different functions of these neurons. Besides, the established threshold autoregressive model can share intracellular ca 2+ with the main nonlinear kinetic展开更多
Introduction Neurons are situated in a microenvironment composed of various biochemical and biophysical cues,where stretching is thought to have a major impact on neurons.For instance,during a moderate traumatic brain...Introduction Neurons are situated in a microenvironment composed of various biochemical and biophysical cues,where stretching is thought to have a major impact on neurons.For instance,during a moderate traumatic brain impact,the injury region in axons exhibits significant longitudinal strain;and in a rat model of spinal cord injury,the most severe axonal injury is located in the largest strain region.Stretching may result in microstructural changes in neural tissue and further leading to abnormal electrophysiological function.Hence,it is of great importance to understand the coupled mechanoelectricalbehaviors of neurons under stretching.In spite of significant experimental efforts,the underlying mechanism remains elusive,more works are needed to provide a detailed description of the process that leads to the observed phenomena.Mathematical modeling is a powerful tool that offers a quantitative description of the underlying mechanism of an observed biological phenomenon,including mechanical and electrophysiological behaviors of neurons.Thus,we developed a mechanoelectrical coupling model of neurons under stretching in this study.Mathematical model The mathematical model consists of three submodels,i.e.,the mechanical submodel,the mechanoelectrical coupling submodel and the electrophysiological submodel.The mechanical submodel deals with the relationship between stretching and the deformation of axons,which has specially considered the plastic deformation of axons.The electrophysiological submodel characterizes the feature of neuronal action potential(AP),which is based on the classical H-H model and the cable theory.The mechanoelectrical coupling submodel links the mechanical and electrophysiological submodels through strain-induced equivalent circuit parameter alteration and ion channel injury.Besides,we have discussed a more general deformation condition,where an expanded model coupling the axonal deformation and electrophysiology alteration was explored.As the most essential parameters in an electrophysiological assessment,the amplitude of the AP,the neuronal firing frequency and the electrophysiological signal conduction velocity,which could be affected by stretching,were used as outputs of the model.Results&discussion To understand the mechanoelectrical coupling of neurons under stretching,we developed a mechanoelectrical coupling model.To verify the model,we simulated a slow stretching on an axon following the experimental study in the literature,we observed that as the strain increases,the peak AP declines faster,which is consistent with the experimental data.Moreover,the reduced AP cannot be restored to the original peak,implying that the damage is irreversible.The simulation results also predict that strain induces a more frequent neuronal firing and a faster conduction.In a realistic situation,in addition to stretching,the loading condition is very complicated,which may induce complex axonal deformation(e.g., necking and swelling along the axons).We also simulated such necking deformation impairment and observed that the AP amplitude decreases at the necking region and recovers after that,indicating a blockage of the AP;and the conduction velocity decreases with the increase in deformation degree.Conclusions In this study,we developed a mechanoelectrical coupling model of neurons under stretching with consideration of axonal plastic deformation.With the model,we found that the effect of mechanical loading on electrophysiology mainly manifests as decreased membrane AP amplitude,a more frequent neuronal firing and a faster electrophysiological signal conduction.The model predicts not only stretch-induced injury but also a more gene ral necking deformation case,which may someday be revealed in future by experiments,providing a reference for the prediction and regulation of neuronal function under mechanical loadings.展开更多
Objective: Neurons in the cochlear nucleus show different response patterns to the short tone bursts. Because of the limitations of animal experiments, it is hard to explore the principle. Therefore, using a model to ...Objective: Neurons in the cochlear nucleus show different response patterns to the short tone bursts. Because of the limitations of animal experiments, it is hard to explore the principle. Therefore, using a model to simulate CN neurons will be a feasible way. Methods: Based on the initial model mentioned in the previous study, we proposed an improved CN model in MATLAB R2012b. Results: By modifying the parameters of the model we found the interchanges among "primary-like", "chopper",and "onset" response patterns. Furthermore, we simulated the "pauser" response pattern by adding an extra input in our model. Conclusion: The results indicate that the synaptic integrations and the input modes can give rise to different characteristics of CN neurons, which eventually determine the response patterns of CN neurons.展开更多
AIM:To establish a rat model suitable to investigate the repetitive relapsing inflammations(RRI)characteristic to Crohn’s disease.METHODS:Colitis was induced by 2,4,6-trinitrobenzenesulfonic acid(TNBS).RRI were mimic...AIM:To establish a rat model suitable to investigate the repetitive relapsing inflammations(RRI)characteristic to Crohn’s disease.METHODS:Colitis was induced by 2,4,6-trinitrobenzenesulfonic acid(TNBS).RRI were mimicked by repeating administrations of TNBS.Tissue samples were taken from control,once,twice and three times treated rats from the inflamed and adjacent non-inflamed colonic segments at different timepoints during the acute intestinal inflammation.The means of the ulcerated area were measured to evaluate the macroscopic mu-cosal damage.The density of myenteric neurons was determined on whole mounts by Hu C/Hu D immunohistochemistry.Heme oxygenase-1(HO-1)expression was evaluated by molecular biological techniques.RESULTS:TNBS-treated rats displayed severe colitis,but the mortality was negligible,and an increase of body weight was characteristic throughout the experimental period.The widespread loss of myenteric neurons,and marked but transient HO-1 up-regulation were demonstrated after the first TNBS administration.After repeated doses the length of the recovery time and extent of the ulcerous colonic segments were markedly decreased,and the neuronal loss was on a smaller scale and was limited to the inflamed area.HO-1 m RNA level was notably greater than after a single dose and overexpression was sustained throughout the timepoints examined.Nevertheless,the HO-1protein up-regulation after the second TNBS treatment proved to be transient.Following the third treatment HO-1 protein expression could not be detected.CONCLUSION:Experimentally provoked RRI may exert a protective preconditioning effect against the mucosal and neuronal damage.The persistent up-regulation of HO-1 m RNA expression may correlate with this.展开更多
The ability to use induced pluripotent stem cells(i PSC)to model brain diseases is a powerful tool for unraveling mechanistic alterations in these disorders.Rodent models of brain diseases have spurred understanding...The ability to use induced pluripotent stem cells(i PSC)to model brain diseases is a powerful tool for unraveling mechanistic alterations in these disorders.Rodent models of brain diseases have spurred understanding of pathology but the concern arises that they may not recapitulate the full spectrum of neuron disruptions associated with human neuropathology.iPSC derived neurons,or other neural cell types,provide the ability to access pathology in cells derived directly from a patient's blood sample or skin biopsy where availability of brain tissue is limiting.Thus,utilization of iPSC to study brain diseases provides an unlimited resource for disease modelling but may also be used for drug screening for effective therapies and may potentially be used to regenerate aged or damaged cells in the future.Many brain diseases across the spectrum of neurodevelopment,neurodegenerative and neuropsychiatric are being approached by iPSC models.The goal of an iPSC based disease model is to identify a cellular phenotype that discriminates the disease-bearing cells from the control cells.In this mini-review,the importance of iPSC cell models validated for pluripotency,germline competency and function assessments is discussed.Selected examples for the variety of brain diseases that are being approached by iPSC technology to discover or establish the molecular basis of the neuropathology are discussed.展开更多
It is well known that the strong coupling can synchronize a network of nonlinear oscillators. Synchronization provides the basis of the remarkable computational performance of the brain. In this paper the FitzHugh-Nag...It is well known that the strong coupling can synchronize a network of nonlinear oscillators. Synchronization provides the basis of the remarkable computational performance of the brain. In this paper the FitzHugh-Nagumo neuron network is constructed. The dependence of the synchronization on the coupling strength, the noise intensity and the size of the neuron network has been discussed. The results indicate that the coupling among neurons works to improve the synchronization, and noise increases the neuron random dynamics and the local fluctuations; the larger the size of network, the worse the synchronization. The dependence of the synchronization on the strength of the electric synapse coupling and chemical synapse coupling has also been discussed, which proves that electric synapse coupling can enhance the synchronization of the neuron network largely.展开更多
Sim and Forger have proposed a mathematical model of circadian pacemaker neurons in the suprachiasmatic nucleus (SCN). This model, which has been formulated on the Hodgkin-Huxley mo-del, is described by a system of no...Sim and Forger have proposed a mathematical model of circadian pacemaker neurons in the suprachiasmatic nucleus (SCN). This model, which has been formulated on the Hodgkin-Huxley mo-del, is described by a system of nonlinear ordinary differential equations. An important feature of the SCN neurons observed in electrophysiological recording is spontaneous repetitive spiking, which is reproduced using this model. In the present study, numerical simulation analysis of this model was performed to evaluate variations in two system parameters of this model: the maximal conductance of calcium current (gCa) and the maximal conductance of sodium current (gNa). Simulation results revealed the spontaneous repetitive spiking states of the model in the (gCa, gNa)-pa-rameter space.展开更多
It has been proved recently that the spike timing can play an important role in information transmission, so in this paper we develop a network with N-unlt FitzHugh-Nagumo neurons coupled by gap junctions and discuss ...It has been proved recently that the spike timing can play an important role in information transmission, so in this paper we develop a network with N-unlt FitzHugh-Nagumo neurons coupled by gap junctions and discuss the dependence of the spike timing precision on synaptic coupling strength, the noise intensity and the size of the neuron ensemble. The calculated results show that the spike timing precision decreases as the noise intensity increases; and the ensemble spike timing precision increases with coupling strength increasing. The electric synapse coupling has a more important effect on the spike timing precision than the chemical synapse coupling.展开更多
A spike response model(SRM)based on the spikes generator circuit(SGC)of adaptive fuzzy spiking neurons(AFSNs)is developed.The SRM is simulated in MatlabTM environment.The proposed model is applied to a configuration o...A spike response model(SRM)based on the spikes generator circuit(SGC)of adaptive fuzzy spiking neurons(AFSNs)is developed.The SRM is simulated in MatlabTM environment.The proposed model is applied to a configuration of a fuzzy exclusive or(fuzzy XOR)operator,as an illustrative example.A description of the comparison of AFSNs with other similar methods is given.The novel method of the AFSNs is used to determine the value of the weights or parameters of the fuzzy XOR,first with dynamic weights or self-tuning parameters that adapt continuously,then with fixed weights obtained after training,finally with fixed weights and a dynamic gain or self-tuning gain for a fine adjustment of amplitude.展开更多
The main objective of this article is to obtain the new analytical and numerical solutions of fractional Fitzhugh-Nagumo equation which arises as a model of reaction-ifusion systems,transmission of nerve impulses,circ...The main objective of this article is to obtain the new analytical and numerical solutions of fractional Fitzhugh-Nagumo equation which arises as a model of reaction-ifusion systems,transmission of nerve impulses,circuit theory,biology and the area of population genetics.For this aim conformable derivative with fractional order which is a well behaved,understandable and applicable definition is used as a tool.The analytical solutions were got by utilizing the fact that the conformable fractional derivative provided the chain rule.By the help of this feature which is not provided by other popular fractional derivatives,nonlinear fractional partial differential equation is turned into an integer order differential equation.The numerical solutions which is obtained with the aid of residual power series method are compared with the analytical results that obtained by performing sub equation method.This comparison is made both with the help of three-dimensional graphical representations and tables for different values of theγ.展开更多
In this paper, we show a fixed point theorem which deduces to both of Lou’s fixed point theorem and de Pascale and de Pascale’s fixed point theorem. Moreover, our result can be applied to show the existence and uniq...In this paper, we show a fixed point theorem which deduces to both of Lou’s fixed point theorem and de Pascale and de Pascale’s fixed point theorem. Moreover, our result can be applied to show the existence and uniqueness of solutions for fractional differential equations with multiple delays. Using the theorem, we discuss the fractional chaos neuron model.展开更多
基金supported financially by the fund from the Ministry of Science and Technology of China(Grant No.2019YFB2205100)the National Science Fund for Distinguished Young Scholars(No.52025022)+3 种基金the National Nature Science Foundation of China(Grant Nos.U19A2091,62004016,51732003,52072065,1197407252272140 and 52372137)the‘111’Project(Grant No.B13013)the Fundamental Research Funds for the Central Universities(Nos.2412023YQ004 and 2412022QD036)the funding from Jilin Province(Grant Nos.20210201062GX,20220502002GH,20230402072GH,20230101017JC and 20210509045RQ)。
文摘Spiking neural network(SNN),widely known as the third-generation neural network,has been frequently investigated due to its excellent spatiotemporal information processing capability,high biological plausibility,and low energy consumption characteristics.Analogous to the working mechanism of human brain,the SNN system transmits information through the spiking action of neurons.Therefore,artificial neurons are critical building blocks for constructing SNN in hardware.Memristors are drawing growing attention due to low consumption,high speed,and nonlinearity characteristics,which are recently introduced to mimic the functions of biological neurons.Researchers have proposed multifarious memristive materials including organic materials,inorganic materials,or even two-dimensional materials.Taking advantage of the unique electrical behavior of these materials,several neuron models are successfully implemented,such as Hodgkin–Huxley model,leaky integrate-and-fire model and integrate-and-fire model.In this review,the recent reports of artificial neurons based on memristive devices are discussed.In addition,we highlight the models and applications through combining artificial neuronal devices with sensors or other electronic devices.Finally,the future challenges and outlooks of memristor-based artificial neurons are discussed,and the development of hardware implementation of brain-like intelligence system based on SNN is also prospected.
基金funded by the National Natural Science Foundation of China(Grant No.12302070)the Ningxia Science and Technology Leading Talent Training Program(Grant No.2022GKLRLX04)。
文摘Dynamical modeling of neural systems plays an important role in explaining and predicting some features of biophysical mechanisms.The electrophysiological environment inside and outside of the nerve cell is different.Due to the continuous and periodical properties of electromagnetic fields in the cell during its operation,electronic components involving two capacitors and a memristor are effective in mimicking these physical features.In this paper,a neural circuit is reconstructed by two capacitors connected by a memristor with periodical mem-conductance.It is found that the memristive neural circuit can present abundant firing patterns without stimulus.The Hamilton energy function is deduced using the Helmholtz theorem.Further,a neuronal network consisting of memristive neurons is proposed by introducing energy coupling.The controllability and flexibility of parameters give the model the ability to describe the dynamics and synchronization behavior of the system.
基金supported by Warren Alpert Foundation and Houston Methodist Academic Institute Laboratory Operating Fund(to HLC).
文摘Rare neurological diseases,while individually are rare,collectively impact millions globally,leading to diverse and often severe neurological symptoms.Often attributed to genetic mutations that disrupt protein function or structure,understanding their genetic basis is crucial for accurate diagnosis and targeted therapies.To investigate the underlying pathogenesis of these conditions,researchers often use non-mammalian model organisms,such as Drosophila(fruit flies),which is valued for their genetic manipulability,cost-efficiency,and preservation of genes and biological functions across evolutionary time.Genetic tools available in Drosophila,including CRISPR-Cas9,offer a means to manipulate gene expression,allowing for a deep exploration of the genetic underpinnings of rare neurological diseases.Drosophila boasts a versatile genetic toolkit,rapid generation turnover,and ease of large-scale experimentation,making it an invaluable resource for identifying potential drug candidates.Researchers can expose flies carrying disease-associated mutations to various compounds,rapidly pinpointing promising therapeutic agents for further investigation in mammalian models and,ultimately,clinical trials.In this comprehensive review,we explore rare neurological diseases where fly research has significantly contributed to our understanding of their genetic basis,pathophysiology,and potential therapeutic implications.We discuss rare diseases associated with both neuron-expressed and glial-expressed genes.Specific cases include mutations in CDK19 resulting in epilepsy and developmental delay,mutations in TIAM1 leading to a neurodevelopmental disorder with seizures and language delay,and mutations in IRF2BPL causing seizures,a neurodevelopmental disorder with regression,loss of speech,and abnormal movements.And we explore mutations in EMC1 related to cerebellar atrophy,visual impairment,psychomotor retardation,and gain-of-function mutations in ACOX1 causing Mitchell syndrome.Loss-of-function mutations in ACOX1 result in ACOX1 deficiency,characterized by very-long-chain fatty acid accumulation and glial degeneration.Notably,this review highlights how modeling these diseases in Drosophila has provided valuable insights into their pathophysiology,offering a platform for the rapid identification of potential therapeutic interventions.Rare neurological diseases involve a wide range of expression systems,and sometimes common phenotypes can be found among different genes that cause abnormalities in neurons or glia.Furthermore,mutations within the same gene may result in varying functional outcomes,such as complete loss of function,partial loss of function,or gain-of-function mutations.The phenotypes observed in patients can differ significantly,underscoring the complexity of these conditions.In conclusion,Drosophila represents an indispensable and cost-effective tool for investigating rare neurological diseases.By facilitating the modeling of these conditions,Drosophila contributes to a deeper understanding of their genetic basis,pathophysiology,and potential therapies.This approach accelerates the discovery of promising drug candidates,ultimately benefiting patients affected by these complex and understudied diseases.
基金supported by the National Natural Science Foundation of China,Nos.82071426,81873784Clinical Cohort Construction Program of Peking University Third Hospital,No.BYSYDL2019002(all to DF)。
文摘Amyotrophic lateral sclerosis is a rare neurodegenerative disease characterized by the involvement of both upper and lower motor neurons.Early bilateral limb involvement significantly affects patients'daily lives and may lead them to be confined to bed.However,the effect of upper and lower motor neuron impairment and other risk factors on bilateral limb involvement is unclear.To address this issue,we retrospectively collected data from 586 amyotrophic lateral sclerosis patients with limb onset diagnosed at Peking University Third Hospital between January 2020 and May 2022.A univariate analysis revealed no significant differences in the time intervals of spread in different directions between individuals with upper motor neuron-dominant amyotrophic lateral sclerosis and those with classic amyotrophic lateral sclerosis.We used causal directed acyclic graphs for risk factor determination and Cox proportional hazards models to investigate the association between the duration of bilateral limb involvement and clinical baseline characteristics in amyotrophic lateral sclerosis patients.Multiple factor analyses revealed that higher upper motor neuron scores(hazard ratio[HR]=1.05,95%confidence interval[CI]=1.01–1.09,P=0.018),onset in the left limb(HR=0.72,95%CI=0.58–0.89,P=0.002),and a horizontal pattern of progression(HR=0.46,95%CI=0.37–0.58,P<0.001)were risk factors for a shorter interval until bilateral limb involvement.The results demonstrated that a greater degree of upper motor neuron involvement might cause contralateral limb involvement to progress more quickly in limb-onset amyotrophic lateral sclerosis patients.These findings may improve the management of amyotrophic lateral sclerosis patients with limb onset and the prediction of patient prognosis.
基金Project supported by the Serbian Ministry of Science(Grant Nos.171017 and 174010)
文摘The minimal two-dimensional model of bursting neuronal dynamics is used to study the influence of time-delay on the properties of synchronization of bursting neurons. Generic properties of bursting and dependence of the stability of synchronization on the time-lag and the strength of coupling are described, and compared with the two common types of synaptical coupling, i.e., time-delayed chemical and electrical synapses.
基金CAMS Innovation Fund for Medical Sciences(CIFMS),Grant/Award Number:2021-I2M-1-034National Natural Science Foundation of China,Grant/Award Number:31970510Young Elite Scientist Sponsorship Program by CAST,Grant/Award Number:2019QNRC001。
文摘Object:Early-life neglect has irreversible emotional effects on the central nervous system.In this work,we aimed to elucidate distinct functional neural changes in me-dial prefrontal cortex(mPFC)of model rats.Methods:Maternal separation with early weaning was used as a rat model of early-life neglect.The excitation of glutamatergic and GABAergic neurons in rat mPFC was recorded and analyzed by whole-cell patch clamp.Results:Glutamatergic and GABAergic neurons of mPFC were distinguished by typi-cal electrophysiological properties.The excitation of mPFC glutamatergic neurons was significantly increased in male groups,while the excitation of mPFC GABAergic neurons was significant in both female and male groups,but mainly in terms of rest membrane potential and amplitude,respectively.Conclusions:Glutamatergic and GABAergic neurons in medial prefrontal cortex showed different excitability changes in a rat model of early-life neglect,which can contribute to distinct mechanisms for emotional and cognitive manifestations.
基金supported by grants from the Spanish Ministry of Economy and Competitivenessthe European Regional Development Fund 2007-2013(BFU2014-56300-P)+4 种基金the Xunta de Galicia(GPC2014/030)supported by a grant from the Xunta de Galicia(2016-PG008)a grant from the crowdfunding platform Precipita(FECYTSpanish Ministry of Economy and Competitivenessgrant number 2017-CP081)
文摘Traumatic brain injury (TBI) is a mechanical injury to brain tissue that leads to an impairment of function and a broad spectrum of symptoms and disabilities; often, it is followed by diffuse axonal injury, which causes denaturation of the white matter and axon retraction, leaving patients with severe brain damage or even in a persistent vegetative state.
文摘The present study revealed the stimulatory effects of NMDA on intracellular ca 2+ concentration in rat dorsal root ganglion (DRG) neurons. Fura 3/AM, an intracellular calcium fluorescent indicator was used to monitor the fluctuation of 〔ca 2+ 〕 i. Here we present the evidence that (1) Confocal microscopy resolved the cells of three different sizes, based on which a cell diameter distribution histogram was drawn. The fluorescence signals originated from the cells of different sizes, small size (diameter<30μm), medium size (diameter between 30 to 50μm),and large size (diameter>50μm); presumably intracellular Ca 2+ concentration was different in the cells of different sizes. (2) The time related variation of fluorescence intensity was observed. In particular, the fluorescence intensity in 0 Ca 2+ bath solution was affected by the application of high ca 2+ solution. (3) In 0 ca 2+ bath solution the intracellular Ca 2+ concentration nonlinear properties of distinct diameter cells was described. (4) A kind of SETAR model was fitted with a medium sized cell.(5)The residuals from the fitted model were tested to see whether they were plausibly Gaussian. These findings indicated that in distinct types of cells intracellular Ca 2+ concentration had different characteristics in different DRG neurons, and contributed to different functions of these neurons. Besides, the established threshold autoregressive model can share intracellular ca 2+ with the main nonlinear kinetic
基金financially supported by the National Natural Science Foundation of China ( 11522219, 11532009)the Projects of International ( Regional) Cooperation and Exchanges of NSFC ( 11761161004)+3 种基金the Natural Science Basic Research Plan in Shaanxi Province of China ( 2017JM1026,2017JM8097)the National Project Cultivating Foundation of Xi’an Medical University ( 2017GJFY23)Young Talent Support Plan of Shaanxi Provincethe China Postdoctoral Science Foundation ( 2018M631141,2018M631173)
文摘Introduction Neurons are situated in a microenvironment composed of various biochemical and biophysical cues,where stretching is thought to have a major impact on neurons.For instance,during a moderate traumatic brain impact,the injury region in axons exhibits significant longitudinal strain;and in a rat model of spinal cord injury,the most severe axonal injury is located in the largest strain region.Stretching may result in microstructural changes in neural tissue and further leading to abnormal electrophysiological function.Hence,it is of great importance to understand the coupled mechanoelectricalbehaviors of neurons under stretching.In spite of significant experimental efforts,the underlying mechanism remains elusive,more works are needed to provide a detailed description of the process that leads to the observed phenomena.Mathematical modeling is a powerful tool that offers a quantitative description of the underlying mechanism of an observed biological phenomenon,including mechanical and electrophysiological behaviors of neurons.Thus,we developed a mechanoelectrical coupling model of neurons under stretching in this study.Mathematical model The mathematical model consists of three submodels,i.e.,the mechanical submodel,the mechanoelectrical coupling submodel and the electrophysiological submodel.The mechanical submodel deals with the relationship between stretching and the deformation of axons,which has specially considered the plastic deformation of axons.The electrophysiological submodel characterizes the feature of neuronal action potential(AP),which is based on the classical H-H model and the cable theory.The mechanoelectrical coupling submodel links the mechanical and electrophysiological submodels through strain-induced equivalent circuit parameter alteration and ion channel injury.Besides,we have discussed a more general deformation condition,where an expanded model coupling the axonal deformation and electrophysiology alteration was explored.As the most essential parameters in an electrophysiological assessment,the amplitude of the AP,the neuronal firing frequency and the electrophysiological signal conduction velocity,which could be affected by stretching,were used as outputs of the model.Results&discussion To understand the mechanoelectrical coupling of neurons under stretching,we developed a mechanoelectrical coupling model.To verify the model,we simulated a slow stretching on an axon following the experimental study in the literature,we observed that as the strain increases,the peak AP declines faster,which is consistent with the experimental data.Moreover,the reduced AP cannot be restored to the original peak,implying that the damage is irreversible.The simulation results also predict that strain induces a more frequent neuronal firing and a faster conduction.In a realistic situation,in addition to stretching,the loading condition is very complicated,which may induce complex axonal deformation(e.g., necking and swelling along the axons).We also simulated such necking deformation impairment and observed that the AP amplitude decreases at the necking region and recovers after that,indicating a blockage of the AP;and the conduction velocity decreases with the increase in deformation degree.Conclusions In this study,we developed a mechanoelectrical coupling model of neurons under stretching with consideration of axonal plastic deformation.With the model,we found that the effect of mechanical loading on electrophysiology mainly manifests as decreased membrane AP amplitude,a more frequent neuronal firing and a faster electrophysiological signal conduction.The model predicts not only stretch-induced injury but also a more gene ral necking deformation case,which may someday be revealed in future by experiments,providing a reference for the prediction and regulation of neuronal function under mechanical loadings.
基金National Natural Science Foundation of Chinagrant number:31171059
文摘Objective: Neurons in the cochlear nucleus show different response patterns to the short tone bursts. Because of the limitations of animal experiments, it is hard to explore the principle. Therefore, using a model to simulate CN neurons will be a feasible way. Methods: Based on the initial model mentioned in the previous study, we proposed an improved CN model in MATLAB R2012b. Results: By modifying the parameters of the model we found the interchanges among "primary-like", "chopper",and "onset" response patterns. Furthermore, we simulated the "pauser" response pattern by adding an extra input in our model. Conclusion: The results indicate that the synaptic integrations and the input modes can give rise to different characteristics of CN neurons, which eventually determine the response patterns of CN neurons.
基金Supported by Hungarian Scientific Research Fund,No.OTKA PD 108309(to Bódi N)European Union and the State of Hungaryco-financed by the European Social Fund in the frame-work of TáMOP 4.2.4.A/2-11/1-2012-0001"National Excellence Program"
文摘AIM:To establish a rat model suitable to investigate the repetitive relapsing inflammations(RRI)characteristic to Crohn’s disease.METHODS:Colitis was induced by 2,4,6-trinitrobenzenesulfonic acid(TNBS).RRI were mimicked by repeating administrations of TNBS.Tissue samples were taken from control,once,twice and three times treated rats from the inflamed and adjacent non-inflamed colonic segments at different timepoints during the acute intestinal inflammation.The means of the ulcerated area were measured to evaluate the macroscopic mu-cosal damage.The density of myenteric neurons was determined on whole mounts by Hu C/Hu D immunohistochemistry.Heme oxygenase-1(HO-1)expression was evaluated by molecular biological techniques.RESULTS:TNBS-treated rats displayed severe colitis,but the mortality was negligible,and an increase of body weight was characteristic throughout the experimental period.The widespread loss of myenteric neurons,and marked but transient HO-1 up-regulation were demonstrated after the first TNBS administration.After repeated doses the length of the recovery time and extent of the ulcerous colonic segments were markedly decreased,and the neuronal loss was on a smaller scale and was limited to the inflamed area.HO-1 m RNA level was notably greater than after a single dose and overexpression was sustained throughout the timepoints examined.Nevertheless,the HO-1protein up-regulation after the second TNBS treatment proved to be transient.Following the third treatment HO-1 protein expression could not be detected.CONCLUSION:Experimentally provoked RRI may exert a protective preconditioning effect against the mucosal and neuronal damage.The persistent up-regulation of HO-1 m RNA expression may correlate with this.
文摘The ability to use induced pluripotent stem cells(i PSC)to model brain diseases is a powerful tool for unraveling mechanistic alterations in these disorders.Rodent models of brain diseases have spurred understanding of pathology but the concern arises that they may not recapitulate the full spectrum of neuron disruptions associated with human neuropathology.iPSC derived neurons,or other neural cell types,provide the ability to access pathology in cells derived directly from a patient's blood sample or skin biopsy where availability of brain tissue is limiting.Thus,utilization of iPSC to study brain diseases provides an unlimited resource for disease modelling but may also be used for drug screening for effective therapies and may potentially be used to regenerate aged or damaged cells in the future.Many brain diseases across the spectrum of neurodevelopment,neurodegenerative and neuropsychiatric are being approached by iPSC models.The goal of an iPSC based disease model is to identify a cellular phenotype that discriminates the disease-bearing cells from the control cells.In this mini-review,the importance of iPSC cell models validated for pluripotency,germline competency and function assessments is discussed.Selected examples for the variety of brain diseases that are being approached by iPSC technology to discover or establish the molecular basis of the neuropathology are discussed.
基金Project supported by the National Natural Science Foundation of China (Grant Nos 10645006 and 10747123)the Natural Science Foundation of Hebei Province (Grant Nos C2005000011and C2007000026)the Key Subject Construction Project of Hebei Provincial University
文摘It is well known that the strong coupling can synchronize a network of nonlinear oscillators. Synchronization provides the basis of the remarkable computational performance of the brain. In this paper the FitzHugh-Nagumo neuron network is constructed. The dependence of the synchronization on the coupling strength, the noise intensity and the size of the neuron network has been discussed. The results indicate that the coupling among neurons works to improve the synchronization, and noise increases the neuron random dynamics and the local fluctuations; the larger the size of network, the worse the synchronization. The dependence of the synchronization on the strength of the electric synapse coupling and chemical synapse coupling has also been discussed, which proves that electric synapse coupling can enhance the synchronization of the neuron network largely.
文摘Sim and Forger have proposed a mathematical model of circadian pacemaker neurons in the suprachiasmatic nucleus (SCN). This model, which has been formulated on the Hodgkin-Huxley mo-del, is described by a system of nonlinear ordinary differential equations. An important feature of the SCN neurons observed in electrophysiological recording is spontaneous repetitive spiking, which is reproduced using this model. In the present study, numerical simulation analysis of this model was performed to evaluate variations in two system parameters of this model: the maximal conductance of calcium current (gCa) and the maximal conductance of sodium current (gNa). Simulation results revealed the spontaneous repetitive spiking states of the model in the (gCa, gNa)-pa-rameter space.
基金Project supported by the National Natural Science Foundation of China (Grant Nos 10375016 and 10474018) and the Natural Science Foundation of Hebei Province (Grant Nos C2005000011and A2004000005) and the Key Subject Construction Project of Hebei Provincial University.
文摘It has been proved recently that the spike timing can play an important role in information transmission, so in this paper we develop a network with N-unlt FitzHugh-Nagumo neurons coupled by gap junctions and discuss the dependence of the spike timing precision on synaptic coupling strength, the noise intensity and the size of the neuron ensemble. The calculated results show that the spike timing precision decreases as the noise intensity increases; and the ensemble spike timing precision increases with coupling strength increasing. The electric synapse coupling has a more important effect on the spike timing precision than the chemical synapse coupling.
文摘A spike response model(SRM)based on the spikes generator circuit(SGC)of adaptive fuzzy spiking neurons(AFSNs)is developed.The SRM is simulated in MatlabTM environment.The proposed model is applied to a configuration of a fuzzy exclusive or(fuzzy XOR)operator,as an illustrative example.A description of the comparison of AFSNs with other similar methods is given.The novel method of the AFSNs is used to determine the value of the weights or parameters of the fuzzy XOR,first with dynamic weights or self-tuning parameters that adapt continuously,then with fixed weights obtained after training,finally with fixed weights and a dynamic gain or self-tuning gain for a fine adjustment of amplitude.
文摘The main objective of this article is to obtain the new analytical and numerical solutions of fractional Fitzhugh-Nagumo equation which arises as a model of reaction-ifusion systems,transmission of nerve impulses,circuit theory,biology and the area of population genetics.For this aim conformable derivative with fractional order which is a well behaved,understandable and applicable definition is used as a tool.The analytical solutions were got by utilizing the fact that the conformable fractional derivative provided the chain rule.By the help of this feature which is not provided by other popular fractional derivatives,nonlinear fractional partial differential equation is turned into an integer order differential equation.The numerical solutions which is obtained with the aid of residual power series method are compared with the analytical results that obtained by performing sub equation method.This comparison is made both with the help of three-dimensional graphical representations and tables for different values of theγ.
文摘In this paper, we show a fixed point theorem which deduces to both of Lou’s fixed point theorem and de Pascale and de Pascale’s fixed point theorem. Moreover, our result can be applied to show the existence and uniqueness of solutions for fractional differential equations with multiple delays. Using the theorem, we discuss the fractional chaos neuron model.