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
V-raf-leukemia viral oncogene 1(RAF1),a serine/threonine protein kinase,is well established to play a crucial role in tumorigenesis and cell development.However,the specific role of hypothalamic RAF1 in regulating ene...V-raf-leukemia viral oncogene 1(RAF1),a serine/threonine protein kinase,is well established to play a crucial role in tumorigenesis and cell development.However,the specific role of hypothalamic RAF1 in regulating energy metabolism remains unknown.In this study,we found that the expression of RAF1 was significantly increased in hypothalamic AgRP neurons of diet-induced obesity(DIO)mice.Under normal chow diet feeding,overexpression of Raf1 in AgRP neurons led to obesity in mice characterized by increased body weight,fat mass,and impaired glucose tolerance.Conversely,Raf1 knockout in AgRP neurons protected against diet-induced obesity,reducing fat mass and improving glucose tolerance.Mechanistically,Raf1 activated the MAPK signaling pathway,culminating in the phosphorylation of cAMP response element-binding protein(CREB),which enhanced transcription of Agrp and Npy.Insulin stimulation further potentiated the RAF1-MEK1/2-ERK1/2-CREB axis,highlighting RAF1's role in integrating hormonal and nutritional signals to regulate energy balance.Collectively,these findings underscore the important role of RAF1 in AgRP neurons in maintaining energy homeostasis and obesity pathogenesis,positioning it and its downstream pathways as potential therapeutic targets for innovative strategies to combat obesity and related metabolic diseases.展开更多
Autophagy is well-known for delivering cargo materials to lysosomes for proteolytic digestion.Recently,autophagy has emerged as a key mechanism in unconventional protein secretion(UPS).This perspective introduces unco...Autophagy is well-known for delivering cargo materials to lysosomes for proteolytic digestion.Recently,autophagy has emerged as a key mechanism in unconventional protein secretion(UPS).This perspective introduces unconventional secretion pathways,focusing on secretory autophagy and its role in secreting protein aggregates associated with neurodegenerative disorders.We also explore additional neuronal functions of secretory autophagy beyond the release of protein aggregates.We propose autophagosomes as transport organelles that deliver cargo material directly from the endoplasmatic reticulum(ER)to the plasma membrane rather than solely to lysosomes.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
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
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
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
The thalamic reticular nucleus(TRN)plays a crucial role in regulating sensory encoding,even at the earliest stages of visual processing,as evidenced by numerous studies.Orientation selectivity,a vital neural response,...The thalamic reticular nucleus(TRN)plays a crucial role in regulating sensory encoding,even at the earliest stages of visual processing,as evidenced by numerous studies.Orientation selectivity,a vital neural response,is essential for detecting objects through edge perception.Here,we demonstrate that somatostatin(SOM)-expressing and parvalbumin(PV)-expressing neurons in the TRN project to the dorsal lateral geniculate nucleus and modulate orientation selectivity and the capacity for visual information processing in the primary visual cortex(V1).These findings show that SOM-positive and PV-positive neurons in the TRN are powerful modulators of visual information encoding in V1,revealing a novel role for this thalamic nucleus in influencing visual processing.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
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
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
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
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
Objective:This study aims to establish an economically viable and easily accessible adult animal model for optogenetic activation of auditory neurons using adeno-associated viruses(AAVs)carrying Ch R2(H134R)to explore...Objective:This study aims to establish an economically viable and easily accessible adult animal model for optogenetic activation of auditory neurons using adeno-associated viruses(AAVs)carrying Ch R2(H134R)to explore the potential of cochlear optogenetics as a hearing restoration technology.Methods:Healthy adult guinea pigs were used in the experiments.The viral vector AAV2/8-Ch R2(H134R)-h Syn-e YFP was administered to the right cochlea via the round window membrane.The confocal microscopy and reverse transcription polymerase chain reaction(RT-PCR)were utilized to analyze the Ch R2(H134R)expression localized to spiral ganglion neurons(SGNs).The auditory pathway activation was assessed by recording the optical compound action potential(oCAP)and acoustic compound action potential(a CAP)at various laser intensities.Results:The Ch R2(H134R)-e YFP expression was confirmed in 90%of the tested animals,localized to the SGNs of the injected ear.Higher m RNA levels of Ch R2(H134R)and e YFP were observed in the injected ear compared to the non-injected ear,while actin(Actb)m RNA levels were not significantly different.The o CAP was successfully elicited by a 470 nm blue light laser stimulus,with similar amplitudes and latency periods to those of a CAPs when the o CAP was evoked by 5.80 m W blue light and the a CAP was evoked by a 40 d B SPL click.The amplitudes of o CAPs increased with increasing laser intensity.Conclusion:This study demonstrates the viability of optogenetic activation of the auditory system in adult guinea pigs through the transduction of AAV-Ch R2(H134R)in SGNs.Cochlear optogenetics demonstrates potential as a hearing restoration technology,providing a basis for further clinical research and opening new avenues for investigation.展开更多
Dear Editor,Post-traumatic stress disorder(PTSD)is a chronic neuropsychiatric disorder triggered by severe traumatic events,characterized by persistent intrusive memories,emotional dysregulation,hyperarousal,and avoid...Dear Editor,Post-traumatic stress disorder(PTSD)is a chronic neuropsychiatric disorder triggered by severe traumatic events,characterized by persistent intrusive memories,emotional dysregulation,hyperarousal,and avoidance behaviors[1,2].PTSD is associated with significant gene expression changes in key brain regions,including the ventral tegmental area(VTA),which may underlie dysregulation of dopaminergic signaling and stress-related behaviors[3].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
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
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
Piezo2,a mechanosensitive ion channel,serves as a crucial mechanotransducer in dental primary afferent(DPA)neurons and is potentially involved in hypersensitivity to mild mechanical irritations observed in dental pati...Piezo2,a mechanosensitive ion channel,serves as a crucial mechanotransducer in dental primary afferent(DPA)neurons and is potentially involved in hypersensitivity to mild mechanical irritations observed in dental patients.Given Piezo2’s widespread expression across diverse subpopulations of DPA neurons,this study aimed to characterize the mechanosensory properties of Piezo2-expressing DPA neurons with a focus on distinct features of voltage-gated sodium channels(VGSCs)and neuropeptide profiles.Using whole-cell patch-clamp recordings,we observed mechanically activated action potentials(APs)and classified AP waveforms based on the presence or absence of a hump during the repolarization phase.Single-cell reverse transcription polymerase chain reaction combined with patch-clamp recordings revealed specific associations between AP waveforms and molecular properties,including tetrodotoxin-resistant VGSCs(NaV1.8 and NaV1.9)and TRPV1 expression.Reanalysis of the transcriptomic dataset of DPA neurons identified correlations between neuropeptides—including two CGRP isoforms(α-CGRP andβ-CGRP),Substance P,and Galanin—and the expression of NaV1.8 and NaV1.9,which were linked to defined AP subtypes.These molecular associations were further validated in Piezo2+DPA neurons using fluorescence in situ hybridization.Together,these findings highlight the electrophysiological and neurochemical heterogeneity of Piezo2-expressing DPA neurons and their specialized roles in distinct mechanosensory signal transmission.展开更多
Our research reveals the critical role of the suprachiasmatic nucleus(SCN)vasoactive intestinal peptide(VIP)neurons in mediating light-induced transient forgetting.Acute exposure to bright light selectively impairs tr...Our research reveals the critical role of the suprachiasmatic nucleus(SCN)vasoactive intestinal peptide(VIP)neurons in mediating light-induced transient forgetting.Acute exposure to bright light selectively impairs trace fear memory by activating VIP neurons in the SCN,as demonstrated by increased c-Fos expression and Ca2+recording.This effect can be replicated and reversed through optogenetic and chemogenetic manipulations of SCN VIP neurons.Furthermore,we identify the SCN→PVT(paraventricular nucleus of the thalamus)VIP neuronal circuitry as essential in this process.These findings establish a novel role for SCN VIP neurons in modulating memory accessibility in response to environmental light cues,extending their known function beyond circadian regulation and revealing a mechanism for transient forgetting.展开更多
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support from various sources,including the National Natural Science Foundation of China(Grant Nos.81570774,82070872,92049118,and 82370854)the Junior Thousand Talents Program of China,and the Nanjing Medical University Startup Fund(All awarded to J.L.)support provided by Jiangsu Province's Innovation Personal as well as Innovative and Entrepreneurial Team of Jiangsu Province(Grant No.JSSCTD2021)(All awarded to J.L.).
文摘V-raf-leukemia viral oncogene 1(RAF1),a serine/threonine protein kinase,is well established to play a crucial role in tumorigenesis and cell development.However,the specific role of hypothalamic RAF1 in regulating energy metabolism remains unknown.In this study,we found that the expression of RAF1 was significantly increased in hypothalamic AgRP neurons of diet-induced obesity(DIO)mice.Under normal chow diet feeding,overexpression of Raf1 in AgRP neurons led to obesity in mice characterized by increased body weight,fat mass,and impaired glucose tolerance.Conversely,Raf1 knockout in AgRP neurons protected against diet-induced obesity,reducing fat mass and improving glucose tolerance.Mechanistically,Raf1 activated the MAPK signaling pathway,culminating in the phosphorylation of cAMP response element-binding protein(CREB),which enhanced transcription of Agrp and Npy.Insulin stimulation further potentiated the RAF1-MEK1/2-ERK1/2-CREB axis,highlighting RAF1's role in integrating hormonal and nutritional signals to regulate energy balance.Collectively,these findings underscore the important role of RAF1 in AgRP neurons in maintaining energy homeostasis and obesity pathogenesis,positioning it and its downstream pathways as potential therapeutic targets for innovative strategies to combat obesity and related metabolic diseases.
基金supported by the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation)grant LU 2347/3-1(to PL).
文摘Autophagy is well-known for delivering cargo materials to lysosomes for proteolytic digestion.Recently,autophagy has emerged as a key mechanism in unconventional protein secretion(UPS).This perspective introduces unconventional secretion pathways,focusing on secretory autophagy and its role in secreting protein aggregates associated with neurodegenerative disorders.We also explore additional neuronal functions of secretory autophagy beyond the release of protein aggregates.We propose autophagosomes as transport organelles that deliver cargo material directly from the endoplasmatic reticulum(ER)to the plasma membrane rather than solely to lysosomes.
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 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,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.
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 Young Scientists Fund of the National Natural Science Foundation of China(32200789)the National Natural Science Foundation of China(32070990).
文摘The thalamic reticular nucleus(TRN)plays a crucial role in regulating sensory encoding,even at the earliest stages of visual processing,as evidenced by numerous studies.Orientation selectivity,a vital neural response,is essential for detecting objects through edge perception.Here,we demonstrate that somatostatin(SOM)-expressing and parvalbumin(PV)-expressing neurons in the TRN project to the dorsal lateral geniculate nucleus and modulate orientation selectivity and the capacity for visual information processing in the primary visual cortex(V1).These findings show that SOM-positive and PV-positive neurons in the TRN are powerful modulators of visual information encoding in V1,revealing a novel role for this thalamic nucleus in influencing visual processing.
基金supported by the National Natural Science Foundation of China(81971058,82371226,82101295,82301398)the National Funded Postdoctoral Researcher Program(GZC20233585)The Boost Plan of Xijing Hospital(XJZT24QN25,XJZT25CX22).
文摘Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsolved issue in pain medicine.Our previous study,using protein kinase C gamma(PKCγ)-tdTomato mice,highlights the spinal feedforward inhibitory circuit involving PKCγ neurons in gating neuropathic allodynia.However,the regulatory mechanisms governing this circuit necessitate further elucidation.We used diverse transgenic mice and advanced techniques to uncover the regulatory role of the descending serotonin(5-HT)facilitation system on spinal PKCγ neurons.Our findings revealed that 5-HT neurons from the rostral ventromedial medulla hyperpolarize spinal inhibitory interneurons via 5-HT_(2C) receptors,disinhibiting the feedforward inhibitory circuit involving PKCγ neurons and exacerbating allodynia.Inhibiting spinal 5-HT_(2C) receptors restored the feedforward inhibitory circuit,effectively preventing neuropathic allodynia.These insights offer promising therapeutic targets for neuropathic allodynia management,emphasizing the potential of spinal 5-HT_(2C) receptors as a novel avenue for intervention.
基金supported by 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 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.
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 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.
基金supported by the Beijing Natural Science Foundation of China under Grant 7222185。
文摘Objective:This study aims to establish an economically viable and easily accessible adult animal model for optogenetic activation of auditory neurons using adeno-associated viruses(AAVs)carrying Ch R2(H134R)to explore the potential of cochlear optogenetics as a hearing restoration technology.Methods:Healthy adult guinea pigs were used in the experiments.The viral vector AAV2/8-Ch R2(H134R)-h Syn-e YFP was administered to the right cochlea via the round window membrane.The confocal microscopy and reverse transcription polymerase chain reaction(RT-PCR)were utilized to analyze the Ch R2(H134R)expression localized to spiral ganglion neurons(SGNs).The auditory pathway activation was assessed by recording the optical compound action potential(oCAP)and acoustic compound action potential(a CAP)at various laser intensities.Results:The Ch R2(H134R)-e YFP expression was confirmed in 90%of the tested animals,localized to the SGNs of the injected ear.Higher m RNA levels of Ch R2(H134R)and e YFP were observed in the injected ear compared to the non-injected ear,while actin(Actb)m RNA levels were not significantly different.The o CAP was successfully elicited by a 470 nm blue light laser stimulus,with similar amplitudes and latency periods to those of a CAPs when the o CAP was evoked by 5.80 m W blue light and the a CAP was evoked by a 40 d B SPL click.The amplitudes of o CAPs increased with increasing laser intensity.Conclusion:This study demonstrates the viability of optogenetic activation of the auditory system in adult guinea pigs through the transduction of AAV-Ch R2(H134R)in SGNs.Cochlear optogenetics demonstrates potential as a hearing restoration technology,providing a basis for further clinical research and opening new avenues for investigation.
基金supported by grants from the National Natural Science Foundation of China(81871062)Guangdong Basic and Applied Basic Research Foundation(2024A1515012913)+1 种基金the Key Research Foundation of Guangdong Provincial Education Bureau(2023ZDZX2037)the Special Fund of Science and Technology Innovation Cultivation of Guangdong University Students(pdjh2024a238,pdjh2025ak133)。
文摘Dear Editor,Post-traumatic stress disorder(PTSD)is a chronic neuropsychiatric disorder triggered by severe traumatic events,characterized by persistent intrusive memories,emotional dysregulation,hyperarousal,and avoidance behaviors[1,2].PTSD is associated with significant gene expression changes in key brain regions,including the ventral tegmental area(VTA),which may underlie dysregulation of dopaminergic signaling and stress-related behaviors[3].
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.
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 Research Foundation(NRF)of Korea(grant number:RS-2022-NR072217 to P.RL,RS-2021-NR059709,RS-2023-00264409,and RS-2024-00441103)funded by the Korean government(MSIT).
文摘Piezo2,a mechanosensitive ion channel,serves as a crucial mechanotransducer in dental primary afferent(DPA)neurons and is potentially involved in hypersensitivity to mild mechanical irritations observed in dental patients.Given Piezo2’s widespread expression across diverse subpopulations of DPA neurons,this study aimed to characterize the mechanosensory properties of Piezo2-expressing DPA neurons with a focus on distinct features of voltage-gated sodium channels(VGSCs)and neuropeptide profiles.Using whole-cell patch-clamp recordings,we observed mechanically activated action potentials(APs)and classified AP waveforms based on the presence or absence of a hump during the repolarization phase.Single-cell reverse transcription polymerase chain reaction combined with patch-clamp recordings revealed specific associations between AP waveforms and molecular properties,including tetrodotoxin-resistant VGSCs(NaV1.8 and NaV1.9)and TRPV1 expression.Reanalysis of the transcriptomic dataset of DPA neurons identified correlations between neuropeptides—including two CGRP isoforms(α-CGRP andβ-CGRP),Substance P,and Galanin—and the expression of NaV1.8 and NaV1.9,which were linked to defined AP subtypes.These molecular associations were further validated in Piezo2+DPA neurons using fluorescence in situ hybridization.Together,these findings highlight the electrophysiological and neurochemical heterogeneity of Piezo2-expressing DPA neurons and their specialized roles in distinct mechanosensory signal transmission.
基金supported by grants from the National Natural Science Foundation of China(32021002 and 31900724)the STI2030-Major Projects(2022ZD0204900)the Tsinghua-Peking Joint Center for Life Sciences.
文摘Our research reveals the critical role of the suprachiasmatic nucleus(SCN)vasoactive intestinal peptide(VIP)neurons in mediating light-induced transient forgetting.Acute exposure to bright light selectively impairs trace fear memory by activating VIP neurons in the SCN,as demonstrated by increased c-Fos expression and Ca2+recording.This effect can be replicated and reversed through optogenetic and chemogenetic manipulations of SCN VIP neurons.Furthermore,we identify the SCN→PVT(paraventricular nucleus of the thalamus)VIP neuronal circuitry as essential in this process.These findings establish a novel role for SCN VIP neurons in modulating memory accessibility in response to environmental light cues,extending their known function beyond circadian regulation and revealing a mechanism for transient forgetting.
