Neural circuits provide an anatomical basis for functional networks.Therefore,dissecting the structure of neural circuits is essential to understanding how the brain works.Recombinant neurotropic viruses are important...Neural circuits provide an anatomical basis for functional networks.Therefore,dissecting the structure of neural circuits is essential to understanding how the brain works.Recombinant neurotropic viruses are important tools for neural circuit tracing with many advantages over non-viral tracers:they allow for anterograde,retrograde,and trans-synaptic delivery of tracers in a cell type-specific,circuit-selective manner.In this review,we summarize the recent developments in the viral tools for neural circuit tracing,discuss the key principles of using viral tools in neuroscience research,and highlight innovations for developing and optimizing viral tools for neural circuit tracing across diverse animal species,including nonhuman primates.展开更多
Reproductive biology is a uniquely important topic since it is about germ cells, which are central for transmitting genetic information from generation to generation. In this review, we discuss recent advances in mamm...Reproductive biology is a uniquely important topic since it is about germ cells, which are central for transmitting genetic information from generation to generation. In this review, we discuss recent advances in mammalian germ cell development,including preimplantation development, fetal germ cell development and postnatal development of oocytes and sperm. We also discuss the etiologies of female and male infertility and describe the emerging technologies for studying reproductive biology such as gene editing and single-cell technologies.展开更多
Two-photon laser scanning microscopy has been extensively applied to study in vivo neuronal activity at cellular and subcellular resolutions in mammalian brains.However,the extent of such studies is typically confined...Two-photon laser scanning microscopy has been extensively applied to study in vivo neuronal activity at cellular and subcellular resolutions in mammalian brains.However,the extent of such studies is typically confined to a single functional region of the brain.Here,we demonstrate a novel technique,termed the multiarea two-photon real-time in vivo explorer(MATRIEX),that allows the user to target multiple functional brain regions distributed within a zone of up to 12mm in diameter,each with a field of view(FOV)of ~200μm in diameter,thus performing two-photon Ca2+imaging with single-cell resolution in all of the regions simultaneously.For example,we demonstrate real-time functional imaging of single-neuron activities in the primary visual cortex,primary motor cortex and hippocampal CA1 region of mice in both anesthetized and awake states.A unique advantage of the MATRIEX technique is the configuration of multiple microscopic FOVs that are distributed in three-dimensional space over macroscopic distances(>1 mm)both laterally and axially but that are imaged by a single conventional laser scanning device.In particular,the MATRIEX technique can be effectively implemented as an add-on optical module for an existing conventional single-beam-scanning two-photon microscope without requiring any modification to the microscope itself.Thus,the MATRIEX technique can be readily applied to substantially facilitate the exploration of multiarea neuronal activity in vivo for studies of brain-wide neural circuit function with single-cell resolution.展开更多
Integrating multisensory inputs to generate accurate perception and guide behavior is among the most critical functions of the brain.Subcortical regions such as the amygdala are involved in sensory processing includin...Integrating multisensory inputs to generate accurate perception and guide behavior is among the most critical functions of the brain.Subcortical regions such as the amygdala are involved in sensory processing including vision and audition,yet their roles in multisensory integration remain unclear.In this study,we systematically investigated the function of neurons in the amygdala and adjacent regions in integrating audiovisual sensory inputs using a semi-chronic multi-electrode array and multiple combinations of audiovisual stimuli.From a sample of 332 neurons,we showed the diverse response patterns to audiovisual stimuli and the neural characteristics of bimodal over unimodal modulation,which could be classified into four types with differentiated regional origins.Using the hierarchical clustering method,neurons were further clustered into five groups and associated with different integrating functions and sub-regions.Finally,regions distinguishing congruent and incongruent bimodal sensory inputs were identified.Overall,visual processing dominates audiovisual integration in the amygdala and adjacent regions.Our findings shed new light on the neural mechanisms of multisensory integration in the primate brain.展开更多
Although the mTOR-4E-BP1 signaling pathway is implicated in aging and aging-related disorders,the role of 4E-BP1 in regulating human stem cell homeostasis remains largely unknown.Here,we report that the expression of ...Although the mTOR-4E-BP1 signaling pathway is implicated in aging and aging-related disorders,the role of 4E-BP1 in regulating human stem cell homeostasis remains largely unknown.Here,we report that the expression of 4E-BP1 decreases along with the senescence of human mesenchymal stem celis(hMSCs).Genetic inactivation of 4E-BP1 in hMSCs compromises mitochondrial respiration,increases mitochondrial reactive oxygen species(Ros)production,and accelerates cellular senescence.Mechanistically,the absence of 4E-BP1 destabilizes proteins in mitochondrial respiration complexes,especially several key subunits of complex III including UQCRC2.Ectopic expression of 4E-BP1 attenuates mitochondrial abnormalities and alleviates cellular senescence in 4E-BP1-deficient hMSCs as well as in physiologically aged hMSCs.These findings together demonstrate that 4E-BP1 functions as a geroprotector to mitigate human stem cell senescence and maintain mitochondrial homeostasis,particularly for the mitochondrial respiration complex Il,thus providing a new potential target to counteract human stem cell senescence.展开更多
Precise targeting of specific regions within the central nervous system(CNS)is crucial for both scientific research and gene therapy in the context of brain diseases.Adeno-associated virus 13(AAV13)is known for its re...Precise targeting of specific regions within the central nervous system(CNS)is crucial for both scientific research and gene therapy in the context of brain diseases.Adeno-associated virus 13(AAV13)is known for its restricted diffusion range within the CNS,making it an ideal choice for precise labeling and administration within small brain regions.However,AAV13 mediates relatively low expression of target genes.Here,we introduced specifically engineered modifications to the AAV13 capsid protein to enhance its transduction efficiency.We first constructed AAV13-YF by mutating tyrosine to phenylalanine on the surface of the AAV13 capsid.We then inserted the 7m8 peptide,known to enhance cell transduction,into positions 587/588 and 585/586 of the AAV13 capsid,resulting in two distinct variants named AAV13-587-7m8 and AAV13-585-7m8,respectively.We found that AAV13-YF exhibited superior in vitro infectivity in HEK293T cells compared to AAV13,while AAV13-587-7m8 and AAV13-585-7m8 showed enhanced CNS infection capabilities in C57BL/6 mice,with AAV13-587-7m8 infection retaining a limited spread range.These modified AAV13 variants hold promising potential for applications in gene therapy and neuroscience research.展开更多
Accurately recognizing facial expressions is essential for effective social interactions.Non-human primates(NHPs)are widely used in the study of the neural mechanisms underpinning facial expression processing,yet it r...Accurately recognizing facial expressions is essential for effective social interactions.Non-human primates(NHPs)are widely used in the study of the neural mechanisms underpinning facial expression processing,yet it remains unclear how well monkeys can recognize the facial expressions of other species such as humans.In this study,we systematically investigated how monkeys process the facial expressions of conspecifics and humans using eye-tracking technology and sophisticated behavioral tasks,namely the temporal discrimination task(TDT)and face scan task(FST).We found that monkeys showed prolonged subjective time perception in response to Negative facial expressions in monkeys while showing longer reaction time to Negative facial expressions in humans.Monkey faces also reliably induced divergent pupil contraction in response to different expressions,while human faces and scrambled monkey faces did not.Furthermore,viewing patterns in the FST indicated that monkeys only showed bias toward emotional expressions upon observing monkey faces.Finally,masking the eye region marginally decreased the viewing duration for monkey faces but not for human faces.By probing facial expression processing in monkeys,our study demonstrates that monkeys are more sensitive to the facial expressions of conspecifics than those of humans,thus shedding new light on inter-species communication through facial expressions between NHPs and humans.展开更多
Dear Editor,Alzheimer's disease(AD)is one of the most devastating neurodegenerative disorders and the most common form of dementia.Synaptic loss is a hallmark of AD pathology and exacerbates cognitive impairment[1...Dear Editor,Alzheimer's disease(AD)is one of the most devastating neurodegenerative disorders and the most common form of dementia.Synaptic loss is a hallmark of AD pathology and exacerbates cognitive impairment[1].Synaptic loss,unlike neuronal loss,is reversible due to the highly dynamic properties of synapses.展开更多
Analyzing the structure and function of the brain's neural network is critical for identifying the working principles of the brain and the mechanisms of brain diseases.Recombinant rabies viral vectors allow for th...Analyzing the structure and function of the brain's neural network is critical for identifying the working principles of the brain and the mechanisms of brain diseases.Recombinant rabies viral vectors allow for the retrograde labeling of projection neurons and cell type-specific trans-monosynaptic tracing,making these vectors powerful candidates for the dissection of synaptic inputs.Although several attenuated rabies viral vectors have been developed,their application in studies of functional networks is hindered by the long preparation cycle and low yield of these vectors.To overcome these limitations,we developed an improved production system for the rapid rescue and preparation of a high-titer CVS-N2c-ΔG virus.Our results showed that the new CVS-N2c-ΔG-based toolkit performed remarkably:(1)N2cG-coated CVS-N2c-ΔG allowed for efficient retrograde access to projection neurons that were unaddressed by rAAV9-Retro,and the efficiency was six times higher than that of rAAV9-Retro;(2)the trans-monosynaptic efficiency of oG-mediated CVS-N2c-ΔG was 2–3 times higher than that of oG-mediated SAD-B19-ΔG;(3)CVS-N2c-ΔG could delivery modified genes for neural activity monitoring,and the time window during which this was maintained was 3 weeks;and(4)CVS-N2c-ΔG could express sufficient recombinases for efficient transgene recombination.These findings demonstrate that new CVS-N2c-ΔG-based toolkit may serve as a versatile tool for structural and functional studies of neural circuits.展开更多
Rabies-viruses-based retrograde tracers can spread across multiple synapses in a retrograde direction in the nervous system of rodents and primates,making them powerful tools for determining the structure and function...Rabies-viruses-based retrograde tracers can spread across multiple synapses in a retrograde direction in the nervous system of rodents and primates,making them powerful tools for determining the structure and function of the complicated neural circuits of the brain.However,they have some limitations,such as posing high risks to human health and the inability to retrograde trans-synaptic label inputs from genetically-de¯ned starter neurons.Here,we established a new retrograde trans-multi-synaptic tracing method through brain-wide rabies virus glycoprotein(RVG)compensation,followed by glycoprotein-deleted rabies virus(RV-△G)infection in specific brain regions.Furthermore,in combination with the avian tumor virus receptor A(TVA)controlled by a cell-type-specific promoter,we found that EnvA-pseudotyped RV-△G can mediate e±cient retrograde trans-multi-synaptic transduction from cell-type-specific starter neurons.This study provides new alternative methods for neuroscience researchers to analyze the input neural networks of rodents and nonhuman primates.展开更多
Drug discovery is a crucial part of human healthcare and has dramatically benefited human lifespan and life quality in recent centuries, however, it is usually time-and effort-consuming. Structural biology has been de...Drug discovery is a crucial part of human healthcare and has dramatically benefited human lifespan and life quality in recent centuries, however, it is usually time-and effort-consuming. Structural biology has been demonstrated as a powerful tool to accelerate drug development. Among different techniques, cryo-electron microscopy(cryo-EM) is emerging as the mainstream of structure determination of biomacromolecules in the past decade and has received increasing attention from the pharmaceutical industry. Although cryo-EM still has limitations in resolution, speed and throughput, a growing number of innovative drugs are being developed with the help of cryo-EM. Here, we aim to provide an overview of how cryo-EM techniques are applied to facilitate drug discovery. The development and typical workflow of cryo-EM technique will be briefly introduced, followed by its specific applications in structure-based drug design, fragment-based drug discovery, proteolysis targeting chimeras, antibody drug development and drug repurposing. Besides cryo-EM, drug discovery innovation usually involves other state-of-the-art techniques such as artificial intelligence(AI), which is increasingly active in diverse areas. The combination of cryo-EM and AI provides an opportunity to minimize limitations of cryo-EM such as automation, throughput and interpretation of mediumresolution maps, and tends to be the new direction of future development of cryo-EM. The rapid development of cryo-EM will make it as an indispensable part of modern drug discovery.展开更多
Connectome-scale structural mapping is fundamental for understanding the underlying mechanisms of brain cognition and brain disease pathogenesis.By combining rapidly developing three-dimensional(3D)imaging techniques ...Connectome-scale structural mapping is fundamental for understanding the underlying mechanisms of brain cognition and brain disease pathogenesis.By combining rapidly developing three-dimensional(3D)imaging techniques and big data analysis methods,researchers are working on mesoscale mapping of mammalian brains at an accelerated pace.Here,we briefly describe existing brain-wide imaging strategies,especially our recently established primateoptimized pipeline capable of pan-brain neuronal connectivity mapping at subcellular resolution,and further discuss their vast application prospects in the big data era of zoology.展开更多
The ability to detect conspecific＇s distress is crucial for animal survival. In rodent models, observational fear （OF） occurs when one animal perceives another fear related negative emotions, which may model certai...The ability to detect conspecific＇s distress is crucial for animal survival. In rodent models, observational fear （OF） occurs when one animal perceives another fear related negative emotions, which may model certain behaviors caused by witnessing traumatic experiences in humans. Anterior cingulate cortex （ACC） has been showed to play a crucial role in OF. However, cellular and neural circuit basis relating to ACC governing OF is poorly understood. Here, we used Designer Receptor Exclusively Activated by a Designer Drug （DREADD） system to investigate the cell type specific circuit mechanism of ACC in OF. Firstly, inhibitory hM4D （Gi） designer receptor together with clozapine N-oxide （CNO） injection was applied to inactivate ACC neurons in the observer mice. We found that, chemogenetic inhibition of ACC resulted in a decreased freezing response in the observer mice. Next, combining PV-ires-Cre mice and Cre-dependent DREADD system, we selectively targeted the ACC parvalbumin （PV） interneurons with the excitatory hM3D （Gq） designer receptor. Activation of ACC PV interneurons following CNO injection reduced freezing response in the observer mice, while had no effect on freezing response in the demon- strator mice. Finally, monosynaptic rabies retrograde tracing revealed that ACC PV interneurons receive inputs from the mediodorsal thalamic nucleus （MD） and the ventromedial thalamic nucleus （VM）, both known for their roles in OF. Taken together, these findings reveal that ACC activation is important for OF, during which PV interneurons in ACC play an important regulatory role. Abnormal function of ACC PV interneurons might contribute to the pathology of empathy- deficits related diseases, such as autism and schizoohrenia.展开更多
Many people affected by fragile X syndrome(FXS)and autism spectrum disorders have sensory processing deficits,such as hypersensitivity to auditory,tactile,and visual stimuli.Like FXS in humans,loss of Fmr1 in rodents ...Many people affected by fragile X syndrome(FXS)and autism spectrum disorders have sensory processing deficits,such as hypersensitivity to auditory,tactile,and visual stimuli.Like FXS in humans,loss of Fmr1 in rodents also cause sensory,behavioral,and cognitive deficits.However,the neural mechanisms underlying sensory impairment,especially vision impairment,remain unclear.It remains elusive whether the visual processing deficits originate from corrupted inputs,impaired perception in the primary sensory cortex,or altered integration in the higher cortex,and there is no effective treatment.In this study,we used a genetic knockout mouse model(Fmr1^(KO)),in vivo imaging,and behavioral measurements to show that the loss of Fmr1 impaired signal processing in the primary visual cortex(V1).Specifically,Fmr1^(KO) mice showed enhanced responses to low-intensity stimuli but normal responses to high-intensity stimuli.This abnormality was accompanied by enhancements in local network connectivity in V1 microcircuits and increased dendritic complexity of V1 neurons.These effects were ameliorated by the acute application of GABAA receptor activators,which enhanced the activity of inhibitory neurons,or by reintroducing Fmr1 gene expression in knockout V1 neurons in both juvenile and young-adult mice.Overall,V1 plays an important role in the visual abnormalities of Fmr1^(KO) mice and it could be possible to rescue the sensory disturbances in developed FXS and autism patients.展开更多
New-generation human body motion sensors for wearable electronics and intelligent medicine are required to comply with stringent requirements in terms of ultralight weight,flexibility,stability,biocompatibility,and ex...New-generation human body motion sensors for wearable electronics and intelligent medicine are required to comply with stringent requirements in terms of ultralight weight,flexibility,stability,biocompatibility,and extreme precision.However,conventional sensors are hard to fulfill all these criteria due to their rigid structure,high-density sensing materials used as the constituents,as well as hermetical and compact assembly strategy.Here,we report an ultralight sensing material based on radial anisotropic porous silver fiber(RAPSF),which has been manufactured by phase separation and temperature-controlled grain growth strategy on a modified blow-spinning system.The resistance of RAPSF could be dynamically adjusted depending on the deflected shape.Furthermore,an all-fiber motion sensor(AFMS)with an ultra-low density of 68.70 mg cm^(−3) and an overall weigh of 7.95 mg was fabricated via layer-by-layer assembly.The sensor exhibited outstanding flexibility,breathability,biocompatibility,and remarkable body motion recognition ability.Moreover,the AFMS was shown to have great potential as an artificial intelligence throat sensor for throat state identification at the accuracy above 85%,allowing one to spot the early onset of the viral throat illness.展开更多
Consciousness lies at the heart of our existence and experience.To probe how perceptual consciousness emerges in the brain,we recorded brainwide intracranial electroencephalography signals from human patients while th...Consciousness lies at the heart of our existence and experience.To probe how perceptual consciousness emerges in the brain,we recorded brainwide intracranial electroencephalography signals from human patients while their perceptual consciousness was effectively manipulated using the continuous flash suppression paradigm.We observed substantial differences in brain activities when visual information gradually enters consciousness.展开更多
Artificial van der Waals(vdWs)heterostructures offer unprecedented opportunities to explore and reveal novel synergistic electronic and optical phenomena,which are beneficial for the development of novel optoelectroni...Artificial van der Waals(vdWs)heterostructures offer unprecedented opportunities to explore and reveal novel synergistic electronic and optical phenomena,which are beneficial for the development of novel optoelectronic devices at atomic limits.However,due to the damage caused by the device fabrication process,their inherent properties such as carrier mobility are obscured,which hinders the improvement of device performance and the incorporation of vdWs materials into next-generation integrated circuits.Herein,combining pump-probe spectroscopic and scanning probe microscopic techniques,the intrinsic optoelectronic properties of PtSe_(2)/MoSe_(2)heterojunction were nondestructively and systematically investigated.The heterojunction exhibits a broad-spectrum optical response and maintains ultrafast carrier dynamics(interfacial charge transfer~0.8 ps and carrier lifetime~38.2 ps)simultaneously.The in-plane exciton diffusion coefficient of the heterojunction was extracted(19.4±7.6 cm^(2)∙s^(−1)),and its exciton mobility as high as 756.8 cm^(2)∙V−1∙s^(−1)was deduced,exceeding the value of its components.This enhancement was attributed to the formation of an n-type Schottky junction between PtSe_(2)and MoSe_(2),and its built-in electric field assisted the ultrafast transfer of photogenerated carriers from MoSe_(2)to PtSe_(2),enhancing the in-plane exciton diffusion of the heterojunction.Our results demonstrate that PtSe_(2)/MoSe_(2)is suitable for the development of broadspectrum and sensitive optoelectronic devices.Meanwhile,the results contribute to a fundamental understanding of the performance of various optoelectronic devices based on such PtSe_(2)two-dimensional(2D)heterostructures.展开更多
To simplify the fabrication process and increase the versatility of neuromorphic systems,the reconfiguration concept has attracted much attention.Here,we developed a novel electrochemical VO_(2)(EC-VO_(2))device,which...To simplify the fabrication process and increase the versatility of neuromorphic systems,the reconfiguration concept has attracted much attention.Here,we developed a novel electrochemical VO_(2)(EC-VO_(2))device,which can be reconfigured as synapses or LIF neurons.The ionic dynamic doping contributed to the resistance changes of VO_(2),which enables the reversible modulation of device states.The analog resistance switching and tunable LIF functions were both measured based on the same device to demonstrate the capacity of reconfiguration.Based on the reconfigurable EC-VO_(2),the simulated spiking neural network model exhibited excellent performances by using low-precision weights and tunable output neurons,whose final accuracy reached 91.92%.展开更多
Light is essential for life on earth.In mammals,light is sensed by three cell types in the retina:rods and cones transduce light for image visualization and perception,while intrinsically photosensitive retinal gangli...Light is essential for life on earth.In mammals,light is sensed by three cell types in the retina:rods and cones transduce light for image visualization and perception,while intrinsically photosensitive retinal ganglion cells(ipRGCs)transduce light for non-image visual functions,including light entrainment of circadian clocks,pupillary light reflex and mood regulation(Do and Yau,2010;LeGates et al.,2014).Consistent with their functions,ipRGCs project directly to a number of subcortical brain regions,while rods and cones project to the lateral geniculate nucleus,which in turn projects to the visual cortex.展开更多
Active exploratory behaviors have often been associated with theta oscillations in rodents,while theta oscillations during active exploration in non-human primates are still not well understood.We recorded neural acti...Active exploratory behaviors have often been associated with theta oscillations in rodents,while theta oscillations during active exploration in non-human primates are still not well understood.We recorded neural activities in the frontal eye field(FEF)and V4 simultaneously when monkeys performed a free-gaze visual search task.Saccades were strongly phase-locked to theta oscillations of V4 and FEF local field potentials,and the phase-locking was dependent on saccade direction.The spiking probability of V4 and FEF units was significantly modulated by the theta phase in addition to the time-locked modulation associated with the evoked response.V4 and FEF units showed significantly stronger responses following saccades initiated at their preferred phases.Granger causality and ridge regression analysis showed modulatory effects of theta oscillations on saccade timing.Together,our study suggests phase-locking of saccades to the theta modulation of neural activity in visual and oculomotor cortical areas,in addition to the theta phase locking caused by saccade-triggered responses.展开更多
基金This review was supported by the National Science and Technology Innovation 2030(2021ZD0201003)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB32030200)+1 种基金the National Natural Science Foundation of China(31830035)the Shenzhen Key Laboratory of Viral Vectors for Biomedicine(ZDSYS20200811142401005).
文摘Neural circuits provide an anatomical basis for functional networks.Therefore,dissecting the structure of neural circuits is essential to understanding how the brain works.Recombinant neurotropic viruses are important tools for neural circuit tracing with many advantages over non-viral tracers:they allow for anterograde,retrograde,and trans-synaptic delivery of tracers in a cell type-specific,circuit-selective manner.In this review,we summarize the recent developments in the viral tools for neural circuit tracing,discuss the key principles of using viral tools in neuroscience research,and highlight innovations for developing and optimizing viral tools for neural circuit tracing across diverse animal species,including nonhuman primates.
文摘Reproductive biology is a uniquely important topic since it is about germ cells, which are central for transmitting genetic information from generation to generation. In this review, we discuss recent advances in mammalian germ cell development,including preimplantation development, fetal germ cell development and postnatal development of oocytes and sperm. We also discuss the etiologies of female and male infertility and describe the emerging technologies for studying reproductive biology such as gene editing and single-cell technologies.
基金supported by the“100-Talents Program for Elite Engineers”of the CAS(H.J.)the Key Scientific Research Equipment Development Project of the CAS(Super-resolution Microscopy Systems and Key Components,ZDYZ2013-1)+3 种基金the“1000-Talents Program for Young Scholars”of China(X.C.)grants from the Ministry of Science and Technology of China(“973 Program”:2015CB759500,2018YFA0109600)the National Natural Science Foundation of China(61705251,81671106,81771175,31700933,81721001)the China Postdoctoral Science Foundation(2018M632374).
文摘Two-photon laser scanning microscopy has been extensively applied to study in vivo neuronal activity at cellular and subcellular resolutions in mammalian brains.However,the extent of such studies is typically confined to a single functional region of the brain.Here,we demonstrate a novel technique,termed the multiarea two-photon real-time in vivo explorer(MATRIEX),that allows the user to target multiple functional brain regions distributed within a zone of up to 12mm in diameter,each with a field of view(FOV)of ~200μm in diameter,thus performing two-photon Ca2+imaging with single-cell resolution in all of the regions simultaneously.For example,we demonstrate real-time functional imaging of single-neuron activities in the primary visual cortex,primary motor cortex and hippocampal CA1 region of mice in both anesthetized and awake states.A unique advantage of the MATRIEX technique is the configuration of multiple microscopic FOVs that are distributed in three-dimensional space over macroscopic distances(>1 mm)both laterally and axially but that are imaged by a single conventional laser scanning device.In particular,the MATRIEX technique can be effectively implemented as an add-on optical module for an existing conventional single-beam-scanning two-photon microscope without requiring any modification to the microscope itself.Thus,the MATRIEX technique can be readily applied to substantially facilitate the exploration of multiarea neuronal activity in vivo for studies of brain-wide neural circuit function with single-cell resolution.
基金supported by the National Natural Science Foundation of China(U20A2017 and 31830037)Guangdong Basic and Applied Basic Research Foundation(2020A1515010785,2020A1515111118,and 2022A1515010134)+5 种基金the Youth Innovation Promotion Association of the Chinese Academy of Sciences(2017120)the Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions(NYKFKT2019009)Shenzhen Technological Research Center for Primate Translational Medicine(F-2021-Z99-504979)the Strategic Research Program of the Chinese Academy of Sciences(XDBS01030100 and XDB32010300)Scientific and Technological Innovation 2030(2021ZD0204300)the Fundamental Research Funds for the Central Universities.
文摘Integrating multisensory inputs to generate accurate perception and guide behavior is among the most critical functions of the brain.Subcortical regions such as the amygdala are involved in sensory processing including vision and audition,yet their roles in multisensory integration remain unclear.In this study,we systematically investigated the function of neurons in the amygdala and adjacent regions in integrating audiovisual sensory inputs using a semi-chronic multi-electrode array and multiple combinations of audiovisual stimuli.From a sample of 332 neurons,we showed the diverse response patterns to audiovisual stimuli and the neural characteristics of bimodal over unimodal modulation,which could be classified into four types with differentiated regional origins.Using the hierarchical clustering method,neurons were further clustered into five groups and associated with different integrating functions and sub-regions.Finally,regions distinguishing congruent and incongruent bimodal sensory inputs were identified.Overall,visual processing dominates audiovisual integration in the amygdala and adjacent regions.Our findings shed new light on the neural mechanisms of multisensory integration in the primate brain.
基金supported by the National Key Research and Development Program of China(2018YFC2000100)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16000000)+9 种基金the National Natural Science Foundation of China(8190143281921006,82125011,92149301,92168201,91949209,92049304,92049116,32121001,82192863,82122024,82071588,81861168034,81922027,81870228,32100937,31900524,82201727)the National Key Research and Development Program of China(2020YFA0804000,2020YFA0113400,2020YFA0112200,2018YFA0107203,the STI2030-Major Projects-2021ZD0202400,2021YFF1201005,2022YFA1103700,2022YFA1103800)CAS Project for Young Scientists in Basic Research(YSBR-076,YSBR-012)the Program of the Beijing Natural Science Foundation(Z190019,JQ20031)K.C.Wong Education Foundation(GJTD-2019-06,GJTD-2019-08)Young Elite Scientists Sponsorship Program by CAST(YESS20200012)Youth Innovation Promotion Association of CAS(EiCAZW0401)the Pilot Project for Public Welfare Development and Reform of Beijing-affliated Medical Research Institutes(11000022T000000461062)the Informatization Plan of Chinese Academy of Sciences(CAS-WX2021SF-0301,CASWX2022SDC-XK14)CAS Special Research Assistant(SRA)Program,and the Tencent Foundation(2021-1045).
文摘Although the mTOR-4E-BP1 signaling pathway is implicated in aging and aging-related disorders,the role of 4E-BP1 in regulating human stem cell homeostasis remains largely unknown.Here,we report that the expression of 4E-BP1 decreases along with the senescence of human mesenchymal stem celis(hMSCs).Genetic inactivation of 4E-BP1 in hMSCs compromises mitochondrial respiration,increases mitochondrial reactive oxygen species(Ros)production,and accelerates cellular senescence.Mechanistically,the absence of 4E-BP1 destabilizes proteins in mitochondrial respiration complexes,especially several key subunits of complex III including UQCRC2.Ectopic expression of 4E-BP1 attenuates mitochondrial abnormalities and alleviates cellular senescence in 4E-BP1-deficient hMSCs as well as in physiologically aged hMSCs.These findings together demonstrate that 4E-BP1 functions as a geroprotector to mitigate human stem cell senescence and maintain mitochondrial homeostasis,particularly for the mitochondrial respiration complex Il,thus providing a new potential target to counteract human stem cell senescence.
基金National Science and Technology Innovation 2030 Grant(2021ZD0201003)National Natural Science Foundation of China(31830035,31771156,21921004)+2 种基金Strategic Priority Research Program of the Chinese Academy of Sciences(XDB32030200)Shenzhen Key Laboratory of Viral Vectors for Biomedicine(ZDSYS20200811142401005)Key Laboratory of Quality Control Technology for Virus-Based Therapeutics,Guangdong Provincial Medical Products Administration(2022ZDZ13)。
文摘Precise targeting of specific regions within the central nervous system(CNS)is crucial for both scientific research and gene therapy in the context of brain diseases.Adeno-associated virus 13(AAV13)is known for its restricted diffusion range within the CNS,making it an ideal choice for precise labeling and administration within small brain regions.However,AAV13 mediates relatively low expression of target genes.Here,we introduced specifically engineered modifications to the AAV13 capsid protein to enhance its transduction efficiency.We first constructed AAV13-YF by mutating tyrosine to phenylalanine on the surface of the AAV13 capsid.We then inserted the 7m8 peptide,known to enhance cell transduction,into positions 587/588 and 585/586 of the AAV13 capsid,resulting in two distinct variants named AAV13-587-7m8 and AAV13-585-7m8,respectively.We found that AAV13-YF exhibited superior in vitro infectivity in HEK293T cells compared to AAV13,while AAV13-587-7m8 and AAV13-585-7m8 showed enhanced CNS infection capabilities in C57BL/6 mice,with AAV13-587-7m8 infection retaining a limited spread range.These modified AAV13 variants hold promising potential for applications in gene therapy and neuroscience research.
基金supported by the National Natural Science Foundation of China (U20A2017)Guangdong Basic and Applied Basic Research Foundation (2022A1515010134,2022A1515110598)+2 种基金Youth Innovation Promotion Association of Chinese Academy of Sciences (2017120)Shenzhen-Hong Kong Institute of Brain Science–Shenzhen Fundamental Research Institutions (NYKFKT2019009)Shenzhen Technological Research Center for Primate Translational Medicine (F-2021-Z99-504979)。
文摘Accurately recognizing facial expressions is essential for effective social interactions.Non-human primates(NHPs)are widely used in the study of the neural mechanisms underpinning facial expression processing,yet it remains unclear how well monkeys can recognize the facial expressions of other species such as humans.In this study,we systematically investigated how monkeys process the facial expressions of conspecifics and humans using eye-tracking technology and sophisticated behavioral tasks,namely the temporal discrimination task(TDT)and face scan task(FST).We found that monkeys showed prolonged subjective time perception in response to Negative facial expressions in monkeys while showing longer reaction time to Negative facial expressions in humans.Monkey faces also reliably induced divergent pupil contraction in response to different expressions,while human faces and scrambled monkey faces did not.Furthermore,viewing patterns in the FST indicated that monkeys only showed bias toward emotional expressions upon observing monkey faces.Finally,masking the eye region marginally decreased the viewing duration for monkey faces but not for human faces.By probing facial expression processing in monkeys,our study demonstrates that monkeys are more sensitive to the facial expressions of conspecifics than those of humans,thus shedding new light on inter-species communication through facial expressions between NHPs and humans.
基金the Frontier Research Program of Biol and Laboratory(Guangzhou Regenerative Medicine and Health Guangdong Laboratory)(2018GZR110105006)the National Natural ScienceFoundation of China(31900735,82171492,and 81922024)the Science,Technology and Innovation Commission of Shenzhen Municipality(RCJC 20200714114556103 and ZDSYS20190902093601675).
文摘Dear Editor,Alzheimer's disease(AD)is one of the most devastating neurodegenerative disorders and the most common form of dementia.Synaptic loss is a hallmark of AD pathology and exacerbates cognitive impairment[1].Synaptic loss,unlike neuronal loss,is reversible due to the highly dynamic properties of synapses.
基金supported by the National Natural Science Foundation of China,Nos.32100899(to KZL),31830035(to FQX),31771156(to FQX),21921004(to FQX)the National Science and Technology Innovation 2030,No.2021ZD0201003(to FQX)+2 种基金the Key-Area Research and Development Program of Guangdong Province,No.2018B030331001(to FQX)the Strategic Priority Research Program of the Chinese Academy of Sciences,No.XDB32030200(to FQX)the Shenzhen Key Laboratory of Viral Vectors for Biomedicine,No.ZDSYS20200811142401005(to FQX)。
文摘Analyzing the structure and function of the brain's neural network is critical for identifying the working principles of the brain and the mechanisms of brain diseases.Recombinant rabies viral vectors allow for the retrograde labeling of projection neurons and cell type-specific trans-monosynaptic tracing,making these vectors powerful candidates for the dissection of synaptic inputs.Although several attenuated rabies viral vectors have been developed,their application in studies of functional networks is hindered by the long preparation cycle and low yield of these vectors.To overcome these limitations,we developed an improved production system for the rapid rescue and preparation of a high-titer CVS-N2c-ΔG virus.Our results showed that the new CVS-N2c-ΔG-based toolkit performed remarkably:(1)N2cG-coated CVS-N2c-ΔG allowed for efficient retrograde access to projection neurons that were unaddressed by rAAV9-Retro,and the efficiency was six times higher than that of rAAV9-Retro;(2)the trans-monosynaptic efficiency of oG-mediated CVS-N2c-ΔG was 2–3 times higher than that of oG-mediated SAD-B19-ΔG;(3)CVS-N2c-ΔG could delivery modified genes for neural activity monitoring,and the time window during which this was maintained was 3 weeks;and(4)CVS-N2c-ΔG could express sufficient recombinases for efficient transgene recombination.These findings demonstrate that new CVS-N2c-ΔG-based toolkit may serve as a versatile tool for structural and functional studies of neural circuits.
基金study was supported by the STI2030-Major Projects(Grant No.2021ZD0201003)the National Natural Science Foundation of China(Grant Nos.31830035,31771156,21921004,and 32100899)+3 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDB32030200)the Shenzhen Key Laboratory of Viral Vectors for Biomedicine(Grant No.ZDSYS20200811142401005)the Key Laboratory of Quality Control Technology for Virus-Based Ther-apeutics,Guangdong Provincial Medical Products Administration(Grant No.2022ZDZ13)Open Project Program of Wuhan National Laboratory for Optoelectronics(Grant No.2019WNLOKF022).
文摘Rabies-viruses-based retrograde tracers can spread across multiple synapses in a retrograde direction in the nervous system of rodents and primates,making them powerful tools for determining the structure and function of the complicated neural circuits of the brain.However,they have some limitations,such as posing high risks to human health and the inability to retrograde trans-synaptic label inputs from genetically-de¯ned starter neurons.Here,we established a new retrograde trans-multi-synaptic tracing method through brain-wide rabies virus glycoprotein(RVG)compensation,followed by glycoprotein-deleted rabies virus(RV-△G)infection in specific brain regions.Furthermore,in combination with the avian tumor virus receptor A(TVA)controlled by a cell-type-specific promoter,we found that EnvA-pseudotyped RV-△G can mediate e±cient retrograde trans-multi-synaptic transduction from cell-type-specific starter neurons.This study provides new alternative methods for neuroscience researchers to analyze the input neural networks of rodents and nonhuman primates.
基金funded by the National Natural Science Foundation of China (NSFC, 31900046, 81972085, 82172465 and 32161133022)the Guangdong Provincial Key Laboratory of Advanced Biomaterials (2022B1212010003)+7 种基金the National Science and Technology Innovation 2030 Major Program (2022ZD0211900)the Shenzhen Key Laboratory of Computer Aided Drug Discovery (ZDSYS20201230165400001)the Chinese Academy of Science President’s International Fellowship Initiative (PIFI)(2020FSB0003)the Guangdong Retired Expert (granted by Guangdong Province)the Shenzhen Pengcheng ScientistNSFC-SNSF Funding (32161133022)Alpha Mol&SIAT Joint LaboratoryShenzhen Government Top-talent Working Funding and Guangdong Province Academician Work Funding。
文摘Drug discovery is a crucial part of human healthcare and has dramatically benefited human lifespan and life quality in recent centuries, however, it is usually time-and effort-consuming. Structural biology has been demonstrated as a powerful tool to accelerate drug development. Among different techniques, cryo-electron microscopy(cryo-EM) is emerging as the mainstream of structure determination of biomacromolecules in the past decade and has received increasing attention from the pharmaceutical industry. Although cryo-EM still has limitations in resolution, speed and throughput, a growing number of innovative drugs are being developed with the help of cryo-EM. Here, we aim to provide an overview of how cryo-EM techniques are applied to facilitate drug discovery. The development and typical workflow of cryo-EM technique will be briefly introduced, followed by its specific applications in structure-based drug design, fragment-based drug discovery, proteolysis targeting chimeras, antibody drug development and drug repurposing. Besides cryo-EM, drug discovery innovation usually involves other state-of-the-art techniques such as artificial intelligence(AI), which is increasingly active in diverse areas. The combination of cryo-EM and AI provides an opportunity to minimize limitations of cryo-EM such as automation, throughput and interpretation of mediumresolution maps, and tends to be the new direction of future development of cryo-EM. The rapid development of cryo-EM will make it as an indispensable part of modern drug discovery.
基金supported by the Ministry of Science and Technology of China(2022ZD0205203)。
文摘Connectome-scale structural mapping is fundamental for understanding the underlying mechanisms of brain cognition and brain disease pathogenesis.By combining rapidly developing three-dimensional(3D)imaging techniques and big data analysis methods,researchers are working on mesoscale mapping of mammalian brains at an accelerated pace.Here,we briefly describe existing brain-wide imaging strategies,especially our recently established primateoptimized pipeline capable of pan-brain neuronal connectivity mapping at subcellular resolution,and further discuss their vast application prospects in the big data era of zoology.
基金partially sponsored by the National Natural Science Foundation of China(NSFC 81425010(L.W.),31630031(L.W.),31500861(Z.Z.),31471109(L.L.)International Partnership Program of Chinese Academy of Sciences,172644KYS820170004(L.W.)+5 种基金External Cooperation Program of the Chinese Academy of Sciences,GJHZ1508(L.W.)Guangdong Provincial Key Laboratory of Brain Connectome and Behavior,2017B030301017(L.W.)Shenzhen Governmental Grants,JCYJ20150529143500959(L.W.),JCYJ20150401150223647(Z.Z.),JCYJ20151030140325151(L.L)Shenzhen Governmental grants KQJSCX20160301144002(L.L.)Shenzhen Discipline Construction Project for Neurobiology DRCSM[2016]1379(L.W.)Ten Thousand Talent Program(L.W.)
文摘The ability to detect conspecific＇s distress is crucial for animal survival. In rodent models, observational fear （OF） occurs when one animal perceives another fear related negative emotions, which may model certain behaviors caused by witnessing traumatic experiences in humans. Anterior cingulate cortex （ACC） has been showed to play a crucial role in OF. However, cellular and neural circuit basis relating to ACC governing OF is poorly understood. Here, we used Designer Receptor Exclusively Activated by a Designer Drug （DREADD） system to investigate the cell type specific circuit mechanism of ACC in OF. Firstly, inhibitory hM4D （Gi） designer receptor together with clozapine N-oxide （CNO） injection was applied to inactivate ACC neurons in the observer mice. We found that, chemogenetic inhibition of ACC resulted in a decreased freezing response in the observer mice. Next, combining PV-ires-Cre mice and Cre-dependent DREADD system, we selectively targeted the ACC parvalbumin （PV） interneurons with the excitatory hM3D （Gq） designer receptor. Activation of ACC PV interneurons following CNO injection reduced freezing response in the observer mice, while had no effect on freezing response in the demon- strator mice. Finally, monosynaptic rabies retrograde tracing revealed that ACC PV interneurons receive inputs from the mediodorsal thalamic nucleus （MD） and the ventromedial thalamic nucleus （VM）, both known for their roles in OF. Taken together, these findings reveal that ACC activation is important for OF, during which PV interneurons in ACC play an important regulatory role. Abnormal function of ACC PV interneurons might contribute to the pathology of empathy- deficits related diseases, such as autism and schizoohrenia.
文摘Many people affected by fragile X syndrome(FXS)and autism spectrum disorders have sensory processing deficits,such as hypersensitivity to auditory,tactile,and visual stimuli.Like FXS in humans,loss of Fmr1 in rodents also cause sensory,behavioral,and cognitive deficits.However,the neural mechanisms underlying sensory impairment,especially vision impairment,remain unclear.It remains elusive whether the visual processing deficits originate from corrupted inputs,impaired perception in the primary sensory cortex,or altered integration in the higher cortex,and there is no effective treatment.In this study,we used a genetic knockout mouse model(Fmr1^(KO)),in vivo imaging,and behavioral measurements to show that the loss of Fmr1 impaired signal processing in the primary visual cortex(V1).Specifically,Fmr1^(KO) mice showed enhanced responses to low-intensity stimuli but normal responses to high-intensity stimuli.This abnormality was accompanied by enhancements in local network connectivity in V1 microcircuits and increased dendritic complexity of V1 neurons.These effects were ameliorated by the acute application of GABAA receptor activators,which enhanced the activity of inhibitory neurons,or by reintroducing Fmr1 gene expression in knockout V1 neurons in both juvenile and young-adult mice.Overall,V1 plays an important role in the visual abnormalities of Fmr1^(KO) mice and it could be possible to rescue the sensory disturbances in developed FXS and autism patients.
基金supported by the Fundamental Research Funds for the Central Universities (2021XD-A04-1)National Natural Science Foundations of China (Grant 62104051,51661135025,51706117 and U1564205)National Basic Research of China (Grants 2018YFB0104404).
文摘New-generation human body motion sensors for wearable electronics and intelligent medicine are required to comply with stringent requirements in terms of ultralight weight,flexibility,stability,biocompatibility,and extreme precision.However,conventional sensors are hard to fulfill all these criteria due to their rigid structure,high-density sensing materials used as the constituents,as well as hermetical and compact assembly strategy.Here,we report an ultralight sensing material based on radial anisotropic porous silver fiber(RAPSF),which has been manufactured by phase separation and temperature-controlled grain growth strategy on a modified blow-spinning system.The resistance of RAPSF could be dynamically adjusted depending on the deflected shape.Furthermore,an all-fiber motion sensor(AFMS)with an ultra-low density of 68.70 mg cm^(−3) and an overall weigh of 7.95 mg was fabricated via layer-by-layer assembly.The sensor exhibited outstanding flexibility,breathability,biocompatibility,and remarkable body motion recognition ability.Moreover,the AFMS was shown to have great potential as an artificial intelligence throat sensor for throat state identification at the accuracy above 85%,allowing one to spot the early onset of the viral throat illness.
基金This work was supported by the National Natural Science Foundation of China(U20A2017,31830037)the Science and Technology Funds of Guangdong Province(2020A1515111118,2022A1515010134)+2 种基金the Youth Innovation Promotion Association of Chinese Academy of Sciences(2017120)the Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions(NYKFKT2019009)the Strategic Priority Research Program of Chinese Academy of Sciences(XDBS01030100,XDB32010300),the Ministry of Science and Technology of the People’s Republic of China(2021ZD0203800),and the Fundamental Research Funds for the Central Universities.
文摘Consciousness lies at the heart of our existence and experience.To probe how perceptual consciousness emerges in the brain,we recorded brainwide intracranial electroencephalography signals from human patients while their perceptual consciousness was effectively manipulated using the continuous flash suppression paradigm.We observed substantial differences in brain activities when visual information gradually enters consciousness.
基金supported by the National Natural Science Foundation of China(Nos.11974088,61975007,52172060,61925401,92064004,61927901,and 92164302)the Beijing Natural Science Foundation(Nos.Z190006 and 4222073)+1 种基金the National Key R&D Program of China(No.2018YFA0208402),the 111 Project(No.B18001)the Fok Ying-Tong Education Foundation,and the Tencent Foundation through the XPLORER PRIZE。
文摘Artificial van der Waals(vdWs)heterostructures offer unprecedented opportunities to explore and reveal novel synergistic electronic and optical phenomena,which are beneficial for the development of novel optoelectronic devices at atomic limits.However,due to the damage caused by the device fabrication process,their inherent properties such as carrier mobility are obscured,which hinders the improvement of device performance and the incorporation of vdWs materials into next-generation integrated circuits.Herein,combining pump-probe spectroscopic and scanning probe microscopic techniques,the intrinsic optoelectronic properties of PtSe_(2)/MoSe_(2)heterojunction were nondestructively and systematically investigated.The heterojunction exhibits a broad-spectrum optical response and maintains ultrafast carrier dynamics(interfacial charge transfer~0.8 ps and carrier lifetime~38.2 ps)simultaneously.The in-plane exciton diffusion coefficient of the heterojunction was extracted(19.4±7.6 cm^(2)∙s^(−1)),and its exciton mobility as high as 756.8 cm^(2)∙V−1∙s^(−1)was deduced,exceeding the value of its components.This enhancement was attributed to the formation of an n-type Schottky junction between PtSe_(2)and MoSe_(2),and its built-in electric field assisted the ultrafast transfer of photogenerated carriers from MoSe_(2)to PtSe_(2),enhancing the in-plane exciton diffusion of the heterojunction.Our results demonstrate that PtSe_(2)/MoSe_(2)is suitable for the development of broadspectrum and sensitive optoelectronic devices.Meanwhile,the results contribute to a fundamental understanding of the performance of various optoelectronic devices based on such PtSe_(2)two-dimensional(2D)heterostructures.
基金Project supported by the National Natural Science Foundation of China (Grant Nos.61925401,92064004,61927901,and 92164302)the 111 Project (Grant No.B18001)+1 种基金support from the Fok Ying-Tong Education Foundationthe Tencent Foundation through the XPLORER PRIZE。
文摘To simplify the fabrication process and increase the versatility of neuromorphic systems,the reconfiguration concept has attracted much attention.Here,we developed a novel electrochemical VO_(2)(EC-VO_(2))device,which can be reconfigured as synapses or LIF neurons.The ionic dynamic doping contributed to the resistance changes of VO_(2),which enables the reversible modulation of device states.The analog resistance switching and tunable LIF functions were both measured based on the same device to demonstrate the capacity of reconfiguration.Based on the reconfigurable EC-VO_(2),the simulated spiking neural network model exhibited excellent performances by using low-precision weights and tunable output neurons,whose final accuracy reached 91.92%.
文摘Light is essential for life on earth.In mammals,light is sensed by three cell types in the retina:rods and cones transduce light for image visualization and perception,while intrinsically photosensitive retinal ganglion cells(ipRGCs)transduce light for non-image visual functions,including light entrainment of circadian clocks,pupillary light reflex and mood regulation(Do and Yau,2010;LeGates et al.,2014).Consistent with their functions,ipRGCs project directly to a number of subcortical brain regions,while rods and cones project to the lateral geniculate nucleus,which in turn projects to the visual cortex.
基金We are grateful for the financial support from the National Natural Science Foundation of China(31671108 and 31800900)the National Key R&D Program of China(2017YFC1307500)+1 种基金the Shenzhen Science and Technology Innovation Commission(JCYJ20180508152240368)the Shenzhen Basic Research Program(JCYJ20200109114805984).
文摘Active exploratory behaviors have often been associated with theta oscillations in rodents,while theta oscillations during active exploration in non-human primates are still not well understood.We recorded neural activities in the frontal eye field(FEF)and V4 simultaneously when monkeys performed a free-gaze visual search task.Saccades were strongly phase-locked to theta oscillations of V4 and FEF local field potentials,and the phase-locking was dependent on saccade direction.The spiking probability of V4 and FEF units was significantly modulated by the theta phase in addition to the time-locked modulation associated with the evoked response.V4 and FEF units showed significantly stronger responses following saccades initiated at their preferred phases.Granger causality and ridge regression analysis showed modulatory effects of theta oscillations on saccade timing.Together,our study suggests phase-locking of saccades to the theta modulation of neural activity in visual and oculomotor cortical areas,in addition to the theta phase locking caused by saccade-triggered responses.
