Mutations in mitochondrial DNA(mtDNA)are maternally inherited and have the potential to cause severe disorders.Mitochondrial replacement therapies,including spindle,polar body,and pronuclear transfers,are promising st...Mutations in mitochondrial DNA(mtDNA)are maternally inherited and have the potential to cause severe disorders.Mitochondrial replacement therapies,including spindle,polar body,and pronuclear transfers,are promising strategies for preventing the hereditary transmission of mtDNA diseases.While pronuclear transfer has been used to generate mitochondrial replacement mouse models and human embryos,its application in non-human primates has not been previously reported.In this study,we successfully generated four healthy cynomolgus monkeys(Macaca fascicularis)via female pronuclear transfer.These individuals all survived for more than two years and exhibited minimal mtDNA carryover(3.8%–6.7%),as well as relatively stable mtDNA heteroplasmy dynamics during development.The successful establishment of this nonhuman primate model highlights the considerable potential of pronuclear transfer in reducing the risk of inherited mtDNA diseases and provides a valuable preclinical research model for advancing mitochondrial replacement therapies in humans.展开更多
An electroencephalographic(EEG)signature of auditory hallucinations(AHs)is important for facilitating the diagnosis and treatment of AHs in schizophrenia.We recorded EEG from 25 schizophrenia patients with recurrent A...An electroencephalographic(EEG)signature of auditory hallucinations(AHs)is important for facilitating the diagnosis and treatment of AHs in schizophrenia.We recorded EEG from 25 schizophrenia patients with recurrent AHs.During the period of AHs,EEG recordings exhibited significantly elevated beta2-band power in the temporal region,as compared to those recorded in the absence of AHs or during stimulation with verbal sounds.We further generated methamphetamine-treated rhesus monkeys exhibiting psychosis-like behaviors,including repetitive sudden searching actions in the absence of external intrusion,suggesting the occurrence of AHs.Epidural EEG beta2-band power in the temporal region of these monkeys was enhanced immediately after methamphetamine treatment and positively correlated with the frequency of sudden searching actions.Thus,the enhancement of temporal beta2-band oscillations represents a signature for AHs in both patients and a monkey model of psychosis,and this monkey model can be used for developing closed-loop neuromodulation approaches for the treatment of refractory AHs in schizophrenia.展开更多
Embryonic stem cells(ESCs)represent a subtype of pluripotent stem cells(PSCs)derived from the inner cell mass of blastocysts.These cells exhibit three principal features:the capacity for unlimited self-replication,the...Embryonic stem cells(ESCs)represent a subtype of pluripotent stem cells(PSCs)derived from the inner cell mass of blastocysts.These cells exhibit three principal features:the capacity for unlimited self-replication,the ability to differentiate into diverse somatic cell types in vitro,and the potential to contribute to chimera animals in vivo upon reintroduction into the host blastocyst.Thus,ESCs are widely used in basic and biomedical research,as well as in applications such as cell replacement therapy and the creation of genetically modified animal models.展开更多
The brain functions as a closed-loop system that continuously generates behavior in response to the external environment and adjusts actions based on the outcomes.Traditional research methodologies in neuroscience,esp...The brain functions as a closed-loop system that continuously generates behavior in response to the external environment and adjusts actions based on the outcomes.Traditional research methodologies in neuroscience,especially those employed in brain imaging experiments,have mainly adopted an open-loop paradigm(Grosenick et al.,2015).Functional neural circuits are analyzed offline and subsequently tested through manipulation of neuronal activities within specific regions or with genetic markers.By establishing a closed-loop research paradigm,functional ensembles can be detected and tested in real time with temporal sequences.These functional ensembles,rather than brain regions or genetically labeled neural populations,serve as fundamental units of neural networks,offering valuable insights into the dissection of neural circuits.The closed-loop research paradigm also enables the capture of high-dimensional activities of internal brain dynamics and precise elucidation of physiological processes such as learning,decision-making,and sleep.展开更多
Dear Editor,The brain has complex molecular and cellular compositions.Current knowledge about the molecular taxonomy of the brain is mainly based on rodent studies.Although they share common ancestors,primates and rod...Dear Editor,The brain has complex molecular and cellular compositions.Current knowledge about the molecular taxonomy of the brain is mainly based on rodent studies.Although they share common ancestors,primates and rodents evolved via different routes,diverging more than 75 million years ago.Thus,studies of other species do not fully inform the unique cognitive abilities of primates.Previous analyses of gene expression profiles across species mainly focus on the hippocampus and prefrontal cortex.展开更多
While viral infections can disturb the host gut microbiome,the dynamic alterations in microbial composition following infection remain poorly characterized.This study identified SRV-8-infected monkeys and classified t...While viral infections can disturb the host gut microbiome,the dynamic alterations in microbial composition following infection remain poorly characterized.This study identified SRV-8-infected monkeys and classified them into five groups based on infection progression.16S rRNA amplicon sequencing revealed significant alterations in the relative and inferred absolute abundance of bacterial genera UCG-002,Agathobacter,Coprococcus,and Holdemanella during the early stage of SRV-8 infection,coinciding with provirus formation.These microbial shifts were accompanied by functional modifications in bacterial communities at the same stage.In contrast,ITS amplicon sequencing indicated no significant differences in fungal composition between healthy wild-type and SRV-8-infected monkeys.Spearman correlation analyses demonstrated close interactions between intestinal bacteria and fungi following SRV-8 infection.Additionally,SRV-8 seropositive groups exhibited significantly elevated mRNA expression levels of pro-inflammatory(TNF-α,IFN-γ,IL-1β,and IL-6)and anti-inflammatory(IL-10)cytokine genes,highlighting close associations between inflammatory cytokines and immune responses.Overall,these findings provide a comprehensive characterization of bacterial and fungal microbiota dynamics and inflammatory cytokine responses associated with SRV-8 infection,clarifying the pathobiological mechanisms underlying SRV-8 infection from the perspective of the gut microbiome.展开更多
The prevalence of autism spectrum disorders(ASD)has been high worldwide,reaching 1/59 children in the United States as reported by the Centers of Disease Control and Prevention.Since genetic components play a major ro...The prevalence of autism spectrum disorders(ASD)has been high worldwide,reaching 1/59 children in the United States as reported by the Centers of Disease Control and Prevention.Since genetic components play a major role in ASD[1],it is astonishing that the occurrence of ASD would be this high probabily due to genetic causes.It is worthy to note that autistic phenotypes of ASD patients show great diversity.The severity of autistic symptoms may be correlated with whether genetic mutations affect neural development.Thus,we argue that the prevalence of severe ASD may be much lower than the common ASD usually reported.展开更多
Beta amyloid （Aβ42）-induced dysfunction and loss of synapses are believed to be major underlying mechanisms for the progressive loss of learning and memory abilities in Alzheimer＇s disease （AD）. The vast majorit...Beta amyloid （Aβ42）-induced dysfunction and loss of synapses are believed to be major underlying mechanisms for the progressive loss of learning and memory abilities in Alzheimer＇s disease （AD）. The vast majority of investigations on AD-related synaptic impairment focus on synaptic plasticity, especially the decline of long-term potentiation of synaptic transmission caused by extracellular Aβ42. Changes in other aspects of synaptic and neuronal functions are less studied or undiscovered. Here, we report that intraneuronal accumulation of Aβ42 induced an age- dependent slowing of neuronal transmission along pathways involving multiple synapses.展开更多
Dear Editor, Parkinson＇s disease （PD） is the second most common neurodegenerative disease after Alzheimer＇s disease （AD）. Although treatments for PD may be beneficial in the early stages of disease, accurate dia...Dear Editor, Parkinson＇s disease （PD） is the second most common neurodegenerative disease after Alzheimer＇s disease （AD）. Although treatments for PD may be beneficial in the early stages of disease, accurate diagnosis during these stages remains a challenge. An ideal diagnosis for PD should be highly specific and sensitive, as well as be able to predict disease progression. Currently, diagnosis of PD relies mainly on the evaluation of clinical features, specifically cardinal signs.展开更多
CRISPR-mediated genome editing is a revolutionary technology for genome manipulation that uses the CRISPR-Cas systems and base editors.Currently,poor efficiency and off-target problems have impeded the application of ...CRISPR-mediated genome editing is a revolutionary technology for genome manipulation that uses the CRISPR-Cas systems and base editors.Currently,poor efficiency and off-target problems have impeded the application of CRISPR systems.The on-target efficiency has been improved in several advanced versions of CRISPR systems,whereas the off-target detection still remains a key challenge.Here,we outline the different versions of CRISPR systems and off-target detection strategies,discuss the merits and limitations of off-target detection methods,and provide potential implications for further gene editing research.展开更多
Methyl-CpG binding protein 2(MeCP2) is a basic nuclear protein involved in the regulation of gene expression and microRNA processing.Duplication of MECP2-containing genomic segments causes MECP2 duplication syndrome,a...Methyl-CpG binding protein 2(MeCP2) is a basic nuclear protein involved in the regulation of gene expression and microRNA processing.Duplication of MECP2-containing genomic segments causes MECP2 duplication syndrome,a severe neurodevelopmental disorder characterized by intellectual disability,motor dysfunction,heightened anxiety,epilepsy,autistic phenotypes,and early death.Reversal of the abnormal phenotypes in adult mice with MECP2 duplication(MECP2-TG) by normalizing the MeCP2 levels across the whole brain has been demonstrated.However,whether different brain areas or neural circuits contribute to different aspects of the behavioral deficits is still unknown.Here,we found that MECP2-TG mice showed a significant social recognition deficit,and were prone to display aversive-like behaviors,including heightened anxiety-like behaviors and a fear generalization phenotype.In addition,reduced locomotor activity was observed in MECP2-TG mice.However,appetitive behaviors and learning and memory were comparable in MECP2-TG and wild-type mice.Functional magnetic resonance imaging illustrated that the differences between MECP2-TG and wild-type mice were mainly concentrated in brain areas regulating emotion and social behaviors.We used the CRISPR-Cas9 method to restore normal MeCP2 levels in the medial prefrontal cortex(mPFC) and bed nuclei of the stria terminalis(BST) of adult MECP2-TG mice,and found that normalization of MeCP2 levels in the mPFC but not in the BST reversed the social recognition deficit.These data indicate that the mPFC is responsible for the social recognition deficit in the transgenic mice,and provide new insight into potential therapies for MECP2 duplication syndrome.展开更多
Emotional contagion, a primary form of empathy, is present in rodents. Among emotional contagion behaviors, social transmission of fear is the most studied.Here, we modified a paradigm used in previous studies to more...Emotional contagion, a primary form of empathy, is present in rodents. Among emotional contagion behaviors, social transmission of fear is the most studied.Here, we modified a paradigm used in previous studies to more robustly assess the social transmission of fear in rats that experienced foot-shock. We used resting-state functional magnetic resonance imaging to show that foot-shock experience enhances the regional connectivity of the anterior cingulate cortex(ACC). We found that lesioning the ACC specifically attenuated the vicarious freezing behavior of foot-shock-experienced observer rats. Furthermore, ablation of projections from the ACC to the mediodorsal thalamus(MDL) bilaterally delayed the vicarious freezing responses, and activation of these projections decreased the vicarious freezing responses.Overall, our results demonstrate that, in rats, the ACC modulates vicarious freezing behavior via a projection to the MDL and provide clues to understanding the mechanisms underlying empathic behavior in humans.展开更多
Aging is closely related to physiology and disease development in animals.Gut microbiota varies with lifecycle and exerts profound influences on the host.To investigate gut microbial alterations during growth and matu...Aging is closely related to physiology and disease development in animals.Gut microbiota varies with lifecycle and exerts profound influences on the host.To investigate gut microbial alterations during growth and maturation,41 female cynomolgus monkeys(Macaca fascicularis)ranging in age from 1 month to 15 years were divided into four groups(infant,young,adult,and middle-aged).展开更多
Parkinson＇s disease （PD） is a common neurodegenerative disorder affecting millions of people worldwide, but its cause and pathogenesis are still not fully understood. Earlier studies have shown that SNCA, which enc...Parkinson＇s disease （PD） is a common neurodegenerative disorder affecting millions of people worldwide, but its cause and pathogenesis are still not fully understood. Earlier studies have shown that SNCA, which encodes α-synuclein, is one of the key genes associated with PD. Single-nucleotide polymorphism （SNP） variants of SNCA are thought to be correlated with disease onset. The underlying mechanisms however are enigmatic. A recent study published in Nature revealed that one of the SNP variants in the SNCA non-coding element elevated α- synuclein expression in human neurons by reducing the binding efficiency of transcription factors, demonstrating a previously uncharted role for SNPs in the pathogenesis of PD.展开更多
Motor development has been extensively studied in human infants and children, with several established scales for the evaluation of motor functions. However, the study of the neuronal mechanisms underlying human motor...Motor development has been extensively studied in human infants and children, with several established scales for the evaluation of motor functions. However, the study of the neuronal mechanisms underlying human motor development is hampered by the lack of good animal models. The common marmoset （Callithrix jacchus）, a small New World monkey, has recently attracted much attention as a potential non- human primate model for understanding human physiology and diseases. However, little is known about its gross motor development. In the present study, we found that marmosets have a critical period for motor development in postnatal weeks 2 to 5, and acquire most of their motor skills by 8 weeks of age. We also developed methods to assess their motor functions, which will be useful for the evaluation of motor performance in marmoset models of human diseases. In addition, we found that marmosets exhibit a ＂head-to-tail＂ sequence of motor development similar to that found in humans, further supporting the notion that they provide a good animal model for studying the neuronal mechanisms underlying human motor development.展开更多
Whether direct manipulation of Parkinson’s disease(PD)risk genes in the adult monkey brain can elicit a Parkinsonian phenotype remains an unsolved issue.Here,we used an adeno-associated virus serotype 9(AAV9)-deliver...Whether direct manipulation of Parkinson’s disease(PD)risk genes in the adult monkey brain can elicit a Parkinsonian phenotype remains an unsolved issue.Here,we used an adeno-associated virus serotype 9(AAV9)-delivered CRISPR/Cas9 system to directly co-edit PINK1 and DJ-1 genes in the substantia nigras(SNs)of two monkey groups:an old group and a middle-aged group.After the operation,the old group exhibited all the classic PD symptoms,including bradykinesia,tremor,and postural instability,accompanied by key pathological hallmarks of PD,such as severe nigral dopaminergic neuron loss(>64%)and evidentα-synuclein pathology in the gene-edited SN.In contrast,the phenotype of their middle-aged counterparts,which also showed clear PD symptoms and pathological hallmarks,were less severe.In addition to the higher final total PD scores and more severe pathological changes,the old group were also more susceptible to gene editing by showing a faster process of PD progression.These results suggested that both genetic and aging factors played important roles in the development of PD in the monkeys.Taken together,this system can effectively develop a large number of genetically-edited PD monkeys in a short time(6–10 months),and thus provides a practical transgenic monkey model for future PD studies.展开更多
Caspases, a family of cysteine proteases, mediate programmed cell death during early neural development and neurodegeneration, as well as following neurotoxic insults. Notably, accumulating lines of evidence have show...Caspases, a family of cysteine proteases, mediate programmed cell death during early neural development and neurodegeneration, as well as following neurotoxic insults. Notably, accumulating lines of evidence have shown non-apoptotic roles of caspases in the structural and functional plasticity of neuronal circuits under physiological conditions, such as growth-cone dynamics and axonal/dendritic pruning, as well as neuronal excitability and plasticity. Here, we summarize recent progress on the roles of caspases in synaptic refinement.展开更多
Glial cells,consisting of astrocytes,oligodendrocyte lineage cells,and microglia,account for>50% of the total number of cells in the mammalian brain.They play key roles in the modulation of various brain activities...Glial cells,consisting of astrocytes,oligodendrocyte lineage cells,and microglia,account for>50% of the total number of cells in the mammalian brain.They play key roles in the modulation of various brain activities under physiological and pathological conditions.Although the typical morphological features and characteristic functions of these cells are well described,the organization of interconnections of the different glial cell populations and their impact on the healthy and diseased brain is not completely understood.Understanding these processes remains a profound challenge.Accumulating evidence suggests that glial cells can form highly complex interconnections with each other.The astroglial network has been well described.Oligodendrocytes and microglia may also contribute to the formation of glial networks under various circumstances.In this review,we discuss the structure and function of glial networks and their pathological relevance to central nervous system diseases.We also highlight opportunities for future research on the glial connectome.展开更多
Autism spectrum disorder(ASD)is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and repetitive behaviors.Although hundreds of ASD risk genes,implicated in synaptic forma...Autism spectrum disorder(ASD)is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and repetitive behaviors.Although hundreds of ASD risk genes,implicated in synaptic formation and transcriptional regulation,have been identified through human genetic studies,the East Asian ASD cohorts are still under-represented in genome-wide genetic studies.Here,we applied whole-exome sequencing to 369 ASD trios including probands and unaffected parents of Chinese origin.Using a joint-calling analytical pipeline based on GATK toolkits,we identified numerous de novo mutations including 55 high-impact variants and 165 moderate-impact variants,as well as de novo copy number variations containing known ASD-related genes.Importantly,combined with single-cell sequencing data from the developing human brain,we found that the expression of genes with de novo mutations was specifically enriched in the pre-,post-central gyrus(PRC,PC)and banks of the superior temporal(BST)regions in the human brain.By further analyzing the brain imaging data with ASD and healthy controls,we found that the gray volume of the right BST in ASD patients was significantly decreased compared to healthy controls,suggesting the potential structural deficits associated with ASD.Finally,we found a decrease in the seed-based functional connectivity between BST/PC/PRC and sensory areas,the insula,as well as the frontal lobes in ASD patients.This work indicated that combinatorial analysis with genome-wide screening,single-cell sequencing,and brain imaging data reveal the brain regions contributing to the etiology of ASD.展开更多
The thalamus and central dopamine signaling have been shown to play important roles in high-level cognitive processes including impulsivity. However, little is known about the role of dopamine receptors in the thalamu...The thalamus and central dopamine signaling have been shown to play important roles in high-level cognitive processes including impulsivity. However, little is known about the role of dopamine receptors in the thalamus in decisional impulsivity. In the present study,rats were tested using a delay discounting task and divided into three groups： high impulsivity（HI）, medium impulsivity（MI）, and low impulsivity（LI）. Subsequent in vivo voxel-based magnetic resonance imaging revealed that the HI rats displayed a markedly reduced density of gray matter in the lateral thalamus compared with the LI rats. In the MI rats, the dopamine D1 receptor antagonist SCH23390 or the D2 receptor antagonist eticlopride was microinjected into the lateral thalamus. SCH23390 significantly decreased their choice of a large, delayed reward and increased their omission of lever presses. In contrast,eticlopride increased the choice of a large, delayed reward but had no effect on the omissions. Together, our results indicate that the lateral thalamus is involved in decisional impulsivity, and dopamine D1 and D2 receptors in the lateral thalamus have distinct effects on decisional impulsive behaviors in rats. These results provide a new insightinto the dopamine signaling in the lateral thalamus in decisional impulsivity.展开更多
基金supported by the National Natural Science Foundation of China (82021001,31825018)National Key Research and Development Program of China (2022YFF0710901)+3 种基金Shanghai Municipal Science and Technology Major Project (2018SHZDZX05)Strategic Priority Research Program of the Chinese Academy of Sciences (XDB32060100)Biological Resources Program of Chinese Academy of Sciences (KFJ-BRP-005)National Science and Technology Innovation 2030 Major Program 2021ZD0200900。
文摘Mutations in mitochondrial DNA(mtDNA)are maternally inherited and have the potential to cause severe disorders.Mitochondrial replacement therapies,including spindle,polar body,and pronuclear transfers,are promising strategies for preventing the hereditary transmission of mtDNA diseases.While pronuclear transfer has been used to generate mitochondrial replacement mouse models and human embryos,its application in non-human primates has not been previously reported.In this study,we successfully generated four healthy cynomolgus monkeys(Macaca fascicularis)via female pronuclear transfer.These individuals all survived for more than two years and exhibited minimal mtDNA carryover(3.8%–6.7%),as well as relatively stable mtDNA heteroplasmy dynamics during development.The successful establishment of this nonhuman primate model highlights the considerable potential of pronuclear transfer in reducing the risk of inherited mtDNA diseases and provides a valuable preclinical research model for advancing mitochondrial replacement therapies in humans.
基金supported by a Shanghai Municipal Science and Technology Major Project(2021SHZDZX,E154N41011)the Lingang Lab Program(LG2021050202 and LG2021060301)+1 种基金the National Nature Science Foundation(82130041)the Shanghai Rising-star Cultivation Program(22YF1439200).
文摘An electroencephalographic(EEG)signature of auditory hallucinations(AHs)is important for facilitating the diagnosis and treatment of AHs in schizophrenia.We recorded EEG from 25 schizophrenia patients with recurrent AHs.During the period of AHs,EEG recordings exhibited significantly elevated beta2-band power in the temporal region,as compared to those recorded in the absence of AHs or during stimulation with verbal sounds.We further generated methamphetamine-treated rhesus monkeys exhibiting psychosis-like behaviors,including repetitive sudden searching actions in the absence of external intrusion,suggesting the occurrence of AHs.Epidural EEG beta2-band power in the temporal region of these monkeys was enhanced immediately after methamphetamine treatment and positively correlated with the frequency of sudden searching actions.Thus,the enhancement of temporal beta2-band oscillations represents a signature for AHs in both patients and a monkey model of psychosis,and this monkey model can be used for developing closed-loop neuromodulation approaches for the treatment of refractory AHs in schizophrenia.
基金supported by the National Natural Science Foundation of China (32170809)。
文摘Embryonic stem cells(ESCs)represent a subtype of pluripotent stem cells(PSCs)derived from the inner cell mass of blastocysts.These cells exhibit three principal features:the capacity for unlimited self-replication,the ability to differentiate into diverse somatic cell types in vitro,and the potential to contribute to chimera animals in vivo upon reintroduction into the host blastocyst.Thus,ESCs are widely used in basic and biomedical research,as well as in applications such as cell replacement therapy and the creation of genetically modified animal models.
文摘The brain functions as a closed-loop system that continuously generates behavior in response to the external environment and adjusts actions based on the outcomes.Traditional research methodologies in neuroscience,especially those employed in brain imaging experiments,have mainly adopted an open-loop paradigm(Grosenick et al.,2015).Functional neural circuits are analyzed offline and subsequently tested through manipulation of neuronal activities within specific regions or with genetic markers.By establishing a closed-loop research paradigm,functional ensembles can be detected and tested in real time with temporal sequences.These functional ensembles,rather than brain regions or genetically labeled neural populations,serve as fundamental units of neural networks,offering valuable insights into the dissection of neural circuits.The closed-loop research paradigm also enables the capture of high-dimensional activities of internal brain dynamics and precise elucidation of physiological processes such as learning,decision-making,and sleep.
基金supported by the National Nature Science Foundation of China(82171173,82071177,91732302,and 82201321)the Shanghai Brain-Intelligence Project of Science and Technology Commission of Shanghai Municipality(16JC1420501 and 22YF1422500)+1 种基金Strategic Priority Research Program of the Chinese Academy of Sciences(XDBS01060200)and the Shanghai Municipal Science and Technology Major Project(2018SHZDZX05)Shanghai Ninth People’s Hospital Grant(JYZP001).
文摘Dear Editor,The brain has complex molecular and cellular compositions.Current knowledge about the molecular taxonomy of the brain is mainly based on rodent studies.Although they share common ancestors,primates and rodents evolved via different routes,diverging more than 75 million years ago.Thus,studies of other species do not fully inform the unique cognitive abilities of primates.Previous analyses of gene expression profiles across species mainly focus on the hippocampus and prefrontal cortex.
基金supported by the National Science and Technology Innovation 2030 Major Program(2021ZD0200900)National Key Research and Development Program of China(2022YFF0710901)+3 种基金National Natural Science Foundation of China(82021001,31825018)Biological Resources Program of the Chinese Academy of Sciences(KFJBRP-005)111 Project D18007a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)。
文摘While viral infections can disturb the host gut microbiome,the dynamic alterations in microbial composition following infection remain poorly characterized.This study identified SRV-8-infected monkeys and classified them into five groups based on infection progression.16S rRNA amplicon sequencing revealed significant alterations in the relative and inferred absolute abundance of bacterial genera UCG-002,Agathobacter,Coprococcus,and Holdemanella during the early stage of SRV-8 infection,coinciding with provirus formation.These microbial shifts were accompanied by functional modifications in bacterial communities at the same stage.In contrast,ITS amplicon sequencing indicated no significant differences in fungal composition between healthy wild-type and SRV-8-infected monkeys.Spearman correlation analyses demonstrated close interactions between intestinal bacteria and fungi following SRV-8 infection.Additionally,SRV-8 seropositive groups exhibited significantly elevated mRNA expression levels of pro-inflammatory(TNF-α,IFN-γ,IL-1β,and IL-6)and anti-inflammatory(IL-10)cytokine genes,highlighting close associations between inflammatory cytokines and immune responses.Overall,these findings provide a comprehensive characterization of bacterial and fungal microbiota dynamics and inflammatory cytokine responses associated with SRV-8 infection,clarifying the pathobiological mechanisms underlying SRV-8 infection from the perspective of the gut microbiome.
文摘The prevalence of autism spectrum disorders(ASD)has been high worldwide,reaching 1/59 children in the United States as reported by the Centers of Disease Control and Prevention.Since genetic components play a major role in ASD[1],it is astonishing that the occurrence of ASD would be this high probabily due to genetic causes.It is worthy to note that autistic phenotypes of ASD patients show great diversity.The severity of autistic symptoms may be correlated with whether genetic mutations affect neural development.Thus,we argue that the prevalence of severe ASD may be much lower than the common ASD usually reported.
基金supported by the National Natural Science Foundation of China(81071026 and 81371400)the National Basic Research Development Program of China(2013CB530900)
文摘Beta amyloid （Aβ42）-induced dysfunction and loss of synapses are believed to be major underlying mechanisms for the progressive loss of learning and memory abilities in Alzheimer＇s disease （AD）. The vast majority of investigations on AD-related synaptic impairment focus on synaptic plasticity, especially the decline of long-term potentiation of synaptic transmission caused by extracellular Aβ42. Changes in other aspects of synaptic and neuronal functions are less studied or undiscovered. Here, we report that intraneuronal accumulation of Aβ42 induced an age- dependent slowing of neuronal transmission along pathways involving multiple synapses.
基金This work was supported by grants from the Chinese Ministry of Science ＆ Technology （No. 2004AA221130）, the Shanghai Metropolitan Fund for Research and Development （No. 07DJ14005）, the National Natural Science Foundation of China （Nos. 30525041, 30721004）, and the State Key Program for Basic Research of China （No. 2006CB500704）.
文摘Dear Editor, Parkinson＇s disease （PD） is the second most common neurodegenerative disease after Alzheimer＇s disease （AD）. Although treatments for PD may be beneficial in the early stages of disease, accurate diagnosis during these stages remains a challenge. An ideal diagnosis for PD should be highly specific and sensitive, as well as be able to predict disease progression. Currently, diagnosis of PD relies mainly on the evaluation of clinical features, specifically cardinal signs.
基金supported by the grants 81771230(W.C.),31922048(E.Z.)and 31522037(H.Y.)from the National Natural Science Foundation of China.
文摘CRISPR-mediated genome editing is a revolutionary technology for genome manipulation that uses the CRISPR-Cas systems and base editors.Currently,poor efficiency and off-target problems have impeded the application of CRISPR systems.The on-target efficiency has been improved in several advanced versions of CRISPR systems,whereas the off-target detection still remains a key challenge.Here,we outline the different versions of CRISPR systems and off-target detection strategies,discuss the merits and limitations of off-target detection methods,and provide potential implications for further gene editing research.
基金supported by National Natural Science Foundation of China grants (31625013 and 91732302)a Shanghai Brain-Intelligence Project of the Science and Technology Commission of Shanghai Municipality(16JC1420501)+4 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences (XDBS01060200)Program of Shanghai Academic Research Leaderthe Open Large Infrastructure Research of Chinese Academy of Sciencesthe Shanghai Municipal Science and Technology Major Project (2018SHZDZX05)National Natural Science Foundation of China (81801354)。
文摘Methyl-CpG binding protein 2(MeCP2) is a basic nuclear protein involved in the regulation of gene expression and microRNA processing.Duplication of MECP2-containing genomic segments causes MECP2 duplication syndrome,a severe neurodevelopmental disorder characterized by intellectual disability,motor dysfunction,heightened anxiety,epilepsy,autistic phenotypes,and early death.Reversal of the abnormal phenotypes in adult mice with MECP2 duplication(MECP2-TG) by normalizing the MeCP2 levels across the whole brain has been demonstrated.However,whether different brain areas or neural circuits contribute to different aspects of the behavioral deficits is still unknown.Here,we found that MECP2-TG mice showed a significant social recognition deficit,and were prone to display aversive-like behaviors,including heightened anxiety-like behaviors and a fear generalization phenotype.In addition,reduced locomotor activity was observed in MECP2-TG mice.However,appetitive behaviors and learning and memory were comparable in MECP2-TG and wild-type mice.Functional magnetic resonance imaging illustrated that the differences between MECP2-TG and wild-type mice were mainly concentrated in brain areas regulating emotion and social behaviors.We used the CRISPR-Cas9 method to restore normal MeCP2 levels in the medial prefrontal cortex(mPFC) and bed nuclei of the stria terminalis(BST) of adult MECP2-TG mice,and found that normalization of MeCP2 levels in the mPFC but not in the BST reversed the social recognition deficit.These data indicate that the mPFC is responsible for the social recognition deficit in the transgenic mice,and provide new insight into potential therapies for MECP2 duplication syndrome.
基金The National Key Research and Development Program of China(2017YFB1300200,2017YFB1300203)the National Natural Science Foundation of China(61627808).
文摘Emotional contagion, a primary form of empathy, is present in rodents. Among emotional contagion behaviors, social transmission of fear is the most studied.Here, we modified a paradigm used in previous studies to more robustly assess the social transmission of fear in rats that experienced foot-shock. We used resting-state functional magnetic resonance imaging to show that foot-shock experience enhances the regional connectivity of the anterior cingulate cortex(ACC). We found that lesioning the ACC specifically attenuated the vicarious freezing behavior of foot-shock-experienced observer rats. Furthermore, ablation of projections from the ACC to the mediodorsal thalamus(MDL) bilaterally delayed the vicarious freezing responses, and activation of these projections decreased the vicarious freezing responses.Overall, our results demonstrate that, in rats, the ACC modulates vicarious freezing behavior via a projection to the MDL and provide clues to understanding the mechanisms underlying empathic behavior in humans.
基金supported by the National Key Research and Development Program of China(2018YFC1003000)National Natural Science Foundation of China(31825018)+2 种基金Strategic Priority Research Program of the Chinese Academy of Sciences(XDB32060100)Shanghai Municipal Science and Technology Major Project(2018SHZDZX05)Shanghai Municipal Government Bureau of Science and Technology(18JC1410100)。
文摘Aging is closely related to physiology and disease development in animals.Gut microbiota varies with lifecycle and exerts profound influences on the host.To investigate gut microbial alterations during growth and maturation,41 female cynomolgus monkeys(Macaca fascicularis)ranging in age from 1 month to 15 years were divided into four groups(infant,young,adult,and middle-aged).
文摘Parkinson＇s disease （PD） is a common neurodegenerative disorder affecting millions of people worldwide, but its cause and pathogenesis are still not fully understood. Earlier studies have shown that SNCA, which encodes α-synuclein, is one of the key genes associated with PD. Single-nucleotide polymorphism （SNP） variants of SNCA are thought to be correlated with disease onset. The underlying mechanisms however are enigmatic. A recent study published in Nature revealed that one of the SNP variants in the SNCA non-coding element elevated α- synuclein expression in human neurons by reducing the binding efficiency of transcription factors, demonstrating a previously uncharted role for SNPs in the pathogenesis of PD.
基金supported by the Youth Innovation Promotion Association of the Chinese Academy of Sciences and an SA-SIBS scholarship to NGthe MoST 973 Program of China (2011CBA00400)the Strategic Priority Research Program of the CAS (XDB02020100)
文摘Motor development has been extensively studied in human infants and children, with several established scales for the evaluation of motor functions. However, the study of the neuronal mechanisms underlying human motor development is hampered by the lack of good animal models. The common marmoset （Callithrix jacchus）, a small New World monkey, has recently attracted much attention as a potential non- human primate model for understanding human physiology and diseases. However, little is known about its gross motor development. In the present study, we found that marmosets have a critical period for motor development in postnatal weeks 2 to 5, and acquire most of their motor skills by 8 weeks of age. We also developed methods to assess their motor functions, which will be useful for the evaluation of motor performance in marmoset models of human diseases. In addition, we found that marmosets exhibit a ＂head-to-tail＂ sequence of motor development similar to that found in humans, further supporting the notion that they provide a good animal model for studying the neuronal mechanisms underlying human motor development.
基金This work was supported by the National Key R&D Program of China(2018YFA0801403)the Key-Area Research and Development Program of Guangdong Province(2019B030335001)+6 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB32060200)the National Program for Key Basic Research Projects(973 Program:2015CB755605)the National Natural Science Foundation of China(81471312,81771387,81460352,81500983,31700897,31700910,31800901,31625013,and 91732302)the Applied Basic Research Programs of Science and Technology Commission Foundation of Yunnan Province(2017FB109,2018FB052,2018FB053,2019FA007,and 202001AT070130)Chinese Academy of Sciences"Light of West China"Program,Shanghai Brain-Intelligence Project from Science and Technology Commission of Shanghai Municipality(16JC1420501)Shanghai Municipal Science and Technology Major Project(2018SHZDZX05)Open Large Infrastructure Research of Chinese Academy of Sciences,and China Postdoctoral Science Foundation(2018M631105).
文摘Whether direct manipulation of Parkinson’s disease(PD)risk genes in the adult monkey brain can elicit a Parkinsonian phenotype remains an unsolved issue.Here,we used an adeno-associated virus serotype 9(AAV9)-delivered CRISPR/Cas9 system to directly co-edit PINK1 and DJ-1 genes in the substantia nigras(SNs)of two monkey groups:an old group and a middle-aged group.After the operation,the old group exhibited all the classic PD symptoms,including bradykinesia,tremor,and postural instability,accompanied by key pathological hallmarks of PD,such as severe nigral dopaminergic neuron loss(>64%)and evidentα-synuclein pathology in the gene-edited SN.In contrast,the phenotype of their middle-aged counterparts,which also showed clear PD symptoms and pathological hallmarks,were less severe.In addition to the higher final total PD scores and more severe pathological changes,the old group were also more susceptible to gene editing by showing a faster process of PD progression.These results suggested that both genetic and aging factors played important roles in the development of PD in the monkeys.Taken together,this system can effectively develop a large number of genetically-edited PD monkeys in a short time(6–10 months),and thus provides a practical transgenic monkey model for future PD studies.
基金supported by grants from the National Natural Science Foundation (31330032,31321091,and 61327902)he National Basic Research Development Program of China (2014CB910203)
文摘Caspases, a family of cysteine proteases, mediate programmed cell death during early neural development and neurodegeneration, as well as following neurotoxic insults. Notably, accumulating lines of evidence have shown non-apoptotic roles of caspases in the structural and functional plasticity of neuronal circuits under physiological conditions, such as growth-cone dynamics and axonal/dendritic pruning, as well as neuronal excitability and plasticity. Here, we summarize recent progress on the roles of caspases in synaptic refinement.
基金supported by grants from the Ministry of Science and Technology of China(2020YFC2002800)the National Natural Science Foundation of China(32230049,U1801681)+2 种基金the Strategic Priority Research Program of the Chinese Academy of Science(XDB32020100)the Shanghai Municipal Science and Technology Major Project(2018SHZDZX05)the Key Realm R&D Program of Guangdong Province(2018B030337001).
文摘Glial cells,consisting of astrocytes,oligodendrocyte lineage cells,and microglia,account for>50% of the total number of cells in the mammalian brain.They play key roles in the modulation of various brain activities under physiological and pathological conditions.Although the typical morphological features and characteristic functions of these cells are well described,the organization of interconnections of the different glial cell populations and their impact on the healthy and diseased brain is not completely understood.Understanding these processes remains a profound challenge.Accumulating evidence suggests that glial cells can form highly complex interconnections with each other.The astroglial network has been well described.Oligodendrocytes and microglia may also contribute to the formation of glial networks under various circumstances.In this review,we discuss the structure and function of glial networks and their pathological relevance to central nervous system diseases.We also highlight opportunities for future research on the glial connectome.
基金This work was supported by the National Natural Science Foundation of China(31625013,81941015,32000726,and 61973086)the Shanghai Brain-Intelligence Project from STCSM(16JC1420501)+2 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDBS01060200)the Program of Shanghai Academic Research LeaderThe Open Large Infrastructure Research of the Chinese Academy of Sciences,and the Shanghai Municipal Science and Technology Major Project(2018SHZDZX01).
文摘Autism spectrum disorder(ASD)is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and repetitive behaviors.Although hundreds of ASD risk genes,implicated in synaptic formation and transcriptional regulation,have been identified through human genetic studies,the East Asian ASD cohorts are still under-represented in genome-wide genetic studies.Here,we applied whole-exome sequencing to 369 ASD trios including probands and unaffected parents of Chinese origin.Using a joint-calling analytical pipeline based on GATK toolkits,we identified numerous de novo mutations including 55 high-impact variants and 165 moderate-impact variants,as well as de novo copy number variations containing known ASD-related genes.Importantly,combined with single-cell sequencing data from the developing human brain,we found that the expression of genes with de novo mutations was specifically enriched in the pre-,post-central gyrus(PRC,PC)and banks of the superior temporal(BST)regions in the human brain.By further analyzing the brain imaging data with ASD and healthy controls,we found that the gray volume of the right BST in ASD patients was significantly decreased compared to healthy controls,suggesting the potential structural deficits associated with ASD.Finally,we found a decrease in the seed-based functional connectivity between BST/PC/PRC and sensory areas,the insula,as well as the frontal lobes in ASD patients.This work indicated that combinatorial analysis with genome-wide screening,single-cell sequencing,and brain imaging data reveal the brain regions contributing to the etiology of ASD.
基金supported by the National Natural Science Foundation(81471353)the National Basic Research Program of China(2015CB553500)the Science Fund for Creative Research Groups from of National Natural Science Foundation of China(81521063)
文摘The thalamus and central dopamine signaling have been shown to play important roles in high-level cognitive processes including impulsivity. However, little is known about the role of dopamine receptors in the thalamus in decisional impulsivity. In the present study,rats were tested using a delay discounting task and divided into three groups： high impulsivity（HI）, medium impulsivity（MI）, and low impulsivity（LI）. Subsequent in vivo voxel-based magnetic resonance imaging revealed that the HI rats displayed a markedly reduced density of gray matter in the lateral thalamus compared with the LI rats. In the MI rats, the dopamine D1 receptor antagonist SCH23390 or the D2 receptor antagonist eticlopride was microinjected into the lateral thalamus. SCH23390 significantly decreased their choice of a large, delayed reward and increased their omission of lever presses. In contrast,eticlopride increased the choice of a large, delayed reward but had no effect on the omissions. Together, our results indicate that the lateral thalamus is involved in decisional impulsivity, and dopamine D1 and D2 receptors in the lateral thalamus have distinct effects on decisional impulsive behaviors in rats. These results provide a new insightinto the dopamine signaling in the lateral thalamus in decisional impulsivity.
