Memtransistors combine memristors and field-effect transistors, which can introduce multi-port control and have significant applications for enriching storage methods. In this paper, multilayer α-In2Se3and MoS2were t...Memtransistors combine memristors and field-effect transistors, which can introduce multi-port control and have significant applications for enriching storage methods. In this paper, multilayer α-In2Se3and MoS2were transferred to the substrate by the mechanical exfoliation method, then a heterojunction MoS_(2)/α-In_(2)Se_(3) memtransistor was prepared. Neural synaptic simulations were performed using electrical and optical pulses as input signals. Through measurements, such as excitatory/inhibitory post-synaptic current(EPSC/IPSC), long-term potentiation/depression(LTP/LTD), and paired-pulse facilitation/depression(PPF/PPD), it can be found that the fabricated device could simulate various functions of neural synapses well, and could work as an electronic synapse in artificial neural networks, proposing a possible solution for neuromorphic storage and computation.展开更多
The onset and mechanisms underlying neurodegenerative diseases remain uncertain. The main features of neurodegenerative diseases have been related with cellular and molecular events like neuronal loss, mitochondrial d...The onset and mechanisms underlying neurodegenerative diseases remain uncertain. The main features of neurodegenerative diseases have been related with cellular and molecular events like neuronal loss, mitochondrial dysfunction and aberrant accumulation of misfolded proteins or peptides in specific areas of the brain. The most prevalent neurodegenerative diseases belonging to age-related pathologies are Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis. Interestingly, mitochondrial dysfunction has been observed to occur during the early onset of several neuropathological events associated to neurodegenerative diseases. The master regulator of mitochondrial quality control and energetic metabolism is the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC-1α). Additionally, it has been observed that PGC-1α appears to be a key factor in maintaining neuronal survival and synaptic transmission. In fact, PGC-1α downregulation in different brain areas(hippocampus, substantia nigra, cortex, striatum and spinal cord) that occurs in function of neurological damage including oxidative stress, neuronal loss, and motor disorders has been seen in several animal and cellular models of neurodegenerative diseases. Current evidence indicates that PGC-1α upregulation may serve as a potent therapeutic approach against development and progression of neuronal damage. Remarkably, increasing evidence shows that PGC-1α deficient mice have neurodegenerative diseases-like features, as well as neurological abnormalities. Finally, we discuss recent studies showing novel specific PGC-1α isoforms in the central nervous system that appear to exert a key role in the age of onset of neurodegenerative diseases and have a neuroprotective function in the central nervous system, thus opening a new molecular strategy for treatment of neurodegenerative diseases. The purpose of this review is to provide an up-to-date overview of the PGC-1α role in the physiopathology of neurodegenerative diseases, as well as establish the importance of PGC-1α function in synaptic transmission and neuronal survival.展开更多
rTg4510 mice are transgenic mice expressing P301L mutant tau and have been developed as an animal model of tauopathies including Alzheimer’s disease(AD).Besides cognitive impairments,rTg4510 mice also show abnormal h...rTg4510 mice are transgenic mice expressing P301L mutant tau and have been developed as an animal model of tauopathies including Alzheimer’s disease(AD).Besides cognitive impairments,rTg4510 mice also show abnormal hyperactivity behavior.Cornel iridoid glycoside(CIG)is an active ingredient extracted from Cornus officinalis,a traditional Chinese herb.The purpose of the present study was to investigate the effects of CIG on the emotional disorders such as hyperactivity,and related mechanisms.The emotional hyperactivity was detected by locomotor activity test and Y maze test.Immunofluorescent and immunohistochemical analyses were conducted to measure neuron loss and phosphorylated tau.Western blotting was used to detect the expression of related proteins.The results showed that intragastric administration of CIG for 3 months decreased the hyperactivity phenotype,prevented neuronal loss,reduced tau hyperphosphorylation and aggregation in the amygdala of rTg4510 mice.Meanwhile,CIG alleviated the synaptic dysfunction by increasing the expression of N-methyl-D-aspartate receptors(NMDARs)subunits GluN1 and GluN2A andαamino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor(AMPAR)subunits GluA1 and GluA2,and increased the level of phosphorylated Ca2+/calmodulin dependent protein kinase IIα(p-CaMK IIα)in the brain of rTg4510 mice.In conclusion,CIG may have potential to treat the emotional disorders in tauopathies such as AD through reducing tau pathology and improving synaptic dysfunction.展开更多
Alzheimer’s disease(AD)is the most common age-dependent disease of dementia,and there is currently no cure available.This hallmark pathologies of AD are the presence of amyloid plaques and neurofibrillary tangles.Alt...Alzheimer’s disease(AD)is the most common age-dependent disease of dementia,and there is currently no cure available.This hallmark pathologies of AD are the presence of amyloid plaques and neurofibrillary tangles.Although the exact etiology of AD remains a mystery,studies over the past 30 have shown that abnormal generation or accumulation of β-amyloid peptides(Aβ)is likely to be a predominant early event in AD pathological development.Aβ is generated from amyloid precursor protein(APP)via proteolytic cleavage by β-site APP cleaving enzyme 1(BACE1).Chemical inhibition of BACE1 has been shown to reduce Aβ in animal studies and in human trials.While BACE1 inhibitors are currently being tested in clinical trials to treat AD patients,it is highly important to understand whether BACE1 inhibition will significantly impact cognitive functions in AD patients.This review summarizes the recent studies on BACE1 synaptic functions.This knowledge will help to guide the proper use of BACE1 inhibitors in AD therapy.展开更多
Sleep benefits the restoration of energy metabolism and thereby suppo rts neuronal plasticity and cognitive behaviors.Sirt6 is a NAD+-dependent protein deacetylase that has been recognized as an essential regulator of...Sleep benefits the restoration of energy metabolism and thereby suppo rts neuronal plasticity and cognitive behaviors.Sirt6 is a NAD+-dependent protein deacetylase that has been recognized as an essential regulator of energy metabolism because it modulates various transcriptional regulators and metabolic enzymes.The aim of this study was to investigate the influence of Sirt6 on cerebral function after chronic sleep deprivation(CSD).We assigned C57BL/6J mice to control or two CSD groups and subjected them to AAV2/9-CMV-EGFP or AAV2/9-CMV-Sirt6-EGFP infection in the prelimbic cortex(PrL).We then assessed cerebral functional connectivity(FC) using resting-state functional MRI,neuron/astrocyte metabolism using a metabolic kinetics analysis;dendritic spine densities using sparse-labeling;and miniature excitato ry postsynaptic currents(mEPSCs) and action potential(AP) firing rates using whole-cell patchclamp recordings.In addition,we evaluated cognition via a comprehensive set of behavioral tests.Compared with controls,Sirt6 was significantly decreased(P<0.05) in the PrL after CSD,accompanied by cognitive deficits and decreased FC between the PrL and accumbens nucleus,piriform cortex,motor co rtex,somatosensory co rtex,olfactory tubercle,insular cortex,and cerebellum.Sirt6 ove rexpression reve rsed CSD-induced cognitive impairment and reduced FC.Our analysis of metabolic kinetics using [1-13C] glucose and [2-13C] acetate showed that CSD reduced neuronal Glu4and GABA2synthesis,which could be fully restored via forced Sirt6 expression.Furthermore,Sirt6 ove rexpression reversed CSD-induced decreases in AP firing rates as well as the frequency and amplitude of mEPSCs in PrL pyramidal neurons.These data indicate that Sirt6 can improve cognitive impairment after CSD by regulating the PrL-associated FC network,neuronal glucose metabolism,and glutamatergic neurotransmission.Thus,Sirt6 activation may have potential as a novel strategy for treating sleep disorder-related diseases.展开更多
Memristors have great potential in neural network computation.Perovskite memristors exhibit excellent resistive-switching(RS)properties between high resistance state(HRS)and low resistance state(LRS)state under applie...Memristors have great potential in neural network computation.Perovskite memristors exhibit excellent resistive-switching(RS)properties between high resistance state(HRS)and low resistance state(LRS)state under applied voltage due to the extraordinary ion migration and superior charge transfer.However,the stability issue of traditional three-dimensional(3D)perovskites is still challenging.Here,one-dimensional(1D)(CH_(3))_(3)SPbI_(3)perovskite passivation layer was in-situ formed on 3D perovskite film,which was further applied in stable synaptic memristor.The memristor was provided with three resistance states due to the heterojunction electric field coupled with ion migration.The on/off ratio of memristors was obviously improved from 10 to over 60.The RS characteristics of 3D/1D perovskite memristor remained unchanged after 10^(3)s read and 300 switching cycles.The 3D/1D perovskite memristor effectively exhibited versatile synaptic plasticity behaviors including long-term potentiation,long-term depression and paired-pulse facilitation by controlling the input voltages.Notably,the novel device provides a new candidate for next-generation neuromorphic computing.展开更多
In the nervous system, neurons contact each other to form neuronal circuits and drive behavior, relying heavily on synaptic connections. The proper development and growth of synapses allows functional transmission of ...In the nervous system, neurons contact each other to form neuronal circuits and drive behavior, relying heavily on synaptic connections. The proper development and growth of synapses allows functional transmission of electrical information between neurons or between neurons and muscle fibers. Defects in synapse-formation or development lead to many diseases. Autophagy, a major determinant of protein turnover, is an essential process that takes place in developing synapses. During the induction of autophagy, proteins and cytoplasmic components are encapsulated in autophagosomes, which fuse with lysosomes to form autolysosomes. The cargoes are subsequently degraded and recycled. However, aberrant autophagic activity may lead to synaptic dysfunction, which is a common pathological characteristic in several disorders. Here, we review the current understanding of autophagy in regulating synaptic development and function. In addition, autophagy-related synaptic dysfunction in human diseases is also summarized.展开更多
Transfer RNA(t RNA)-derived small RNAs(ts RNAs) are a recently established family of regulatory small non-coding RNAs that modulate diverse biological processes. Growing evidence indicates that ts RNAs are involved in...Transfer RNA(t RNA)-derived small RNAs(ts RNAs) are a recently established family of regulatory small non-coding RNAs that modulate diverse biological processes. Growing evidence indicates that ts RNAs are involved in neurological disorders and play a role in the pathogenesis of neurodegenerative disease. However, whether ts RNAs are involved in traumatic brain injury-induced secondary injury remains poorly understood. In this study, a mouse controlled cortical impact model of traumatic brain injury was established, and integrated ts RNA and messenger RNA(m RNA) transcriptome sequencing were used. The results revealed that 103 ts RNAs were differentially expressed in the mouse model of traumatic brain injury at 72 hours, of which 56 ts RNAs were upregulated and 47 ts RNAs were downregulated. Based on micro RNA-like seed matching and Pearson correlation analysis, 57 differentially expressed ts RNA-m RNA interaction pairs were identified, including 29 ts RNAs and 26 m RNAs. Moreover, Gene Ontology annotation of target genes revealed that the significantly enriched terms were primarily associated with inflammation and synaptic function. Collectively, our findings suggest that ts RNAs may be associated with traumatic brain injury-induced secondary brain injury, and are thus a potential therapeutic target for traumatic brain injury. The study was approved by the Beijing Neurosurgical Institute Animal Care and Use Committee(approval No. 20190411) on April 11, 2019.展开更多
Synaptic devices that merge memory and processing functions into one unit have broad application potentials in neuromorphic computing, soft robots, and humanmachine interfaces. However, most previously reported synapt...Synaptic devices that merge memory and processing functions into one unit have broad application potentials in neuromorphic computing, soft robots, and humanmachine interfaces. However, most previously reported synaptic devices exhibit fixed performance once been fabricated,which limits their application in diverse scenarios. Here, we report floating-gate photosensitive synaptic transistors with charge-trapping perovskite quantum dots(PQDs) and atomic layer deposited(ALD) Al_(2)O_(3) tunneling layers, which exhibit typical synaptic behaviors including excitatory postsynaptic current(EPSC), pair-pulse facilitation and dynamic filtering characteristics under both electrical or optical signal stimulation. Further, the combination of the high-quality Al2O3 tuning layer and highly photosensitive PQDs charge-trapping layer provides the devices with extensively tunable synaptic performance under optical and electrical co-modulation. Applying light during electrical modulation can significantly improve both the synaptic weight changes and the nonlinearity of weight updates, while the memory effect under light modulation can be obviously adjusted by the gate voltage.The pattern learning and forgetting processes for "0" and "1"with different synaptic weights and memory times are further demonstrated in the device array. Overall, this work provides synaptic devices with tunable functions for building complex and robust artificial neural networks.展开更多
The amyloid-β(Aβ)oligomer,rather than the Aβmonomer,is considered to be the primary initiator of Alzheimer’s disease.It was hypothesized that p(Aβ3-10)10-MT,the recombinant Aβ3-10 gene vaccine of the Aβoligomer...The amyloid-β(Aβ)oligomer,rather than the Aβmonomer,is considered to be the primary initiator of Alzheimer’s disease.It was hypothesized that p(Aβ3-10)10-MT,the recombinant Aβ3-10 gene vaccine of the Aβoligomer has the potential to treat Alzheimer’s disease.In this study,we intramuscularly injected the p(Aβ3-10)10-MT vaccine into the left hindlimb of APP/PS1/tau triple-transgenic mice,which are a model for Alzheimer’s disease.Our results showed that the p(Aβ3-10)10-MT vaccine effectively reduced Aβoligomer levels and plaque deposition in the cerebral cortex and hippocampus,decreased the levels tau protein variants,reduced synaptic loss,protected synaptic function,reduced neuron loss,and ameliorated memory impairment without causing any cerebral hemorrhaging.Therefore,this novel DNA vaccine,which is safe and highly effective in mouse models of Alzheimer’s disease,holds a lot of promise for the treatment of Alzheimer’s disease in humans.展开更多
The human brain contains an estimated 100 billion neurons that must be systematically organized into functional neural circuits for it to function properly.These circuits range from short-range local signaling network...The human brain contains an estimated 100 billion neurons that must be systematically organized into functional neural circuits for it to function properly.These circuits range from short-range local signaling networks between neighboring neurons to long-range networks formed between various brain regions.Compelling converging evidence indicates that alterations in neural circuits arising from abnormalities during early neuronal development or neurodegeneration contribute significantly to the etiology of neurological disorders.Supporting this notion,efforts to identify genetic causes of these disorders have uncovered an over-representation of genes encoding proteins involved in the processes of neuronal differentiation,maturation,synaptogenesis and synaptic function.Fasciculation and elongation protein zeta-1,a Kinesin-1 adapter,has emerged as a key central player involved in many of these processes.Fasciculation and elongation protein zeta-1-dependent transport of synaptic cargoes and mitochondria is essential for neuronal development and synapse establishment.Furthermore,it acts downstream of guidance cue pathways to regulate axo-dendritic development.Significantly,perturbing its function causes abnormalities in neuronal development and synapse formation both in the brain as well as the peripheral nervous system.Mutations and deletions of the fasciculation and elongation protein zeta-1 gene are linked to neurodevelopmental disorders.Moreover,altered phosphorylation of the protein contributes to neurodegenerative disorders.Together,these findings strongly implicate the importance of fasciculation and elongation protein zeta-1 in the establishment of neuronal circuits and its maintenance.展开更多
Neurons and glial cells, particularly astrocytes, are the two main cell populations in the central nervous system. While it is established that brain functions primarily rely on neuronal activity, an active contributi...Neurons and glial cells, particularly astrocytes, are the two main cell populations in the central nervous system. While it is established that brain functions primarily rely on neuronal activity, an active contribution of astrocytes to information processing is only starting to be considered. There is growing evidence that astrocytes, as part of the tripartite synapse, participate in this challenge by receiving and integrating neuronal signals and, in turn, by sending signals that target neurons[1]. The involvement of astrocytes in information processing has mainly been studied at the level of the single astrocyte, often missing the role of astrocyte networks in this process.展开更多
Objective To study the role of HLB-1 in regulating the organization and function of neuromuscular junctions in nematode Caenorhabditis elegans. Methods To evaluate the functions of HLB-1 in regulating the organization...Objective To study the role of HLB-1 in regulating the organization and function of neuromuscular junctions in nematode Caenorhabditis elegans. Methods To evaluate the functions of HLB-1 in regulating the organization and function of neuromuscular junctions, effects of hlb-1 mutation on the synaptic structures were revealed by uncovering the expression patterns of SNB-1 ：：GFP and UNC-49：GFP, and pharmacologic assays with aldicarb and levamisole were also used to test the synaptic functions. Further rescue and mosaic analysis confirmed HLB-1＇s role in regulating the organization and function of neuromuscular junctions. Results Loss of HLB-1 function did not result in defects in neuronal outgrowth or neuronal loss, but caused obvious defects of SNB-1：：GFP and UNC-49：：GFP puncta localization, suggesting the altered presynaptic and postsynaptic structures. The mutant animals exhibited severe defects in locomotion behaviors and altered responses to an inhibitor of acetylcholinesterase and a cholinergic agonist, indicating the altered presynaptic and postsynaptic functions. Rescue and mosaic analysis experiments suggested that HLB-1 regulated synaptic functions in a cell nonautonomously way. Moreover, HLB- 1 expression was not required for the presynaptic active zone morphology. Genetic evidence further demonstrated that hlb-1 acted in a parallel pathway with syd-2 to regulate the synaptic functions. Conclusion HLB-1 appeared as a new regulator for the organization and function of neuromuscular junctions in C. elegans.展开更多
Photonic synaptic transistors are promising neuromorphic computing systems that are expected to circumvent the intrinsic limitations of von Neumann-based computation.The design and construction of photonic synaptic tr...Photonic synaptic transistors are promising neuromorphic computing systems that are expected to circumvent the intrinsic limitations of von Neumann-based computation.The design and construction of photonic synaptic transistors with a facile fabrication process and highefficiency information processing ability are highly desired,while it remains a tremendous challenge.Herein,a new approach based on spin coating of a blend of CsPbBr_(3) perovskite quantum dot(QD)and PDVT-10 conjugated polymer is reported for the fabrication of photonic synaptic transistors.The combination of flat surface,outstanding optical absorption,and remarkable charge transporting performance contributes to high-efficiency photon-to-electron conversion for such perovskite-based synapses.High-performance photonic synaptic transistors are thus fabricated with essential synaptic functionalities,including excitatory postsynaptic current(EPSC),paired-pulse facilitation(PPF),and long-term memory.By utilizing the photonic potentiation and electrical depression features,perovskite-based photonic synaptic transistors are also explored for neuromorphic computing simulations,showing high pattern recognition accuracy of up to 89.98%,which is one of the best values reported so far for synaptic transistors used in pattern recognition.This work provides an effective and convenient pathway for fabricating perovskite-based neuromorphic systems with high pattern recognition accuracy.展开更多
Acid-sensing ion channels(ASICs),the main H^(+)receptors in the central nervous system,sense extracellular pH fluctuations and mediate cation influx.ASIC1a,the major subunit responsible for acid-activated current,is w...Acid-sensing ion channels(ASICs),the main H^(+)receptors in the central nervous system,sense extracellular pH fluctuations and mediate cation influx.ASIC1a,the major subunit responsible for acid-activated current,is widely expressed in brain neurons,where it plays pivotal roles in diverse functions including synaptic transmission and plasticity.However,the underlying molecular mechanisms for these functions remain mysterious.Using extracellular epitope tagging and a novel antibody recognizing the hASIC1a ectodomain,we examined the membrane targeting and dynamic trafficking of hASIC1a in cultured cortical neurons.Surface hASIC1a was distributed throughout somata and dendrites,clustered in spine heads,and co-localized with postsynaptic markers.By extracellular pHluorin tagging and fluorescence recovery after photobleaching,we detected movement of hASIC1a in synaptic spine heads.Single-particle tracking along with use of the anti-hASIC1a ectodomain antibody revealed long-distance migration and local movement of surface hASIC1a puncta on dendrites.Importantly,enhancing synaptic activity with brain-derived neurotrophic factor accelerated the trafficking and lateral mobility of hASIC1a.With this newly-developed toolbox,our data demonstrate the synaptic location and high dynamics of functionallyrelevant hASIC1a on the surface of excitatory synapses,supporting its involvement in synaptic functions.展开更多
Objective To investigate whether genes required for synaptogenesis and synaptic function are also involved in fat storage control in Caenorhabditis elegans. Methods Fat storage was examined in mutants of genes affecti...Objective To investigate whether genes required for synaptogenesis and synaptic function are also involved in fat storage control in Caenorhabditis elegans. Methods Fat storage was examined in mutants of genes affecting the synaptogenesis and synaptic function. In addition, the genetic interactions of SNAREs syntaxin/unc-64 and SNAP-25/ric-4 with daf-2, daf-7, nhr-49, sbp-1 and mdt-15 in regulating fat storage were further investigated. The tissue-specific activities of unc-64 and ric-4 were investigated to study the roles of unc-64 and ric-4 in regulating fat storage in the nervous system and/or the intestine. Results Mutations of genes required for the formation of presynaptic neurotransmission site did not obviously influence fat storage. However, among the genes required for synaptic function, the plasma membrane-associated SNAREs syntaxin/unc-64 and SNAP-25/ric-4 genes were involved in the fat storage control. Fat storage in the intestinal cells was dramatically increased in unc-64 and ric-4 mutants as revealed by Sudan Black and Nile Red strainings, although the fat droplet size was not significantly changed. Moreover, in both the nervous system and the intestine, expression of unc-64 significantly inhibited the increase in fat storage observed in unc-64 mutant. And expression of ric-4 in the nervous system completely restored fat storage in ric-4 mutant. Genetic interaction assay further indicated that both unc-64 and ric-4 regulated fat storage independently of daf-2 [encoding an insulin-like growth factor-I （IGF-I） receptor], daf-7 [encoding a transforming growth factor-β （TGF-β） ligand], and nhr-49 （encoding a nuclear hormone receptor）. Besides, mutation of daf-16 did not obviously affect the phenotype of increased fat storage in unc-64 or ric-4 mutant. Furthermore, unc-64 and ric-4 regulated fat storage probably through the ARC105/mdt-15- and SREBP/sbp-1-mediated signaling pathways. In addition, fat storage in unc-64; ric-4 was higher than that in either unc-64 or ric-4 single mutant nematodes, suggesting that unc-64 functions in parallel with ric-4 in regulating fat storage. Conclusion The plasma membrane-associated SNAREs syntaxin/ unc-64 and SNAP-25/ric-4 function in parallel in regulating fat storage in C. elegans, probably through the ARC105/mdt-15- and SREBP/sbp-1-mediated signaling pathways.展开更多
Objective To investigate the role of environmental factor—temperature in the regulation of aging process by unc-13 and sbt-1 in Caenorhabditis elegans. Methods The lifespan, the speed of pharynx pumping, and the inte...Objective To investigate the role of environmental factor—temperature in the regulation of aging process by unc-13 and sbt-1 in Caenorhabditis elegans. Methods The lifespan, the speed of pharynx pumping, and the intestinal autofluorescence of unc-13 and sbt-1 mutants were examined at different temperature conditions. In addition, to exclude the possible influences from other factors in unc-13 and sbt-1 mutants, the dauer formation, the thermotaxis, the brood size and the population percentage of the mutants expressing hsp16.2-gfp were further investigated. Results Mutations of unc-13 and sbt-1 significantly increased the mean and the maximum lifespans of nematodes cultured at 20 oC and 25 oC, while no noticeable increase was found at 15 oC in either the mean or the maximum lifespan. Investigations on the speed of pharynx pumping and the intestinal autofluorescence suggested that at 20 oC and 25 oC, mutations of unc-13 and sbt-1 could slow the aging process and delay the accumulation of aging-related cellular damage. Meanwhile, mutations of unc-13 or sbt-1 did not affect the dauer formation or the thermotaxis to different temperatures in nematodes. In contrast, at 20 oC and 25 oC conditions, mutations of unc-13 and sbt-1 significantly decreased the brood size and the percentage of nematodes expressing hsp16.2-gfp, while no such differences were detected at 15 oC. Moreover, the thermotolerance of unc-13 and sbt-1 mutants could be greatly strengthened after the 16-h heat shock at 35 oC. Conclusion The regulation of aging by unc-13 and sbt-1 is temperature-dependent. And the alterations in reproduction capability and stress response may be associated with the formation of this temperature-dependent property.展开更多
Death-mediating proteases such as caspases and caspase-3 in particular, have been implicated in neurodegenerative processes, aging and Alzheimer＇s disease. However, emerging evidence suggests that in addition to thei...Death-mediating proteases such as caspases and caspase-3 in particular, have been implicated in neurodegenerative processes, aging and Alzheimer＇s disease. However, emerging evidence suggests that in addition to their classical role in cell death, caspases play a key role in modulating synaptic function. It is remarkable that active caspases-3, which can trigger widespread damage and degeneration, aggregates in structures as delicate as synapses and persists in neurons without causing acute cell death. Here, we evaluate this dichotomy, and discuss the hypothesis that caspase-3 may be a bifurcation point in cellular signaling, able to orient the neuronal response to stress down either pathological/apoptotic pathways or towards physiological cellular remodeling. We propose that temporal, spatial and other regulators of caspase activity are key determinants of the ultimate effect of caspase-3 activation in neurons. This concept has implications for differential roles of caspase-3 activation across the lifespan. Specifically, we propose that limited caspase-3 activation is critical for synaptic function in the healthy adult brain while chronic activation is involved in degenerative processes in the aging brain.展开更多
2D polymers(2DPs)have attracted increasing interests in sensors,catalysis,and gas storage applications.Furthermore,2DPs with unique band structure and tunable photophysical properties also have immense potential for a...2D polymers(2DPs)have attracted increasing interests in sensors,catalysis,and gas storage applications.Furthermore,2DPs with unique band structure and tunable photophysical properties also have immense potential for application in photonic neuromorphic computing.Here,photonic synaptic transistors based on 2DPs as the light-tunable charge-trapping medium are developed for the first time.The resulted organic transistors can successfully emulate common synaptic functions,including excitatory postsynaptic current,pair-pulse facilitation,the transition of short-term memory to long-term memory,and dynamic filtering.Benefitting from the high photosensitivity of the 2DP,the devices can be operated under a low operating voltage of0.1 V,and achieve an ultralow energy consumption of~0.29 pJ per event.In addition,the heterostructure formed between the 2DP and organic semiconductor enables spectrum-dependent synaptic responses,which facilitates the simulation of visual learning and memory processes in distinct emotional states.The underlying mechanism of spectrum-dependent synaptic-like behaviors is systematically validated with in situ atomic force microscopy based electrical techniques.The spectrum-enabled tunability of synaptic behaviors further promotes the realization of optical logic functions and associative learning.This work inspires the new application of 2DPs in photonic synapses for future neuromorphic computing.展开更多
基金Project supported by the National Natural Science Foundation of China (Grant No. 51702245)。
文摘Memtransistors combine memristors and field-effect transistors, which can introduce multi-port control and have significant applications for enriching storage methods. In this paper, multilayer α-In2Se3and MoS2were transferred to the substrate by the mechanical exfoliation method, then a heterojunction MoS_(2)/α-In_(2)Se_(3) memtransistor was prepared. Neural synaptic simulations were performed using electrical and optical pulses as input signals. Through measurements, such as excitatory/inhibitory post-synaptic current(EPSC/IPSC), long-term potentiation/depression(LTP/LTD), and paired-pulse facilitation/depression(PPF/PPD), it can be found that the fabricated device could simulate various functions of neural synapses well, and could work as an electronic synapse in artificial neural networks, proposing a possible solution for neuromorphic storage and computation.
基金supported by Fondecyt 1200908(to JF)the Conicyt 21141247(to JDP)。
文摘The onset and mechanisms underlying neurodegenerative diseases remain uncertain. The main features of neurodegenerative diseases have been related with cellular and molecular events like neuronal loss, mitochondrial dysfunction and aberrant accumulation of misfolded proteins or peptides in specific areas of the brain. The most prevalent neurodegenerative diseases belonging to age-related pathologies are Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis. Interestingly, mitochondrial dysfunction has been observed to occur during the early onset of several neuropathological events associated to neurodegenerative diseases. The master regulator of mitochondrial quality control and energetic metabolism is the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC-1α). Additionally, it has been observed that PGC-1α appears to be a key factor in maintaining neuronal survival and synaptic transmission. In fact, PGC-1α downregulation in different brain areas(hippocampus, substantia nigra, cortex, striatum and spinal cord) that occurs in function of neurological damage including oxidative stress, neuronal loss, and motor disorders has been seen in several animal and cellular models of neurodegenerative diseases. Current evidence indicates that PGC-1α upregulation may serve as a potent therapeutic approach against development and progression of neuronal damage. Remarkably, increasing evidence shows that PGC-1α deficient mice have neurodegenerative diseases-like features, as well as neurological abnormalities. Finally, we discuss recent studies showing novel specific PGC-1α isoforms in the central nervous system that appear to exert a key role in the age of onset of neurodegenerative diseases and have a neuroprotective function in the central nervous system, thus opening a new molecular strategy for treatment of neurodegenerative diseases. The purpose of this review is to provide an up-to-date overview of the PGC-1α role in the physiopathology of neurodegenerative diseases, as well as establish the importance of PGC-1α function in synaptic transmission and neuronal survival.
基金This research was supported by National Natural Science Foundation of China(Nos.81473373,81874351,81673406)Capital Science and Technology Leading Talent Training Project(No.Z 191100006119017)+1 种基金Beijing Hospitals Authority Ascent Plan(No.DFL20190803)Cultivation Fund of Capital Medical University(No.PYZ19134).
文摘rTg4510 mice are transgenic mice expressing P301L mutant tau and have been developed as an animal model of tauopathies including Alzheimer’s disease(AD).Besides cognitive impairments,rTg4510 mice also show abnormal hyperactivity behavior.Cornel iridoid glycoside(CIG)is an active ingredient extracted from Cornus officinalis,a traditional Chinese herb.The purpose of the present study was to investigate the effects of CIG on the emotional disorders such as hyperactivity,and related mechanisms.The emotional hyperactivity was detected by locomotor activity test and Y maze test.Immunofluorescent and immunohistochemical analyses were conducted to measure neuron loss and phosphorylated tau.Western blotting was used to detect the expression of related proteins.The results showed that intragastric administration of CIG for 3 months decreased the hyperactivity phenotype,prevented neuronal loss,reduced tau hyperphosphorylation and aggregation in the amygdala of rTg4510 mice.Meanwhile,CIG alleviated the synaptic dysfunction by increasing the expression of N-methyl-D-aspartate receptors(NMDARs)subunits GluN1 and GluN2A andαamino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor(AMPAR)subunits GluA1 and GluA2,and increased the level of phosphorylated Ca2+/calmodulin dependent protein kinase IIα(p-CaMK IIα)in the brain of rTg4510 mice.In conclusion,CIG may have potential to treat the emotional disorders in tauopathies such as AD through reducing tau pathology and improving synaptic dysfunction.
基金R Yan is supported by grants(MH103942,NS074256 and AG046929)from the National Institutes of Health.
文摘Alzheimer’s disease(AD)is the most common age-dependent disease of dementia,and there is currently no cure available.This hallmark pathologies of AD are the presence of amyloid plaques and neurofibrillary tangles.Although the exact etiology of AD remains a mystery,studies over the past 30 have shown that abnormal generation or accumulation of β-amyloid peptides(Aβ)is likely to be a predominant early event in AD pathological development.Aβ is generated from amyloid precursor protein(APP)via proteolytic cleavage by β-site APP cleaving enzyme 1(BACE1).Chemical inhibition of BACE1 has been shown to reduce Aβ in animal studies and in human trials.While BACE1 inhibitors are currently being tested in clinical trials to treat AD patients,it is highly important to understand whether BACE1 inhibition will significantly impact cognitive functions in AD patients.This review summarizes the recent studies on BACE1 synaptic functions.This knowledge will help to guide the proper use of BACE1 inhibitors in AD therapy.
基金National Natural Science Foundation of China,Nos.81771160 (to ZZ),81671060 (to CC),31970973 (to JW),21921004 (to FX)Translational Medicine and In terdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University,No.ZNJC201934 (to ZZ)。
文摘Sleep benefits the restoration of energy metabolism and thereby suppo rts neuronal plasticity and cognitive behaviors.Sirt6 is a NAD+-dependent protein deacetylase that has been recognized as an essential regulator of energy metabolism because it modulates various transcriptional regulators and metabolic enzymes.The aim of this study was to investigate the influence of Sirt6 on cerebral function after chronic sleep deprivation(CSD).We assigned C57BL/6J mice to control or two CSD groups and subjected them to AAV2/9-CMV-EGFP or AAV2/9-CMV-Sirt6-EGFP infection in the prelimbic cortex(PrL).We then assessed cerebral functional connectivity(FC) using resting-state functional MRI,neuron/astrocyte metabolism using a metabolic kinetics analysis;dendritic spine densities using sparse-labeling;and miniature excitato ry postsynaptic currents(mEPSCs) and action potential(AP) firing rates using whole-cell patchclamp recordings.In addition,we evaluated cognition via a comprehensive set of behavioral tests.Compared with controls,Sirt6 was significantly decreased(P<0.05) in the PrL after CSD,accompanied by cognitive deficits and decreased FC between the PrL and accumbens nucleus,piriform cortex,motor co rtex,somatosensory co rtex,olfactory tubercle,insular cortex,and cerebellum.Sirt6 ove rexpression reve rsed CSD-induced cognitive impairment and reduced FC.Our analysis of metabolic kinetics using [1-13C] glucose and [2-13C] acetate showed that CSD reduced neuronal Glu4and GABA2synthesis,which could be fully restored via forced Sirt6 expression.Furthermore,Sirt6 ove rexpression reversed CSD-induced decreases in AP firing rates as well as the frequency and amplitude of mEPSCs in PrL pyramidal neurons.These data indicate that Sirt6 can improve cognitive impairment after CSD by regulating the PrL-associated FC network,neuronal glucose metabolism,and glutamatergic neurotransmission.Thus,Sirt6 activation may have potential as a novel strategy for treating sleep disorder-related diseases.
基金funded by the National Natural Science Foundation of China(52172205)。
文摘Memristors have great potential in neural network computation.Perovskite memristors exhibit excellent resistive-switching(RS)properties between high resistance state(HRS)and low resistance state(LRS)state under applied voltage due to the extraordinary ion migration and superior charge transfer.However,the stability issue of traditional three-dimensional(3D)perovskites is still challenging.Here,one-dimensional(1D)(CH_(3))_(3)SPbI_(3)perovskite passivation layer was in-situ formed on 3D perovskite film,which was further applied in stable synaptic memristor.The memristor was provided with three resistance states due to the heterojunction electric field coupled with ion migration.The on/off ratio of memristors was obviously improved from 10 to over 60.The RS characteristics of 3D/1D perovskite memristor remained unchanged after 10^(3)s read and 300 switching cycles.The 3D/1D perovskite memristor effectively exhibited versatile synaptic plasticity behaviors including long-term potentiation,long-term depression and paired-pulse facilitation by controlling the input voltages.Notably,the novel device provides a new candidate for next-generation neuromorphic computing.
基金supported by the National Natural Science Foundation of China (81401043 and 81273491)Zhejiang Provincial Natural Science Foundation of China (LQ13H310004 and LY12H31010)+3 种基金the Health Bureau of Zhejiang Province (2013KYA147)a Key Laboratory of Hangzhou City Project (20090233T12)the Science Foundation of Hangzhou Normal University (2012QDL048)the Program of "Xinmiao" Talents in Zhejiang Province,China (2015R423054)
文摘In the nervous system, neurons contact each other to form neuronal circuits and drive behavior, relying heavily on synaptic connections. The proper development and growth of synapses allows functional transmission of electrical information between neurons or between neurons and muscle fibers. Defects in synapse-formation or development lead to many diseases. Autophagy, a major determinant of protein turnover, is an essential process that takes place in developing synapses. During the induction of autophagy, proteins and cytoplasmic components are encapsulated in autophagosomes, which fuse with lysosomes to form autolysosomes. The cargoes are subsequently degraded and recycled. However, aberrant autophagic activity may lead to synaptic dysfunction, which is a common pathological characteristic in several disorders. Here, we review the current understanding of autophagy in regulating synaptic development and function. In addition, autophagy-related synaptic dysfunction in human diseases is also summarized.
基金supported by grants from the National Natural Science Foundation of China,Nos.81471238,81771327Construction of Central Nervous System Injury Basic Science and Clinical Translational Research Platform,Budget of Beijing Municipal Health Commission 2020,No.PXM2020_026280_000002(all to BYL)。
文摘Transfer RNA(t RNA)-derived small RNAs(ts RNAs) are a recently established family of regulatory small non-coding RNAs that modulate diverse biological processes. Growing evidence indicates that ts RNAs are involved in neurological disorders and play a role in the pathogenesis of neurodegenerative disease. However, whether ts RNAs are involved in traumatic brain injury-induced secondary injury remains poorly understood. In this study, a mouse controlled cortical impact model of traumatic brain injury was established, and integrated ts RNA and messenger RNA(m RNA) transcriptome sequencing were used. The results revealed that 103 ts RNAs were differentially expressed in the mouse model of traumatic brain injury at 72 hours, of which 56 ts RNAs were upregulated and 47 ts RNAs were downregulated. Based on micro RNA-like seed matching and Pearson correlation analysis, 57 differentially expressed ts RNA-m RNA interaction pairs were identified, including 29 ts RNAs and 26 m RNAs. Moreover, Gene Ontology annotation of target genes revealed that the significantly enriched terms were primarily associated with inflammation and synaptic function. Collectively, our findings suggest that ts RNAs may be associated with traumatic brain injury-induced secondary brain injury, and are thus a potential therapeutic target for traumatic brain injury. The study was approved by the Beijing Neurosurgical Institute Animal Care and Use Committee(approval No. 20190411) on April 11, 2019.
基金supported by the National Natural Science Foundation of China (61874029)。
文摘Synaptic devices that merge memory and processing functions into one unit have broad application potentials in neuromorphic computing, soft robots, and humanmachine interfaces. However, most previously reported synaptic devices exhibit fixed performance once been fabricated,which limits their application in diverse scenarios. Here, we report floating-gate photosensitive synaptic transistors with charge-trapping perovskite quantum dots(PQDs) and atomic layer deposited(ALD) Al_(2)O_(3) tunneling layers, which exhibit typical synaptic behaviors including excitatory postsynaptic current(EPSC), pair-pulse facilitation and dynamic filtering characteristics under both electrical or optical signal stimulation. Further, the combination of the high-quality Al2O3 tuning layer and highly photosensitive PQDs charge-trapping layer provides the devices with extensively tunable synaptic performance under optical and electrical co-modulation. Applying light during electrical modulation can significantly improve both the synaptic weight changes and the nonlinearity of weight updates, while the memory effect under light modulation can be obviously adjusted by the gate voltage.The pattern learning and forgetting processes for "0" and "1"with different synaptic weights and memory times are further demonstrated in the device array. Overall, this work provides synaptic devices with tunable functions for building complex and robust artificial neural networks.
基金supported by the National Nature Science Foundation of China,No.81870819(to YPC)the Natural Science Foundation of Liaoning Province of China,No.2019-MS-200(to XNX).
文摘The amyloid-β(Aβ)oligomer,rather than the Aβmonomer,is considered to be the primary initiator of Alzheimer’s disease.It was hypothesized that p(Aβ3-10)10-MT,the recombinant Aβ3-10 gene vaccine of the Aβoligomer has the potential to treat Alzheimer’s disease.In this study,we intramuscularly injected the p(Aβ3-10)10-MT vaccine into the left hindlimb of APP/PS1/tau triple-transgenic mice,which are a model for Alzheimer’s disease.Our results showed that the p(Aβ3-10)10-MT vaccine effectively reduced Aβoligomer levels and plaque deposition in the cerebral cortex and hippocampus,decreased the levels tau protein variants,reduced synaptic loss,protected synaptic function,reduced neuron loss,and ameliorated memory impairment without causing any cerebral hemorrhaging.Therefore,this novel DNA vaccine,which is safe and highly effective in mouse models of Alzheimer’s disease,holds a lot of promise for the treatment of Alzheimer’s disease in humans.
基金the Singapore Ministry of Education(T1-2015 Apr-03)the National University of SingaporeInstitute for Health Innovation and Technology to JJEC.
文摘The human brain contains an estimated 100 billion neurons that must be systematically organized into functional neural circuits for it to function properly.These circuits range from short-range local signaling networks between neighboring neurons to long-range networks formed between various brain regions.Compelling converging evidence indicates that alterations in neural circuits arising from abnormalities during early neuronal development or neurodegeneration contribute significantly to the etiology of neurological disorders.Supporting this notion,efforts to identify genetic causes of these disorders have uncovered an over-representation of genes encoding proteins involved in the processes of neuronal differentiation,maturation,synaptogenesis and synaptic function.Fasciculation and elongation protein zeta-1,a Kinesin-1 adapter,has emerged as a key central player involved in many of these processes.Fasciculation and elongation protein zeta-1-dependent transport of synaptic cargoes and mitochondria is essential for neuronal development and synapse establishment.Furthermore,it acts downstream of guidance cue pathways to regulate axo-dendritic development.Significantly,perturbing its function causes abnormalities in neuronal development and synapse formation both in the brain as well as the peripheral nervous system.Mutations and deletions of the fasciculation and elongation protein zeta-1 gene are linked to neurodevelopmental disorders.Moreover,altered phosphorylation of the protein contributes to neurodegenerative disorders.Together,these findings strongly implicate the importance of fasciculation and elongation protein zeta-1 in the establishment of neuronal circuits and its maintenance.
文摘Neurons and glial cells, particularly astrocytes, are the two main cell populations in the central nervous system. While it is established that brain functions primarily rely on neuronal activity, an active contribution of astrocytes to information processing is only starting to be considered. There is growing evidence that astrocytes, as part of the tripartite synapse, participate in this challenge by receiving and integrating neuronal signals and, in turn, by sending signals that target neurons[1]. The involvement of astrocytes in information processing has mainly been studied at the level of the single astrocyte, often missing the role of astrocyte networks in this process.
基金the National Natural Science Foundation of China (No. 30771113, 30870810)the Program for New Century Excellent Talents in University, Ministry of Education, China
文摘Objective To study the role of HLB-1 in regulating the organization and function of neuromuscular junctions in nematode Caenorhabditis elegans. Methods To evaluate the functions of HLB-1 in regulating the organization and function of neuromuscular junctions, effects of hlb-1 mutation on the synaptic structures were revealed by uncovering the expression patterns of SNB-1 ：：GFP and UNC-49：GFP, and pharmacologic assays with aldicarb and levamisole were also used to test the synaptic functions. Further rescue and mosaic analysis confirmed HLB-1＇s role in regulating the organization and function of neuromuscular junctions. Results Loss of HLB-1 function did not result in defects in neuronal outgrowth or neuronal loss, but caused obvious defects of SNB-1：：GFP and UNC-49：：GFP puncta localization, suggesting the altered presynaptic and postsynaptic structures. The mutant animals exhibited severe defects in locomotion behaviors and altered responses to an inhibitor of acetylcholinesterase and a cholinergic agonist, indicating the altered presynaptic and postsynaptic functions. Rescue and mosaic analysis experiments suggested that HLB-1 regulated synaptic functions in a cell nonautonomously way. Moreover, HLB- 1 expression was not required for the presynaptic active zone morphology. Genetic evidence further demonstrated that hlb-1 acted in a parallel pathway with syd-2 to regulate the synaptic functions. Conclusion HLB-1 appeared as a new regulator for the organization and function of neuromuscular junctions in C. elegans.
基金supported by the Ministry of Science and Technology of the People’s Republic of China(2018YFA0703200)the National Natural Science Foundation of China(91833306,51633006,51703160,51733004,51725304,and 52003189)Fujian Science&Technology Innovation Laboratory for Optoelectronic Information of China(2021ZZ130 and 2021ZZ129)。
文摘Photonic synaptic transistors are promising neuromorphic computing systems that are expected to circumvent the intrinsic limitations of von Neumann-based computation.The design and construction of photonic synaptic transistors with a facile fabrication process and highefficiency information processing ability are highly desired,while it remains a tremendous challenge.Herein,a new approach based on spin coating of a blend of CsPbBr_(3) perovskite quantum dot(QD)and PDVT-10 conjugated polymer is reported for the fabrication of photonic synaptic transistors.The combination of flat surface,outstanding optical absorption,and remarkable charge transporting performance contributes to high-efficiency photon-to-electron conversion for such perovskite-based synapses.High-performance photonic synaptic transistors are thus fabricated with essential synaptic functionalities,including excitatory postsynaptic current(EPSC),paired-pulse facilitation(PPF),and long-term memory.By utilizing the photonic potentiation and electrical depression features,perovskite-based photonic synaptic transistors are also explored for neuromorphic computing simulations,showing high pattern recognition accuracy of up to 89.98%,which is one of the best values reported so far for synaptic transistors used in pattern recognition.This work provides an effective and convenient pathway for fabricating perovskite-based neuromorphic systems with high pattern recognition accuracy.
基金This work was supported by grants from the National Natural Science Foundation of China(81961128024 and 81730095)the Innovative Research Team of High-level Local Universities in Shanghai+2 种基金the Science and Technology Commission of Shanghai Municipality(18JC1420302)the Shanghai Municipal Science and Technology Major Project(2018SHZDZX05)the US National Institutes of Health(NS114716).
文摘Acid-sensing ion channels(ASICs),the main H^(+)receptors in the central nervous system,sense extracellular pH fluctuations and mediate cation influx.ASIC1a,the major subunit responsible for acid-activated current,is widely expressed in brain neurons,where it plays pivotal roles in diverse functions including synaptic transmission and plasticity.However,the underlying molecular mechanisms for these functions remain mysterious.Using extracellular epitope tagging and a novel antibody recognizing the hASIC1a ectodomain,we examined the membrane targeting and dynamic trafficking of hASIC1a in cultured cortical neurons.Surface hASIC1a was distributed throughout somata and dendrites,clustered in spine heads,and co-localized with postsynaptic markers.By extracellular pHluorin tagging and fluorescence recovery after photobleaching,we detected movement of hASIC1a in synaptic spine heads.Single-particle tracking along with use of the anti-hASIC1a ectodomain antibody revealed long-distance migration and local movement of surface hASIC1a puncta on dendrites.Importantly,enhancing synaptic activity with brain-derived neurotrophic factor accelerated the trafficking and lateral mobility of hASIC1a.With this newly-developed toolbox,our data demonstrate the synaptic location and high dynamics of functionallyrelevant hASIC1a on the surface of excitatory synapses,supporting its involvement in synaptic functions.
基金supported by the grants from the National Natural Science Foundation of China(No. 30771113, 30870810)the Program for New Century Excellent Talents in University
文摘Objective To investigate whether genes required for synaptogenesis and synaptic function are also involved in fat storage control in Caenorhabditis elegans. Methods Fat storage was examined in mutants of genes affecting the synaptogenesis and synaptic function. In addition, the genetic interactions of SNAREs syntaxin/unc-64 and SNAP-25/ric-4 with daf-2, daf-7, nhr-49, sbp-1 and mdt-15 in regulating fat storage were further investigated. The tissue-specific activities of unc-64 and ric-4 were investigated to study the roles of unc-64 and ric-4 in regulating fat storage in the nervous system and/or the intestine. Results Mutations of genes required for the formation of presynaptic neurotransmission site did not obviously influence fat storage. However, among the genes required for synaptic function, the plasma membrane-associated SNAREs syntaxin/unc-64 and SNAP-25/ric-4 genes were involved in the fat storage control. Fat storage in the intestinal cells was dramatically increased in unc-64 and ric-4 mutants as revealed by Sudan Black and Nile Red strainings, although the fat droplet size was not significantly changed. Moreover, in both the nervous system and the intestine, expression of unc-64 significantly inhibited the increase in fat storage observed in unc-64 mutant. And expression of ric-4 in the nervous system completely restored fat storage in ric-4 mutant. Genetic interaction assay further indicated that both unc-64 and ric-4 regulated fat storage independently of daf-2 [encoding an insulin-like growth factor-I （IGF-I） receptor], daf-7 [encoding a transforming growth factor-β （TGF-β） ligand], and nhr-49 （encoding a nuclear hormone receptor）. Besides, mutation of daf-16 did not obviously affect the phenotype of increased fat storage in unc-64 or ric-4 mutant. Furthermore, unc-64 and ric-4 regulated fat storage probably through the ARC105/mdt-15- and SREBP/sbp-1-mediated signaling pathways. In addition, fat storage in unc-64; ric-4 was higher than that in either unc-64 or ric-4 single mutant nematodes, suggesting that unc-64 functions in parallel with ric-4 in regulating fat storage. Conclusion The plasma membrane-associated SNAREs syntaxin/ unc-64 and SNAP-25/ric-4 function in parallel in regulating fat storage in C. elegans, probably through the ARC105/mdt-15- and SREBP/sbp-1-mediated signaling pathways.
基金supported by grants from the National Natural Science Foundation of China (No.30771113, 30870810)the Program for New Century Excellent Talents in Universitythe Innovative Research Program for Undergraduates in China (No. C2007052)
文摘Objective To investigate the role of environmental factor—temperature in the regulation of aging process by unc-13 and sbt-1 in Caenorhabditis elegans. Methods The lifespan, the speed of pharynx pumping, and the intestinal autofluorescence of unc-13 and sbt-1 mutants were examined at different temperature conditions. In addition, to exclude the possible influences from other factors in unc-13 and sbt-1 mutants, the dauer formation, the thermotaxis, the brood size and the population percentage of the mutants expressing hsp16.2-gfp were further investigated. Results Mutations of unc-13 and sbt-1 significantly increased the mean and the maximum lifespans of nematodes cultured at 20 oC and 25 oC, while no noticeable increase was found at 15 oC in either the mean or the maximum lifespan. Investigations on the speed of pharynx pumping and the intestinal autofluorescence suggested that at 20 oC and 25 oC, mutations of unc-13 and sbt-1 could slow the aging process and delay the accumulation of aging-related cellular damage. Meanwhile, mutations of unc-13 or sbt-1 did not affect the dauer formation or the thermotaxis to different temperatures in nematodes. In contrast, at 20 oC and 25 oC conditions, mutations of unc-13 and sbt-1 significantly decreased the brood size and the percentage of nematodes expressing hsp16.2-gfp, while no such differences were detected at 15 oC. Moreover, the thermotolerance of unc-13 and sbt-1 mutants could be greatly strengthened after the 16-h heat shock at 35 oC. Conclusion The regulation of aging by unc-13 and sbt-1 is temperature-dependent. And the alterations in reproduction capability and stress response may be associated with the formation of this temperature-dependent property.
基金supported by a grant (AG012694-16) from the National Institue of Aging,USA
文摘Death-mediating proteases such as caspases and caspase-3 in particular, have been implicated in neurodegenerative processes, aging and Alzheimer＇s disease. However, emerging evidence suggests that in addition to their classical role in cell death, caspases play a key role in modulating synaptic function. It is remarkable that active caspases-3, which can trigger widespread damage and degeneration, aggregates in structures as delicate as synapses and persists in neurons without causing acute cell death. Here, we evaluate this dichotomy, and discuss the hypothesis that caspase-3 may be a bifurcation point in cellular signaling, able to orient the neuronal response to stress down either pathological/apoptotic pathways or towards physiological cellular remodeling. We propose that temporal, spatial and other regulators of caspase activity are key determinants of the ultimate effect of caspase-3 activation in neurons. This concept has implications for differential roles of caspase-3 activation across the lifespan. Specifically, we propose that limited caspase-3 activation is critical for synaptic function in the healthy adult brain while chronic activation is involved in degenerative processes in the aging brain.
基金Beijing National Laboratory for Molecular Sciences,Grant/Award Number:BNLMS201904Fundamental Research Funds for the Central Universities+4 种基金Large Scale Instrument Test Funds of Tongji University,Grant/Award Number:2021GX002National Key Research and Development Program of China,Grant/Award Number:2017YFA0103904National Natural Science Foundation of China,Grant/Award Numbers:61822405,62074111Science and Technology Foundation of Shanghai,Grant/Award Numbers:19JC1412402,20JC1415600Shuguang Program supported by Shanghai Education Development Foundation and Shanghai Municipal Education Commission,Grant/Award Number:18SG20。
文摘2D polymers(2DPs)have attracted increasing interests in sensors,catalysis,and gas storage applications.Furthermore,2DPs with unique band structure and tunable photophysical properties also have immense potential for application in photonic neuromorphic computing.Here,photonic synaptic transistors based on 2DPs as the light-tunable charge-trapping medium are developed for the first time.The resulted organic transistors can successfully emulate common synaptic functions,including excitatory postsynaptic current,pair-pulse facilitation,the transition of short-term memory to long-term memory,and dynamic filtering.Benefitting from the high photosensitivity of the 2DP,the devices can be operated under a low operating voltage of0.1 V,and achieve an ultralow energy consumption of~0.29 pJ per event.In addition,the heterostructure formed between the 2DP and organic semiconductor enables spectrum-dependent synaptic responses,which facilitates the simulation of visual learning and memory processes in distinct emotional states.The underlying mechanism of spectrum-dependent synaptic-like behaviors is systematically validated with in situ atomic force microscopy based electrical techniques.The spectrum-enabled tunability of synaptic behaviors further promotes the realization of optical logic functions and associative learning.This work inspires the new application of 2DPs in photonic synapses for future neuromorphic computing.
