Transforming growth factor-beta 1(TGF-β1)has been extensively studied for its pleiotropic effects on central nervous system diseases.The neuroprotective or neurotoxic effects of TGF-β1 in specific brain areas may de...Transforming growth factor-beta 1(TGF-β1)has been extensively studied for its pleiotropic effects on central nervous system diseases.The neuroprotective or neurotoxic effects of TGF-β1 in specific brain areas may depend on the pathological process and cell types involved.Voltage-gated sodium channels(VGSCs)are essential ion channels for the generation of action potentials in neurons,and are involved in various neuroexcitation-related diseases.However,the effects of TGF-β1 on the functional properties of VGSCs and firing properties in cortical neurons remain unclear.In this study,we investigated the effects of TGF-β1 on VGSC function and firing properties in primary cortical neurons from mice.We found that TGF-β1 increased VGSC current density in a dose-and time-dependent manner,which was attributable to the upregulation of Nav1.3 expression.Increased VGSC current density and Nav1.3 expression were significantly abolished by preincubation with inhibitors of mitogen-activated protein kinase kinase(PD98059),p38 mitogen-activated protein kinase(SB203580),and Jun NH2-terminal kinase 1/2 inhibitor(SP600125).Interestingly,TGF-β1 significantly increased the firing threshold of action potentials but did not change their firing rate in cortical neurons.These findings suggest that TGF-β1 can increase Nav1.3 expression through activation of the ERK1/2-JNK-MAPK pathway,which leads to a decrease in the firing threshold of action potentials in cortical neurons under pathological conditions.Thus,this contributes to the occurrence and progression of neuroexcitatory-related diseases of the central nervous system.展开更多
Pain is often comorbid with emotional disorders such as anxiety and depression.Hyperexcitability of the anterior cingulate cortex has been implicated in pain and pain-related negative emotions that arise from impairme...Pain is often comorbid with emotional disorders such as anxiety and depression.Hyperexcitability of the anterior cingulate cortex has been implicated in pain and pain-related negative emotions that arise from impairments in inhibitory gamma-aminobutyric acid neurotransmission.This review primarily aims to outline the main circuitry(including the input and output connectivity)of the anterior cingulate cortex and classification and functions of different gamma-aminobutyric acidergic neurons;it also describes the neurotransmitters/neuromodulators affecting these neurons,their intercommunication with other neurons,and their importance in mental comorbidities associated with chronic pain disorders.Improving understanding on their role in pain-related mental comorbidities may facilitate the development of more effective treatments for these conditions.However,the mechanisms that regulate gamma-aminobutyric acidergic systems remain elusive.It is also unclear as to whether the mechanisms are presynaptic or postsynaptic.Further exploration of the complexities of this system may reveal new pathways for research and drug development.展开更多
Memristors have a synapse-like two-terminal structure and electrical properties,which are widely used in the construc-tion of artificial synapses.However,compared to inorganic materials,organic materials are rarely us...Memristors have a synapse-like two-terminal structure and electrical properties,which are widely used in the construc-tion of artificial synapses.However,compared to inorganic materials,organic materials are rarely used for artificial spiking synapses due to their relatively poor memrisitve performance.Here,for the first time,we present an organic memristor based on an electropolymerized dopamine-based memristive layer.This polydopamine-based memristor demonstrates the improve-ments in key performance,including a low threshold voltage of 0.3 V,a thin thickness of 16 nm,and a high parasitic capaci-tance of about 1μF·mm^(-2).By leveraging these properties in combination with its stable threshold switching behavior,we con-struct a capacitor-free and low-power artificial spiking neuron capable of outputting the oscillation voltage,whose spiking fre-quency increases with the increase of current stimulation analogous to a biological neuron.The experimental results indicate that our artificial spiking neuron holds potential for applications in neuromorphic computing and systems.展开更多
The progressive loss of dopaminergic neurons in affected patient brains is one of the pathological features of Parkinson's disease,the second most common human neurodegenerative disease.Although the detailed patho...The progressive loss of dopaminergic neurons in affected patient brains is one of the pathological features of Parkinson's disease,the second most common human neurodegenerative disease.Although the detailed pathogenesis accounting for dopaminergic neuron degeneration in Parkinson's disease is still unclear,the advancement of stem cell approaches has shown promise for Parkinson's disease research and therapy.The induced pluripotent stem cells have been commonly used to generate dopaminergic neurons,which has provided valuable insights to improve our understanding of Parkinson's disease pathogenesis and contributed to anti-Parkinson's disease therapies.The current review discusses the practical approaches and potential applications of induced pluripotent stem cell techniques for generating and differentiating dopaminergic neurons from induced pluripotent stem cells.The benefits of induced pluripotent stem cell-based research are highlighted.Various dopaminergic neuron differentiation protocols from induced pluripotent stem cells are compared.The emerging three-dimension-based brain organoid models compared with conventional two-dimensional cell culture are evaluated.Finally,limitations,challenges,and future directions of induced pluripotent stem cell–based approaches are analyzed and proposed,which will be significant to the future application of induced pluripotent stem cell-related techniques for Parkinson's disease.展开更多
Spike-based neural networks,which use spikes or action potentialsto represent information,have gained a lot of attention because of their high energyefficiency and low power consumption.To fully leverage its advantage...Spike-based neural networks,which use spikes or action potentialsto represent information,have gained a lot of attention because of their high energyefficiency and low power consumption.To fully leverage its advantages,convertingthe external analog signals to spikes is an essential prerequisite.Conventionalapproaches including analog-to-digital converters or ring oscillators,and sensorssuffer from high power and area costs.Recent efforts are devoted to constructingartificial sensory neurons based on emerging devices inspired by the biologicalsensory system.They can simultaneously perform sensing and spike conversion,overcoming the deficiencies of traditional sensory systems.This review summarizesand benchmarks the recent progress of artificial sensory neurons.It starts with thepresentation of various mechanisms of biological signal transduction,followed bythe systematic introduction of the emerging devices employed for artificial sensoryneurons.Furthermore,the implementations with different perceptual capabilitiesare briefly outlined and the key metrics and potential applications are also provided.Finally,we highlight the challenges and perspectives for the future development of artificial sensory neurons.展开更多
Objective:To anatomically and phenotypically characterize the insular cortex(IC)-nucleus tractus soli-tari(NTS)neural pathway.Methods:Adult male Sprague-Dawley rats were divided into three experimental cohorts for neu...Objective:To anatomically and phenotypically characterize the insular cortex(IC)-nucleus tractus soli-tari(NTS)neural pathway.Methods:Adult male Sprague-Dawley rats were divided into three experimental cohorts for neural circuit tracing.Anterograde labeling was achieved by injecting anterograde self-complementary adeno-associated viruses(scAAVs)into the IC.Retrograde tracing involved NTS injections of either retrograde scAAVs or FluoroGold(FG),combined with immunofluorescence histochemical staining to identify IC-originating projection neurons.For postsynaptic neurochemical phenotype characterization,IC was injected with AAV2/1-CaMKII-Cre,while a mixture of AAV2/9-Syn-DIO-mCherry and AAV2/9-VGAT1-EGFP was injected into the NTS.The rats were allowed to survive for one week following scAAVs or FG injection or four weeks after recombinase-dependent systems injection.Then the rats were sacrificed,and serial brain sections were prepared for immunofluorescence histochemical staining(brain section containing FG)and subsequent fluorescence/confocal microscopic analysis.Results:(1)Anterograde viral tracing re-vealed dense axonal terminals from the IC projecting to the medial subnucleus of the NTS,while retrograde tracing re-vealed that IC neurons projecting to the NTS were predominantly localized within the dysgranular layer;(2)IC-NTS projection neurons were exclusive glutamatergic(100%,n=3);(3)NTS neurons receiving IC inputs were mainly lo-calized in the medial subnucleus,and were predominantly GABAergic(79.8±3.2%,n=3).Conclusion:The pres-ent results indicate that a descending pathway from excitatory neurons of the IC terminates onto inhibitory neurons of the NTS,which might represent a potential neuromodulatory target for visceral pain disorders.展开更多
Unwarranted death of neurons is a major cause of neurodegenerative diseases.Since mature neurons are postmitotic and do not replicate,their death usually constitutes an irreversible step in pathology.A logical strateg...Unwarranted death of neurons is a major cause of neurodegenerative diseases.Since mature neurons are postmitotic and do not replicate,their death usually constitutes an irreversible step in pathology.A logical strategy to prevent neurodegeneration would then be to save all neurons that are still alive,i.e.protecting the ones that are still healthy as well as trying to rescue the ones that are damaged and in the process of dying.Regarding the latter,recent experiments have indicated that the possibility of reversing the cell death process and rescuing dying cells is more significant than previously anticipated.In many situations,the elimination of the cell death trigger alone enables dying cells to spontaneously repair their damage,recover,and survive.In this review,we explore the factors,which determine the fate of neurons engaged in the cell death process.A deeper insight into cell death mechanisms and the intrinsic capacity of cells to recover could pave the way for novel therapeutic approaches to neurodegenerative diseases.展开更多
Nonhuman primates are increasingly being used as animal models in neuroscience research.However,efficient neuronal tracing techniques for labeling motor neurons and primary sensory afferents in the monkey spinal cord ...Nonhuman primates are increasingly being used as animal models in neuroscience research.However,efficient neuronal tracing techniques for labeling motor neurons and primary sensory afferents in the monkey spinal cord are lacking.Here,by injecting the cholera toxin B subunit into the sciatic nerve of a rhesus monkey,we successfully labeled the motor neurons and primary sensory afferents in the lumbar and sacralspinal cord.Labeled alpha motor neurons were located in lamina IX of the L6–S1 segments,which innervate both flexors and extensors.The labeled primary sensory afferents were mainly myelinated Aβfibers that terminated mostly in laminae I and II of the L4–L7 segments.Together with the labeled proprioceptive afferents,the primary sensory afferents formed excitatory synapses with multiple types of spinal neurons.In summary,our methods successfully traced neuronal connections in the monkey spinal cord and can be used in spinal cord studies when nonhuman primates are used.展开更多
As traditional von Neumann architectures face limitations in handling the demands of big data and complex computa-tional tasks,neuromorphic computing has emerged as a promising alternative,inspired by the human brain&...As traditional von Neumann architectures face limitations in handling the demands of big data and complex computa-tional tasks,neuromorphic computing has emerged as a promising alternative,inspired by the human brain's neural networks.Volatile memristors,particularly Mott and diffusive memristors,have garnered significant attention for their ability to emulate neuronal dynamics,such as spiking and firing patterns,enabling the development of reconfigurable and adaptive computing systems.Recent advancements include the implementation of leaky integrate-and-fire neurons,Hodgkin-Huxley neurons,opto-electronic neurons,and time-surface neurons,all utilizing volatile memristors to achieve efficient,low-power,and highly inte-grated neuromorphic systems.This paper reviews the latest progress in volatile memristor-based artificial neurons,highlight-ing their potential for energy-efficient computing and integration with artificial synapses.We conclude by addressing chal-lenges such as improving memristor reliability and exploring new architectures to advance memristor-based neuromorphic com-puting.展开更多
Stromal interaction molecules(STIM)s are Ca^(2+)sensors in internal Ca^(2+)stores of the endoplasmic reticulum.They activate the store-operated Ca^(2+)channels,which are the main source of Ca^(2+)entry in non-excitabl...Stromal interaction molecules(STIM)s are Ca^(2+)sensors in internal Ca^(2+)stores of the endoplasmic reticulum.They activate the store-operated Ca^(2+)channels,which are the main source of Ca^(2+)entry in non-excitable cells.Moreover,STIM proteins interact with other Ca^(2+)channel subunits and active transporters,making STIMs an important intermediate molecule in orchestrating a wide variety of Ca^(2+)influxes into excitable cells.Nevertheless,little is known about the role of STIM proteins in brain functioning.Being involved in many signaling pathways,STIMs replenish internal Ca^(2+)stores in neurons and mediate synaptic transmission and neuronal excitability.Ca^(2+)dyshomeostasis is a signature of many pathological conditions of the brain,including neurodegenerative diseases,injuries,stroke,and epilepsy.STIMs play a role in these disturbances not only by supporting abnormal store-operated Ca^(2+)entry but also by regulating Ca^(2+)influx through other channels.Here,we review the present knowledge of STIMs in neurons and their involvement in brain pathology.展开更多
Erratum to:Current Medical Science 44(5):987–1000,2024 https://doi.org/10.1007/s11596-024-2908-9 In the originally published article,there was an error in the funding information.Instead of“Shenzhen Science and Tech...Erratum to:Current Medical Science 44(5):987–1000,2024 https://doi.org/10.1007/s11596-024-2908-9 In the originally published article,there was an error in the funding information.Instead of“Shenzhen Science and Technology Program(No.2021-22154)”,it should be corrected to“Shenzhen Science and Technology Program(No.JCYJ20210324111609024)”.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.展开更多
Epilepsy is a leading cause of disability and mortality worldwide. However, despite the availability of more than 20 antiseizure medications, more than one-third of patients continue to experience seizures. Given the ...Epilepsy is a leading cause of disability and mortality worldwide. However, despite the availability of more than 20 antiseizure medications, more than one-third of patients continue to experience seizures. Given the urgent need to explore new treatment strategies for epilepsy, recent research has highlighted the potential of targeting gliosis, metabolic disturbances, and neural circuit abnormalities as therapeutic strategies. Astrocytes, the largest group of nonneuronal cells in the central nervous system, play several crucial roles in maintaining ionic and energy metabolic homeostasis in neurons, regulating neurotransmitter levels, and modulating synaptic plasticity. This article briefly reviews the critical role of astrocytes in maintaining balance within the central nervous system. Building on previous research, we discuss how astrocyte dysfunction contributes to the onset and progression of epilepsy through four key aspects: the imbalance between excitatory and inhibitory neuronal signaling, dysregulation of metabolic homeostasis in the neuronal microenvironment, neuroinflammation, and the formation of abnormal neural circuits. We summarize relevant basic research conducted over the past 5 years that has focused on modulating astrocytes as a therapeutic approach for epilepsy. We categorize the therapeutic targets proposed by these studies into four areas: restoration of the excitation–inhibition balance, reestablishment of metabolic homeostasis, modulation of immune and inflammatory responses, and reconstruction of abnormal neural circuits. These targets correspond to the pathophysiological mechanisms by which astrocytes contribute to epilepsy. Additionally, we need to consider the potential challenges and limitations of translating these identified therapeutic targets into clinical treatments. These limitations arise from interspecies differences between humans and animal models, as well as the complex comorbidities associated with epilepsy in humans. We also highlight valuable future research directions worth exploring in the treatment of epilepsy and the regulation of astrocytes, such as gene therapy and imaging strategies. The findings presented in this review may help open new therapeutic avenues for patients with drugresistant epilepsy and for those suffering from other central nervous system disorders associated with astrocytic dysfunction.展开更多
The high-order cognitive and executive functions are necessary for an individual to survive.The densely bidirectional innervations between the medial prefrontal cortex(mPFC)and the mediodorsal thalamus(MD)play a vital...The high-order cognitive and executive functions are necessary for an individual to survive.The densely bidirectional innervations between the medial prefrontal cortex(mPFC)and the mediodorsal thalamus(MD)play a vital role in regulating high-order functions.Pyramidal neurons in mPFC have been classified into several subclasses according to their morphological and electrophysi-ological properties,but the properties of the input-specific pyramidal neurons in mPFC remain poorly understood.The present study aimed to profile the morphological and electrophysiological properties of mPFC pyramidal neurons innervated by MD.In the past,the studies for characterizing the morphological and electrophysiological properties of neurons mainly relied on the electrophysiological recording of a large number of neurons and their morphologic reconstructions.But,it is a low efficient method for characterizing the circuit-specific neurons.The present study combined the advantages of traditional morphological and electrophysiological methods with machine learning to address the shortcomings of the past method,to establish a classification model for the morphological and electrophysiological properties of mPFC pyramidal neurons,and to achieve more accurate and efficient identification of the properties from a small size sample of neurons.We labeled MD-innervated pyramidal neurons of mPFC using the trans-synaptic neural circuitry tracing method and obtained their morphological properties using whole-cell patch-clamp recording and morphologic reconstructions.The results showed that the classification model established in the present study could predict the electrophysiological properties of MD-innervated pyramidal neurons based on their morphology.MD-innervated pyramidal neurons exhibit larger basal dendritic length but lower apical dendrite complexity compared to non-MD-innervated neurons in the mPFC.The morphological characteristics of the two subtypes(ET-1 and ET-2)of mPFC pyramidal neurons innervated by MD are different,with the apical dendrites of ET-1 neurons being longer and more complex than those of ET-2 neurons.These results suggest that the electrophysiological properties of MD-innervated pyramidal neurons within mPFC correlate with their morphological properties,indicating that the different roles of these two subclasses in local circuits within PFC,as well as in PFC-cortical/subcortical brain region circuits.展开更多
With the rapid development of artificial intelligence(AI)technology,the demand for high-performance and energyefficient computing is increasingly growing.The limitations of the traditional von Neumann computing archit...With the rapid development of artificial intelligence(AI)technology,the demand for high-performance and energyefficient computing is increasingly growing.The limitations of the traditional von Neumann computing architecture have prompted researchers to explore neuromorphic computing as a solution.Neuromorphic computing mimics the working principles of the human brain,characterized by high efficiency,low energy consumption,and strong fault tolerance,providing a hardware foundation for the development of new generation AI technology.Artificial neurons and synapses are the two core components of neuromorphic computing systems.Artificial perception is a crucial aspect of neuromorphic computing,where artificial sensory neurons play an irreplaceable role thus becoming a frontier and hot topic of research.This work reviews recent advances in artificial sensory neurons and their applications.First,biological sensory neurons are briefly described.Then,different types of artificial neurons,such as transistor neurons and memristive neurons,are discussed in detail,focusing on their device structures and working mechanisms.Next,the research progress of artificial sensory neurons and their applications in artificial perception systems is systematically elaborated,covering various sensory types,including vision,touch,hearing,taste,and smell.Finally,challenges faced by artificial sensory neurons at both device and system levels are summarized.展开更多
During the process of organizing our original data,we unfortunately identified two error in the figures within our published article.In Fig.1,the online version incorrectly labels the SNI+NAC group as the sham+NAC gro...During the process of organizing our original data,we unfortunately identified two error in the figures within our published article.In Fig.1,the online version incorrectly labels the SNI+NAC group as the sham+NAC group.We have revised the grouping annotations in Fig.1 and have labeled the DHE staining in the figure to present the experimental design more clearly.展开更多
Background:Mesenchymal stem cells(MSCs)have shown great potential in treating neurodegenerative diseases,incuding Parkinson's disease(PD),due to their ability to differentiate into neurons and secrete neurotrophic...Background:Mesenchymal stem cells(MSCs)have shown great potential in treating neurodegenerative diseases,incuding Parkinson's disease(PD),due to their ability to differentiate into neurons and secrete neurotrophic factors.Genetic modification of MSCs for PD treatment has become a research focus.Methods:In this study,rat pulmonary mesenchymal stem cells(PMSCs)were transduced with lentiviral vectors carrying Lmxla/NeuroDI to establish genetically engineered PMSCs(LN-PMSCs)and induce their diferentiation into dopaminergic neurons.The LN-PMSCs were then transplanted into the right medial forebrain bundle region of PD model rats prepared using the 6-Hydroxydopamine(6-OHDA)method.Four weeks post-transplantation,the survival and diferentiation of the cells in the brain and motor function of the PD rats were evaluated.Results:The results showed that after 12 days of induction,the genetically modified LN-PMSCs had differentiated into a large number of dopaminergic neurons.Four weeks post-transplantation,these cells significantly improved motor dysfunction in PD rats and promoted the expression of neuron marker TUI,dopaminergic neuron markers FOXA2 and TH,gamma-aminobutyric acid-ergic(GABAergic)neuron marker GABA,astrocyte marker GFAP,presynaptic marker SYN,and postsynaptic marker PSD95 in the transplantation area.Conclusion:Our findings suggest that the gene-engineered PMSCs cell line overexpressing Lmxla and NeuroDI(LN-PMSCs)transplantation could be a potential therapeutic strategy for treating PD.展开更多
Parvalbumin-positive(PV^(+))interneuron dysfunction is believed to be linked to autism spectrum disorder(ASD),a neurodevelopmental disorder characterized by social deficits and stereotypical behaviors.However,the mech...Parvalbumin-positive(PV^(+))interneuron dysfunction is believed to be linked to autism spectrum disorder(ASD),a neurodevelopmental disorder characterized by social deficits and stereotypical behaviors.However,the mechanisms behind PV^(+)interneuron dysfunction remain largely unclear.Here,we found that a deficiency of Biorientation Defective 1(Bod1)in PV^(+)interneurons led to an ASD-like phenotype in Pvalb-Cre;Bod1f/f mice.Mechanistically,we observed that Bod1 deficiency induced hypoactivity of PV^(+)interneurons and hyperactivity of calcium/calmodulin-dependent protein kinaseⅡalpha(CaMKⅡα)neurons in the medial prefrontal cortex,as determined by whole-cell patch-clamp recording.Additionally,Bod1 deficiency decreased the power of highgamma oscillation,assessed by in vivo multi-channel electrophysiological recording.Furthermore,we found that Bod1 deficiency enhanced the inwardly rectifying K^(+)current,leading to an increase in the resting membrane potential of PV^(+)interneurons.Importantly,the gain-of-function of Bod1 improved social deficits and stereotypical behaviors in Pvalb-Cre;Bod1f/f mice.These findings provide mechanistic insights into the PV^(+)interneuron dysfunction and suggest new strategies for developing PV^(+)interneuron-targeted therapies for ASD.展开更多
Dear Editor,General anesthetics play a pivotal role in inducing a safe and reversible loss of consciousness in patients,the importance of which cannot be overstated[1].Among the intravenous anesthetics,propofol stands...Dear Editor,General anesthetics play a pivotal role in inducing a safe and reversible loss of consciousness in patients,the importance of which cannot be overstated[1].Among the intravenous anesthetics,propofol stands out for its rapid onset and swift systemic clearance,effectively eliminating the prolonged sedation associated with earlier agents[2].展开更多
Background:Parkinson’s disease(PD)is a common neurodegenerative disease,characterized by symptoms like tremors,muscle rigidity,and slowmovement.Themain cause of these symptoms is the loss of dopamineproducing neurons...Background:Parkinson’s disease(PD)is a common neurodegenerative disease,characterized by symptoms like tremors,muscle rigidity,and slowmovement.Themain cause of these symptoms is the loss of dopamineproducing neurons in a brain area called the substantia nigra.Various genetic and environmental factors contribute to this neuronal loss.Once symptoms of PD begin,they worsen with age,which also impacts several critical cellular processes.Leucine-rich repeat kinase 2(LRRK2)is a gene associated with PD.Certain mutations in LRRK2,such as G2019S,increase its activity,disrupting cellular mechanisms necessary for healthy neuron function,including autophagy and lysosomal activity.Exposure to rotenone(RTN)promotes LRRK2 activity in neurons and contributes to cellular senescence andα-syn accumulation.Methods:In this study,human dopaminergic progenitor cells were reprogrammed to study the effects of RTN with the co-treatment of LRRK2 inhibitor on cellular senescence.We measured the cellular senescence using quantifying proteins of senescence markers,such as p53,p21,Rb,phosphorylated Rb,andβ-galatocidase,and the enzymatic activity of senescence-associatedβ-galatocidase.And we estimated the levels of accumulatedα-synuclein(α-syn),which is increased via the impaired autophagy-lysosomal pathway by cellular senescence.Then,we evaluated the association of the G2019S LRRK2 mutation and senescence-associatedβ-galatocidase and the levels of accumulated or secretedα-syn,and the neuroinflammatory responses mediated by the secretedα-syn in rat primary microglia were determined using the release of pro-inflammatory cytokines.Results:RTN raised senescence markers and affected the phosphorylation of Rab10,a substrate of LRRK2.The inhibiting agent MLI2 reduced these senescence markers and Rab10 phosphorylations.Additionally,RTN increasedα-syn levels in the neurons,while MLI2 aided in degrading it.When focusing on cells from PD patients with the G2019S mutation,an increase in cellular senescence and release ofα-syn was observed,provoking neuroinflammation.Treatment with the LRRK2 inhibitor MLI2 decreased both cellular senescence andα-syn secretion,thereby mitigating inflammatory responses.Conclusion:Overall,inhibiting LRRK2 may provide a beneficial strategy formanaging PD.展开更多
Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsol...Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsolved issue in pain medicine.Our previous study,using protein kinase C gamma(PKCγ)-tdTomato mice,highlights the spinal feedforward inhibitory circuit involving PKCγ neurons in gating neuropathic allodynia.However,the regulatory mechanisms governing this circuit necessitate further elucidation.We used diverse transgenic mice and advanced techniques to uncover the regulatory role of the descending serotonin(5-HT)facilitation system on spinal PKCγ neurons.Our findings revealed that 5-HT neurons from the rostral ventromedial medulla hyperpolarize spinal inhibitory interneurons via 5-HT_(2C) receptors,disinhibiting the feedforward inhibitory circuit involving PKCγ neurons and exacerbating allodynia.Inhibiting spinal 5-HT_(2C) receptors restored the feedforward inhibitory circuit,effectively preventing neuropathic allodynia.These insights offer promising therapeutic targets for neuropathic allodynia management,emphasizing the potential of spinal 5-HT_(2C) receptors as a novel avenue for intervention.展开更多
基金supported by the Natural Science Foundation of Guangdong Province,Nos.2019A1515010649(to WC),2022A1515012044(to JS)the China Postdoctoral Science Foundation,No.2018M633091(to JS).
文摘Transforming growth factor-beta 1(TGF-β1)has been extensively studied for its pleiotropic effects on central nervous system diseases.The neuroprotective or neurotoxic effects of TGF-β1 in specific brain areas may depend on the pathological process and cell types involved.Voltage-gated sodium channels(VGSCs)are essential ion channels for the generation of action potentials in neurons,and are involved in various neuroexcitation-related diseases.However,the effects of TGF-β1 on the functional properties of VGSCs and firing properties in cortical neurons remain unclear.In this study,we investigated the effects of TGF-β1 on VGSC function and firing properties in primary cortical neurons from mice.We found that TGF-β1 increased VGSC current density in a dose-and time-dependent manner,which was attributable to the upregulation of Nav1.3 expression.Increased VGSC current density and Nav1.3 expression were significantly abolished by preincubation with inhibitors of mitogen-activated protein kinase kinase(PD98059),p38 mitogen-activated protein kinase(SB203580),and Jun NH2-terminal kinase 1/2 inhibitor(SP600125).Interestingly,TGF-β1 significantly increased the firing threshold of action potentials but did not change their firing rate in cortical neurons.These findings suggest that TGF-β1 can increase Nav1.3 expression through activation of the ERK1/2-JNK-MAPK pathway,which leads to a decrease in the firing threshold of action potentials in cortical neurons under pathological conditions.Thus,this contributes to the occurrence and progression of neuroexcitatory-related diseases of the central nervous system.
基金supported by the National Natural Science Foundation of China,Nos.82374561(to JD),82174490(to JF)the Medical and Health Science and Technology Program of Zhejiang Province,No.2021RC098(to JD)the Research Project of Zhejiang Chinese Medical University,Nos.2022JKZKTS44(to JD),2022FSYYZZ07(to JF).
文摘Pain is often comorbid with emotional disorders such as anxiety and depression.Hyperexcitability of the anterior cingulate cortex has been implicated in pain and pain-related negative emotions that arise from impairments in inhibitory gamma-aminobutyric acid neurotransmission.This review primarily aims to outline the main circuitry(including the input and output connectivity)of the anterior cingulate cortex and classification and functions of different gamma-aminobutyric acidergic neurons;it also describes the neurotransmitters/neuromodulators affecting these neurons,their intercommunication with other neurons,and their importance in mental comorbidities associated with chronic pain disorders.Improving understanding on their role in pain-related mental comorbidities may facilitate the development of more effective treatments for these conditions.However,the mechanisms that regulate gamma-aminobutyric acidergic systems remain elusive.It is also unclear as to whether the mechanisms are presynaptic or postsynaptic.Further exploration of the complexities of this system may reveal new pathways for research and drug development.
基金support from the Beijing Natural Science Foundation-Xiaomi Innovation Joint Fund(No.L233009)National Natural Science Foundation of China(NSFC Nos.62422409,62174152,and 62374159)from the Youth Innovation Promotion Association of Chinese Academy of Sciences(No.2020115).
文摘Memristors have a synapse-like two-terminal structure and electrical properties,which are widely used in the construc-tion of artificial synapses.However,compared to inorganic materials,organic materials are rarely used for artificial spiking synapses due to their relatively poor memrisitve performance.Here,for the first time,we present an organic memristor based on an electropolymerized dopamine-based memristive layer.This polydopamine-based memristor demonstrates the improve-ments in key performance,including a low threshold voltage of 0.3 V,a thin thickness of 16 nm,and a high parasitic capaci-tance of about 1μF·mm^(-2).By leveraging these properties in combination with its stable threshold switching behavior,we con-struct a capacitor-free and low-power artificial spiking neuron capable of outputting the oscillation voltage,whose spiking fre-quency increases with the increase of current stimulation analogous to a biological neuron.The experimental results indicate that our artificial spiking neuron holds potential for applications in neuromorphic computing and systems.
基金supported by Singapore National Medical Research Council(NMRC)grants,including CS-IRG,HLCA2022(to ZDZ),STaR,OF LCG 000207(to EKT)a Clinical Translational Research Programme in Parkinson's DiseaseDuke-Duke-NUS collaboration pilot grant(to ZDZ)。
文摘The progressive loss of dopaminergic neurons in affected patient brains is one of the pathological features of Parkinson's disease,the second most common human neurodegenerative disease.Although the detailed pathogenesis accounting for dopaminergic neuron degeneration in Parkinson's disease is still unclear,the advancement of stem cell approaches has shown promise for Parkinson's disease research and therapy.The induced pluripotent stem cells have been commonly used to generate dopaminergic neurons,which has provided valuable insights to improve our understanding of Parkinson's disease pathogenesis and contributed to anti-Parkinson's disease therapies.The current review discusses the practical approaches and potential applications of induced pluripotent stem cell techniques for generating and differentiating dopaminergic neurons from induced pluripotent stem cells.The benefits of induced pluripotent stem cell-based research are highlighted.Various dopaminergic neuron differentiation protocols from induced pluripotent stem cells are compared.The emerging three-dimension-based brain organoid models compared with conventional two-dimensional cell culture are evaluated.Finally,limitations,challenges,and future directions of induced pluripotent stem cell–based approaches are analyzed and proposed,which will be significant to the future application of induced pluripotent stem cell-related techniques for Parkinson's disease.
基金supported by the Key-Area Research and Development Program of Guangdong Province(Grants No.2021B0909060002)National Natural Science Foundation of China(Grants No.62204219,62204140)Major Program of Natural Science Foundation of Zhejiang Province(Grants No.LDT23F0401).
文摘Spike-based neural networks,which use spikes or action potentialsto represent information,have gained a lot of attention because of their high energyefficiency and low power consumption.To fully leverage its advantages,convertingthe external analog signals to spikes is an essential prerequisite.Conventionalapproaches including analog-to-digital converters or ring oscillators,and sensorssuffer from high power and area costs.Recent efforts are devoted to constructingartificial sensory neurons based on emerging devices inspired by the biologicalsensory system.They can simultaneously perform sensing and spike conversion,overcoming the deficiencies of traditional sensory systems.This review summarizesand benchmarks the recent progress of artificial sensory neurons.It starts with thepresentation of various mechanisms of biological signal transduction,followed bythe systematic introduction of the emerging devices employed for artificial sensoryneurons.Furthermore,the implementations with different perceptual capabilitiesare briefly outlined and the key metrics and potential applications are also provided.Finally,we highlight the challenges and perspectives for the future development of artificial sensory neurons.
文摘Objective:To anatomically and phenotypically characterize the insular cortex(IC)-nucleus tractus soli-tari(NTS)neural pathway.Methods:Adult male Sprague-Dawley rats were divided into three experimental cohorts for neural circuit tracing.Anterograde labeling was achieved by injecting anterograde self-complementary adeno-associated viruses(scAAVs)into the IC.Retrograde tracing involved NTS injections of either retrograde scAAVs or FluoroGold(FG),combined with immunofluorescence histochemical staining to identify IC-originating projection neurons.For postsynaptic neurochemical phenotype characterization,IC was injected with AAV2/1-CaMKII-Cre,while a mixture of AAV2/9-Syn-DIO-mCherry and AAV2/9-VGAT1-EGFP was injected into the NTS.The rats were allowed to survive for one week following scAAVs or FG injection or four weeks after recombinase-dependent systems injection.Then the rats were sacrificed,and serial brain sections were prepared for immunofluorescence histochemical staining(brain section containing FG)and subsequent fluorescence/confocal microscopic analysis.Results:(1)Anterograde viral tracing re-vealed dense axonal terminals from the IC projecting to the medial subnucleus of the NTS,while retrograde tracing re-vealed that IC neurons projecting to the NTS were predominantly localized within the dysgranular layer;(2)IC-NTS projection neurons were exclusive glutamatergic(100%,n=3);(3)NTS neurons receiving IC inputs were mainly lo-calized in the medial subnucleus,and were predominantly GABAergic(79.8±3.2%,n=3).Conclusion:The pres-ent results indicate that a descending pathway from excitatory neurons of the IC terminates onto inhibitory neurons of the NTS,which might represent a potential neuromodulatory target for visceral pain disorders.
基金supported by the following foundations:“Stichting Oogfonds Nederland(No.2023-26)”the“Landelijke Stichting voor Blinden en Slechtzienden(No.2023-24)”that contributed through UitZicht,ZonMw grant(No.435005020)a grant of the Chinese Scholarship Council(No.201809110169)(to TGMFG,CPMR,and WY).
文摘Unwarranted death of neurons is a major cause of neurodegenerative diseases.Since mature neurons are postmitotic and do not replicate,their death usually constitutes an irreversible step in pathology.A logical strategy to prevent neurodegeneration would then be to save all neurons that are still alive,i.e.protecting the ones that are still healthy as well as trying to rescue the ones that are damaged and in the process of dying.Regarding the latter,recent experiments have indicated that the possibility of reversing the cell death process and rescuing dying cells is more significant than previously anticipated.In many situations,the elimination of the cell death trigger alone enables dying cells to spontaneously repair their damage,recover,and survive.In this review,we explore the factors,which determine the fate of neurons engaged in the cell death process.A deeper insight into cell death mechanisms and the intrinsic capacity of cells to recover could pave the way for novel therapeutic approaches to neurodegenerative diseases.
基金supported by a grant from Ministry of Science and Technology China,No.2022ZD0204704(to WW)the National Natural Science Foundation of China,No.82301572(to XZ)the China Postdoctoral Science Foundation,No.2023M731202(to XZ)。
文摘Nonhuman primates are increasingly being used as animal models in neuroscience research.However,efficient neuronal tracing techniques for labeling motor neurons and primary sensory afferents in the monkey spinal cord are lacking.Here,by injecting the cholera toxin B subunit into the sciatic nerve of a rhesus monkey,we successfully labeled the motor neurons and primary sensory afferents in the lumbar and sacralspinal cord.Labeled alpha motor neurons were located in lamina IX of the L6–S1 segments,which innervate both flexors and extensors.The labeled primary sensory afferents were mainly myelinated Aβfibers that terminated mostly in laminae I and II of the L4–L7 segments.Together with the labeled proprioceptive afferents,the primary sensory afferents formed excitatory synapses with multiple types of spinal neurons.In summary,our methods successfully traced neuronal connections in the monkey spinal cord and can be used in spinal cord studies when nonhuman primates are used.
基金supported by the Joint R&D Fund of Beijing Smartchip Microelectronics Technology Co.,Ltd.,SGSC0000XSQT2207067.
文摘As traditional von Neumann architectures face limitations in handling the demands of big data and complex computa-tional tasks,neuromorphic computing has emerged as a promising alternative,inspired by the human brain's neural networks.Volatile memristors,particularly Mott and diffusive memristors,have garnered significant attention for their ability to emulate neuronal dynamics,such as spiking and firing patterns,enabling the development of reconfigurable and adaptive computing systems.Recent advancements include the implementation of leaky integrate-and-fire neurons,Hodgkin-Huxley neurons,opto-electronic neurons,and time-surface neurons,all utilizing volatile memristors to achieve efficient,low-power,and highly inte-grated neuromorphic systems.This paper reviews the latest progress in volatile memristor-based artificial neurons,highlight-ing their potential for energy-efficient computing and integration with artificial synapses.We conclude by addressing chal-lenges such as improving memristor reliability and exploring new architectures to advance memristor-based neuromorphic com-puting.
基金supported by grants from the Russian Science Foundation(23-44-00054)the National Natural Science Foundation of China(32261133525).
文摘Stromal interaction molecules(STIM)s are Ca^(2+)sensors in internal Ca^(2+)stores of the endoplasmic reticulum.They activate the store-operated Ca^(2+)channels,which are the main source of Ca^(2+)entry in non-excitable cells.Moreover,STIM proteins interact with other Ca^(2+)channel subunits and active transporters,making STIMs an important intermediate molecule in orchestrating a wide variety of Ca^(2+)influxes into excitable cells.Nevertheless,little is known about the role of STIM proteins in brain functioning.Being involved in many signaling pathways,STIMs replenish internal Ca^(2+)stores in neurons and mediate synaptic transmission and neuronal excitability.Ca^(2+)dyshomeostasis is a signature of many pathological conditions of the brain,including neurodegenerative diseases,injuries,stroke,and epilepsy.STIMs play a role in these disturbances not only by supporting abnormal store-operated Ca^(2+)entry but also by regulating Ca^(2+)influx through other channels.Here,we review the present knowledge of STIMs in neurons and their involvement in brain pathology.
文摘Erratum to:Current Medical Science 44(5):987–1000,2024 https://doi.org/10.1007/s11596-024-2908-9 In the originally published article,there was an error in the funding information.Instead of“Shenzhen Science and Technology Program(No.2021-22154)”,it should be corrected to“Shenzhen Science and Technology Program(No.JCYJ20210324111609024)”.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.
基金supported by the National Key Research and Development Program of China,No. 2023YFF0714200 (to CW)the National Natural Science Foundation of China,Nos. 82472038 and 82202224 (both to CW)+3 种基金the Shanghai Rising-Star Program,No. 23QA1407700 (to CW)the Construction Project of Shanghai Key Laboratory of Molecular Imaging,No. 18DZ2260400 (to CW)the National Science Foundation for Distinguished Young Scholars,No. 82025019 (to CL)the Greater Bay Area Institute of Precision Medicine (Guangzhou)(to CW)。
文摘Epilepsy is a leading cause of disability and mortality worldwide. However, despite the availability of more than 20 antiseizure medications, more than one-third of patients continue to experience seizures. Given the urgent need to explore new treatment strategies for epilepsy, recent research has highlighted the potential of targeting gliosis, metabolic disturbances, and neural circuit abnormalities as therapeutic strategies. Astrocytes, the largest group of nonneuronal cells in the central nervous system, play several crucial roles in maintaining ionic and energy metabolic homeostasis in neurons, regulating neurotransmitter levels, and modulating synaptic plasticity. This article briefly reviews the critical role of astrocytes in maintaining balance within the central nervous system. Building on previous research, we discuss how astrocyte dysfunction contributes to the onset and progression of epilepsy through four key aspects: the imbalance between excitatory and inhibitory neuronal signaling, dysregulation of metabolic homeostasis in the neuronal microenvironment, neuroinflammation, and the formation of abnormal neural circuits. We summarize relevant basic research conducted over the past 5 years that has focused on modulating astrocytes as a therapeutic approach for epilepsy. We categorize the therapeutic targets proposed by these studies into four areas: restoration of the excitation–inhibition balance, reestablishment of metabolic homeostasis, modulation of immune and inflammatory responses, and reconstruction of abnormal neural circuits. These targets correspond to the pathophysiological mechanisms by which astrocytes contribute to epilepsy. Additionally, we need to consider the potential challenges and limitations of translating these identified therapeutic targets into clinical treatments. These limitations arise from interspecies differences between humans and animal models, as well as the complex comorbidities associated with epilepsy in humans. We also highlight valuable future research directions worth exploring in the treatment of epilepsy and the regulation of astrocytes, such as gene therapy and imaging strategies. The findings presented in this review may help open new therapeutic avenues for patients with drugresistant epilepsy and for those suffering from other central nervous system disorders associated with astrocytic dysfunction.
基金supported by the National Natural Science Foundation of China(No.31571098,32071026)Shanghai Municipal Science and Technology Major Project(No.2018SHZDZX01),ZJ Lab.and Shanghai Center for Brain Science and Brain-Inspired Technology。
文摘The high-order cognitive and executive functions are necessary for an individual to survive.The densely bidirectional innervations between the medial prefrontal cortex(mPFC)and the mediodorsal thalamus(MD)play a vital role in regulating high-order functions.Pyramidal neurons in mPFC have been classified into several subclasses according to their morphological and electrophysi-ological properties,but the properties of the input-specific pyramidal neurons in mPFC remain poorly understood.The present study aimed to profile the morphological and electrophysiological properties of mPFC pyramidal neurons innervated by MD.In the past,the studies for characterizing the morphological and electrophysiological properties of neurons mainly relied on the electrophysiological recording of a large number of neurons and their morphologic reconstructions.But,it is a low efficient method for characterizing the circuit-specific neurons.The present study combined the advantages of traditional morphological and electrophysiological methods with machine learning to address the shortcomings of the past method,to establish a classification model for the morphological and electrophysiological properties of mPFC pyramidal neurons,and to achieve more accurate and efficient identification of the properties from a small size sample of neurons.We labeled MD-innervated pyramidal neurons of mPFC using the trans-synaptic neural circuitry tracing method and obtained their morphological properties using whole-cell patch-clamp recording and morphologic reconstructions.The results showed that the classification model established in the present study could predict the electrophysiological properties of MD-innervated pyramidal neurons based on their morphology.MD-innervated pyramidal neurons exhibit larger basal dendritic length but lower apical dendrite complexity compared to non-MD-innervated neurons in the mPFC.The morphological characteristics of the two subtypes(ET-1 and ET-2)of mPFC pyramidal neurons innervated by MD are different,with the apical dendrites of ET-1 neurons being longer and more complex than those of ET-2 neurons.These results suggest that the electrophysiological properties of MD-innervated pyramidal neurons within mPFC correlate with their morphological properties,indicating that the different roles of these two subclasses in local circuits within PFC,as well as in PFC-cortical/subcortical brain region circuits.
基金supported by the National Natural Science Foundation of China(Nos.U20A20209 and 62304228)the China National Postdoctoral Program for Innovative Talents(No.BX2021326)+3 种基金the China Postdoctoral Science Foundation(No.2021M703310)the Zhejiang Provincial Natural Science Foundation of China(No.LQ22F040003)the Ningbo Natural Science Foundation of China(No.2023J356)the State Key Laboratory for Environment-Friendly Energy Materials(No.20kfhg09).
文摘With the rapid development of artificial intelligence(AI)technology,the demand for high-performance and energyefficient computing is increasingly growing.The limitations of the traditional von Neumann computing architecture have prompted researchers to explore neuromorphic computing as a solution.Neuromorphic computing mimics the working principles of the human brain,characterized by high efficiency,low energy consumption,and strong fault tolerance,providing a hardware foundation for the development of new generation AI technology.Artificial neurons and synapses are the two core components of neuromorphic computing systems.Artificial perception is a crucial aspect of neuromorphic computing,where artificial sensory neurons play an irreplaceable role thus becoming a frontier and hot topic of research.This work reviews recent advances in artificial sensory neurons and their applications.First,biological sensory neurons are briefly described.Then,different types of artificial neurons,such as transistor neurons and memristive neurons,are discussed in detail,focusing on their device structures and working mechanisms.Next,the research progress of artificial sensory neurons and their applications in artificial perception systems is systematically elaborated,covering various sensory types,including vision,touch,hearing,taste,and smell.Finally,challenges faced by artificial sensory neurons at both device and system levels are summarized.
文摘During the process of organizing our original data,we unfortunately identified two error in the figures within our published article.In Fig.1,the online version incorrectly labels the SNI+NAC group as the sham+NAC group.We have revised the grouping annotations in Fig.1 and have labeled the DHE staining in the figure to present the experimental design more clearly.
基金supported by the National Natural Science Foundation of China(NSFC grant Nos.82371382,81771381)the Natural Science Foundation of the Higher Education Institutions of Anhui Province(grant Nos.KJ2021ZD0085,2022AH051434,2024AH051296 and 2024AH040193)+3 种基金the Anhui Provincial Key Research and Development Project(grantNos.2022e07020030 and 2022e07020032)the Science Research Project of BengbuMedical College(grant No.2021byfy002)the Postgraduate Innovative Training Program of BengbuMedical College(grant No.Byycx23006)the Undergraduate Innovative Training Program of China(grant Nos.202310367015,202410367002,202410367012,202410367079).
文摘Background:Mesenchymal stem cells(MSCs)have shown great potential in treating neurodegenerative diseases,incuding Parkinson's disease(PD),due to their ability to differentiate into neurons and secrete neurotrophic factors.Genetic modification of MSCs for PD treatment has become a research focus.Methods:In this study,rat pulmonary mesenchymal stem cells(PMSCs)were transduced with lentiviral vectors carrying Lmxla/NeuroDI to establish genetically engineered PMSCs(LN-PMSCs)and induce their diferentiation into dopaminergic neurons.The LN-PMSCs were then transplanted into the right medial forebrain bundle region of PD model rats prepared using the 6-Hydroxydopamine(6-OHDA)method.Four weeks post-transplantation,the survival and diferentiation of the cells in the brain and motor function of the PD rats were evaluated.Results:The results showed that after 12 days of induction,the genetically modified LN-PMSCs had differentiated into a large number of dopaminergic neurons.Four weeks post-transplantation,these cells significantly improved motor dysfunction in PD rats and promoted the expression of neuron marker TUI,dopaminergic neuron markers FOXA2 and TH,gamma-aminobutyric acid-ergic(GABAergic)neuron marker GABA,astrocyte marker GFAP,presynaptic marker SYN,and postsynaptic marker PSD95 in the transplantation area.Conclusion:Our findings suggest that the gene-engineered PMSCs cell line overexpressing Lmxla and NeuroDI(LN-PMSCs)transplantation could be a potential therapeutic strategy for treating PD.
基金supported by the National Key Research and Development Program of China(Grant No.2022YFE0108600 to Y.M.L.)the National Natural Science Foundations of China(Grant Nos.82473918 and 82104162 to X.X.L.).
文摘Parvalbumin-positive(PV^(+))interneuron dysfunction is believed to be linked to autism spectrum disorder(ASD),a neurodevelopmental disorder characterized by social deficits and stereotypical behaviors.However,the mechanisms behind PV^(+)interneuron dysfunction remain largely unclear.Here,we found that a deficiency of Biorientation Defective 1(Bod1)in PV^(+)interneurons led to an ASD-like phenotype in Pvalb-Cre;Bod1f/f mice.Mechanistically,we observed that Bod1 deficiency induced hypoactivity of PV^(+)interneurons and hyperactivity of calcium/calmodulin-dependent protein kinaseⅡalpha(CaMKⅡα)neurons in the medial prefrontal cortex,as determined by whole-cell patch-clamp recording.Additionally,Bod1 deficiency decreased the power of highgamma oscillation,assessed by in vivo multi-channel electrophysiological recording.Furthermore,we found that Bod1 deficiency enhanced the inwardly rectifying K^(+)current,leading to an increase in the resting membrane potential of PV^(+)interneurons.Importantly,the gain-of-function of Bod1 improved social deficits and stereotypical behaviors in Pvalb-Cre;Bod1f/f mice.These findings provide mechanistic insights into the PV^(+)interneuron dysfunction and suggest new strategies for developing PV^(+)interneuron-targeted therapies for ASD.
基金supported by grants from the National Natural Science Foundation of China(82101273)the Second Affiliated Hospital of the Army Medical University Incubation Program for Young Doctoral Talents(2023YQB007).
文摘Dear Editor,General anesthetics play a pivotal role in inducing a safe and reversible loss of consciousness in patients,the importance of which cannot be overstated[1].Among the intravenous anesthetics,propofol stands out for its rapid onset and swift systemic clearance,effectively eliminating the prolonged sedation associated with earlier agents[2].
基金supportedby a grant from the Korean Fundfor Regenerative Medicine(KFRM),which is funded by the Korean government’s Ministry of Science and ICT and the Ministry of Health&Welfare(23A0102L1 to Janghwan Kim)by KRIBB Research Initiative Program(KGM5362521 to Janghwan Kim)+1 种基金supported by a grant fromthe National Research Foundation of Korea(NRF)which is funded by theMinistry of Science and ICT(MSIT)of the Korean government(RS-2023-NR077070 to SungWoo Park).
文摘Background:Parkinson’s disease(PD)is a common neurodegenerative disease,characterized by symptoms like tremors,muscle rigidity,and slowmovement.Themain cause of these symptoms is the loss of dopamineproducing neurons in a brain area called the substantia nigra.Various genetic and environmental factors contribute to this neuronal loss.Once symptoms of PD begin,they worsen with age,which also impacts several critical cellular processes.Leucine-rich repeat kinase 2(LRRK2)is a gene associated with PD.Certain mutations in LRRK2,such as G2019S,increase its activity,disrupting cellular mechanisms necessary for healthy neuron function,including autophagy and lysosomal activity.Exposure to rotenone(RTN)promotes LRRK2 activity in neurons and contributes to cellular senescence andα-syn accumulation.Methods:In this study,human dopaminergic progenitor cells were reprogrammed to study the effects of RTN with the co-treatment of LRRK2 inhibitor on cellular senescence.We measured the cellular senescence using quantifying proteins of senescence markers,such as p53,p21,Rb,phosphorylated Rb,andβ-galatocidase,and the enzymatic activity of senescence-associatedβ-galatocidase.And we estimated the levels of accumulatedα-synuclein(α-syn),which is increased via the impaired autophagy-lysosomal pathway by cellular senescence.Then,we evaluated the association of the G2019S LRRK2 mutation and senescence-associatedβ-galatocidase and the levels of accumulated or secretedα-syn,and the neuroinflammatory responses mediated by the secretedα-syn in rat primary microglia were determined using the release of pro-inflammatory cytokines.Results:RTN raised senescence markers and affected the phosphorylation of Rab10,a substrate of LRRK2.The inhibiting agent MLI2 reduced these senescence markers and Rab10 phosphorylations.Additionally,RTN increasedα-syn levels in the neurons,while MLI2 aided in degrading it.When focusing on cells from PD patients with the G2019S mutation,an increase in cellular senescence and release ofα-syn was observed,provoking neuroinflammation.Treatment with the LRRK2 inhibitor MLI2 decreased both cellular senescence andα-syn secretion,thereby mitigating inflammatory responses.Conclusion:Overall,inhibiting LRRK2 may provide a beneficial strategy formanaging PD.
基金supported by the National Natural Science Foundation of China(81971058,82371226,82101295,82301398)the National Funded Postdoctoral Researcher Program(GZC20233585)The Boost Plan of Xijing Hospital(XJZT24QN25,XJZT25CX22).
文摘Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsolved issue in pain medicine.Our previous study,using protein kinase C gamma(PKCγ)-tdTomato mice,highlights the spinal feedforward inhibitory circuit involving PKCγ neurons in gating neuropathic allodynia.However,the regulatory mechanisms governing this circuit necessitate further elucidation.We used diverse transgenic mice and advanced techniques to uncover the regulatory role of the descending serotonin(5-HT)facilitation system on spinal PKCγ neurons.Our findings revealed that 5-HT neurons from the rostral ventromedial medulla hyperpolarize spinal inhibitory interneurons via 5-HT_(2C) receptors,disinhibiting the feedforward inhibitory circuit involving PKCγ neurons and exacerbating allodynia.Inhibiting spinal 5-HT_(2C) receptors restored the feedforward inhibitory circuit,effectively preventing neuropathic allodynia.These insights offer promising therapeutic targets for neuropathic allodynia management,emphasizing the potential of spinal 5-HT_(2C) receptors as a novel avenue for intervention.
