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Forebrain excitatory neuron-specific loss of Brpf1 attenuates excitatory synaptic transmission and impairs spatial and fear memory

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Neural Regeneration Research 2024年第5期19卷 1133-1141页

作者： Baicheng Zhao Hang Zhang Ying Liu Gaoyu Zu Yuxiao Zhang Jiayi Hu Shuai Liu Linya You Department of Human Anatomy&Histoembryology School of Basic Medical SciencesFudan UniversityShanghaiChina shanghai key laboratory of brain functional genomics(Ministry of Education) Affiliated Mental Health Center(ECNU)School of Psychology and Cognitive ScienceEast China Normal UniversityShanghaiChina shanghai Changning Mental Health Center ShanghaiChina NYU-ECNU institute of brain and Cognitive Science at NYU shanghai ShanghaiChina key laboratory of Medical Imaging Computing and Computer Assisted Intervention of shanghai ShanghaiChina

Bromodomain and plant homeodomain(PHD)finger containing protein 1(Brpf1)is an activator and scaffold protein of a multiunit complex that includes other components involving lysine acetyltransferase(KAT)6A/6B/***1,KAT6A,and KAT6B mutations were identified as the causal genes of neurodevelopmental disorders leading to intellectual *** previous work revealed strong and specific expression of Brpf1 in both the postnatal and adult forebrain,especially the hippocampus,which has essential roles in learning and ***,we hypothesized that Brpf1 plays critical roles in the function of forebrain excitatory neurons,and that its deficiency leads to learning and memory *** test this,we knocked out Brpf1 in forebrain excitatory neurons using *** found that Brpf1 deficiency reduced the frequency of miniature excitatory postsynaptic currents and downregulated the expression of genes Pcdhgb1,Slc16a7,Robo3,and Rho,which are related to neural development,synapse function,and memory,thereby damaging spatial and fear memory in *** findings help explain the mechanisms of intellectual impairment in patients with BRPF1 mutation.

关键词： behavioral test Brpf1 CAMKIIa-Cre intellectual disability miniature excitatory postsynaptic current mRNA-Seq

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Shedding light on gene therapy of Parkinson’s disease in non-human primates

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The Innovation 2024年第1期5卷 15-16页

作者： Xunyi Yan Xin Jin New Cornerstone Science laboratory Center for Motor Control and DiseaseKey Laboratory of Brain Functional GenomicsEast China Normal University3663 North Zhongshan RoadShanghai 200062China NYU–ECNU institute of brain and Cognitive Science New York University Shanghai3663 North Zhongshan RoadShanghai 200062China

Parkinson’s disease(PD)is a progressive neurodegeneration disease initially described by James *** is typically diagnosed based on clinical features such as bradykinesia,resting tremor,rigidity,and,in later stages,postural ***,the prevalence of PD ranges from 5 to over 35 cases per 100,000 population,with the majority affecting individuals aged 50 years or *** risk increases with age,particularly in *** factors,including genetics,lifestyle,specific environmental influences,and geometry,contribute to the disease.

关键词： clinical rigidity initially

SH2B1 Tunes Hippocampal ERK Signaling to Influence Fluid Intelligence in Humans and Mice

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Research 2024年第3期2023卷 369-389页

作者： Xiujuan Du Yuhua Yan Juehua Yu Tailin Zhu Chu-Chung Huang Lingli Zhang Xingyue Shan Ren Li Yuan Dai Hui LV Xiao-Yong Zhang Jianfeng Feng Wei-Guang Li Qiang Luo Fei Li Developmental and Behavioral Pediatric Department Brain and Behavioral Research Unit of Shanghai Institute for Pediatric Research and Ministry of Education-Shanghai Key Laboratory for Children's Environmental HealthXinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200092China Developmental and Behavioral Pediatric Department Shanghai Xinhua Children's HospitalShanghai 200092China National Clinical Research Center for Aging and Medicine at Huashan Hospital Institute of Science and Technology for Brain-lnspired IntelligenceMinistry of Education-Key Laboratory of Computational Neuroscience and Brain-lnspired IntelligenceFudan UniversityShanghai 200433China State key laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for brain Science Institutes of Brain Science and Human Phenom InstituteFudan UniversityShanghai 200032China shanghai key laboratory of brain functional genomics(Ministry of Education) School of Life SciencesEast China Normal UniversityShanghai 200062China Department of Rehabilitation Medicine Huashan HospitalInstitute for Translational Brain ResearchState Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain ScienceFudan UniversityShanghai 200032China Center for Experimental Studies and Research The First Affliated Hospital of Kunming Medical UniversityKunming 650032China shanghai Research Center for brain Science and brain-lnspired Intelligence Shanghai201210China institute of Cognitive Neuroscience School of Psychology and Cognitive ScienceEast China Normal UniversityShanghai 200062China.

Fluid intelligence is a cognitive domain that encompasses general reasoning, pattern recognition, and problem-solving abilities independent of task-specific experience. Understanding its genetic and neural underpinnings is critical yet challenging for predicting human development, lifelong health, and well-being. One approach to address this challenge is to map the network of correlations between intelligence and other constructs. In the current study, we performed a genome-wide association study using fluid intelligence quotient scores from the UK Biobank to explore the genetic architecture of the associations between obesity risk and fluid intelligence. Our results revealed novel common genetic loci (SH2B1, TUFM, ATP2A1, and FOXO3) underlying the association between fluid intelligence and body metabolism. Surprisingly, we demonstrated that SH2B1 variation influenced fluid intelligence independently of its effects on metabolism but partially mediated its association with bilateral hippocampal volume. Consistently, selective genetic ablation of Sh2b1 in the mouse hippocampus, particularly in inhibitory neurons, but not in excitatory neurons, significantly impaired working memory, short-term novel object recognition memory, and behavioral flexibility, but not spatial learning and memory, mirroring the human intellectual performance. Single-cell genetic profiling of Sh2B1-regulated molecular pathways revealed that Sh2b1 deletion resulted in aberrantly enhanced extracellular signal-regulated kinase (ERK) signaling, whereas pharmacological inhibition of ERK signaling reversed the associated behavioral impairment. Our cross-species study thus provides unprecedented insight into the role of SH2B1 in fluid intelligence and has implications for understanding the genetic and neural underpinnings of lifelong mental health and well-being.

关键词： metabolism impaired reversed

Harnessing innate immune pathways for therapeutic advancement in cancer

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1506-1564页

作者： Ankang Hu Li Sun Hao Lin Yuheng Liao Hui Yang Ying Mao Department of Neurosurgery Huashan HospitalFudan UniversityShanghaiP.R.China institute for Translational brain Research Shanghai Medical CollegeFudan University ShanghaiPR.China National Center for Neurological Disorders Huashan HospitalShanghai Medical CollegeFudan UniversityShanghaiP.R.China shanghai key laboratory of brain Function Restoration and Neural Regeneration Shanghai Clinical Medical Center of NeurosurgeryNeurosurgical Institute of Fudan UniversityHuashan HospitalShanghai Medical CollegeFudan UniversityShanghaiP.R.China State key laboratory of Medical Neurobiology and MOE Frontiers Center for brain Science and MOE Frontiers Center for brain Science Institutes of Brain ScienceShanghai Medical CollegeFudan UniversityShanghaiP.R.China shanghai key laboratory of Medical Epigenetics International Co-laboratory of Medical Epigenetics and Metabolism(Ministry of Science and Technology)and Key Laboratory of Metabolism and Molecular Medicine(Ministry of Education)and Molecular and Cell Biology LabInstitutes of Biomedical SciencesShanghai Medical College of Fudan UniversityShanghaiP.R.China

The innate immune pathway is receiving increasing attention in cancer *** pathway is ubiquitous across various cell types,not only in innate immune cells but also in adaptive immune cells,tumor cells,and stromal *** targeting the innate immune pathway have shown profound changes in the tumor microenvironment(TME)and improved tumor prognosis in preclinical ***,to date,the clinical success of drugs targeting the innate immune pathway remains ***,recent studies have shown that activation of the innate immune pathway can paradoxically promote tumor *** uncertainty surrounding the therapeutic effectiveness of targeted drugs for the innate immune pathway is a critical issue that needs immediate *** this review,we observe that the role of the innate immune pathway demonstrates heterogeneity,linked to the tumor development stage,pathway status,and specific cell *** propose that within the TME,the innate immune pathway exhibits multidimensional *** diversity is fundamentally rooted in cellular heterogeneity and is manifested as a variety of signaling *** pro-tumor effect of innate immune pathway activation essentially reflects the suppression of classical pathways and the activation of potential pro-tumor alternative *** our understanding of the tumor's innate immune pathway network and employing appropriate targeting strategies can enhance our ability to harness the anti-tumor potential of the innate immune pathway and ultimately bridge the gap from preclinical to clinicalapplication.

关键词： drugs therapeutic innate

Enhanced Beta2-band Oscillations Denote Auditory Hallucination in Schizophrenia Patients and a Monkey Model of Psychosis

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Neuroscience Bulletin 2024年第3期40卷 325-338页

作者： Shuo Ma Tianzhen Chen Wenjun Jia Jie Liu Shihan Ding Puzhe Li Hong Gan Dapeng Zhang Shuxin Shao Mu-Ming Poo Min Zhao Bomin Sun Jian Jiang Department of Neurosurgery Ruijin HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200020China shanghai Mental Health Center Shanghai Jiao Tong University School of MedicineShanghai200030China shanghai Center for brain Science and brain-inspired Technology Lingang LaboratoryShanghai201602China University of California at Berkeley BerkeleyCA94720USA School of Life Science and Technology ShanghaiTech UniversityShanghai201210China institute of Neuroscience CAS Center for Excellence in Brain Science and Intelligence TechnologyCAS Key Laboratory of Primate NeurobiologyState Key Laboratory of NeuroscienceChinese Academy of SciencesShanghai200031China shanghai Center for brain Science and brain-Inspired Intelligence Technology Lingang LaboratoryShanghai201210China Fuyang Third People’s Hospital Fuyang Mental Health CenterFuyang236052China shanghai key laboratory of Psychotic Disorders Shanghai200030China institute of Psychological and Behavioral Science Shanghai Jiao Tong UniversityShanghai200030China shanghai Quanlan Technology Co. LtdShanghai201602China

An electroencephalographic(EEG)signature of auditory hallucinations(AHs)is important for facilitating the diagnosis and treatment of AHs in *** recorded EEG from 25 schizophrenia patients with recurrent *** 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 *** 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 *** 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 ***,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.

关键词： Schizophrenia Auditory hallucinations Non-human primate Methamphetamine Electroencephalography

Peripheral Mechanism of Cancer-Induced Bone Pain

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Neuroscience Bulletin 2024年第6期40卷 815-830页

作者： Yachen Yang Wei Yang Ruofan Zhang Yanqing Wang Department of Integrative Medicine and Neurobiology School of Basic Medical SciencesShanghai Medical CollegeInstitute of Acupuncture ResearchInstitutes of Integrative MedicineFudan UniversityShanghai200032China shanghai key laboratory of Acupuncture Mechanism and Acupoint Function Shanghai Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain ScienceInstitutes of Brain ScienceFudan UniversityShanghai200032China Zhongshan-Fudan Joint Innovation Center Zhongshan528437China

Cancer-induced bone pain(CIBP)is a type of ongoing or breakthrough pain caused by a primary bone tumor or bone *** constitutes a specific pain state with distinct characteristics;however,it shares similarities with inflammatory and neuropathic *** present,although various therapies have been developed for this condition,complete relief from CIBP in patients with cancer is yet to be ***,it is urgent to study the mechanism underlying CIBP to develop efficient analgesic ***,we focused on the peripheral mechanism associated with the initiation of CIBP,which involves tissue injury in the bone and changes in the tumor microenvironment(TME)and dorsal root *** nerve–cancer and cancer–immunocyte cross-talk in the TME creates circumstances that promote tumor growth and metastasis,ultimately leading to *** peripheral mechanism of CIBP and current treatments as well as potential therapeutic targets are discussed in this review.

关键词： Cancer-induced bone pain Peripheral mechanism Tumor microenvironment Sensory nerve Immunocytes

Imitating and exploring the human brain's resting and task-performing states via brain computing: scaling and architecture

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National Science Review 2024年第5期11卷 17-28页

作者： Wenlian Lu Longbin Zeng Jiexiang Wang Shitong Xiang Yang Qi Qibao Zheng Ningsheng Xu Jianfeng Feng DTB Consortium institute of Science and Technology for brain-Inspired Intelligence Fudan University key laboratory of Computational Neuroscience and brain-Inspired Intelligence(Fudan University) Ministry of Education Fudan University shanghai Center for Mathematical Sciences Fudan University Department of Computer Science University of Warwick Zhangjiang Fudan International Innovation Center Fudan University

A computational human brain model with the voxel-wise assimilation method was established based on individual structural and functional imaging data. We found that the more similar the brain model is to the biological counterpart in both scale and architecture, the more similarity was found between the assimilated model and the biological brain both in resting states and during tasks by quantitative metrics. The hypothesis that resting state activity reflects internal body states was validated by the interoceptive circuit's capability to enhance the similarity between the simulation model and the biological brain. We identified that the removal of connections from the primary visual cortex(V1) to downstream visual pathways significantly decreased the similarity at the hippocampus between the model and its biological counterpart,despite a slight influence on the whole brain. In conclusion, the model and methodology present a solid quantitative framework for a digital twin brain for discovering the relationship between brain architecture and functions, and for digitally trying and testing diverse cognitive, medical and lesioning approaches that would otherwise be unfeasible in real subjects.

关键词： digital twin brain computational cortico-subcortical model fMRI data assimilation interoceptive circuit

The structure of TRAF7 coiled-coil trimer provides insight into its function in zebrafish embryonic development

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Journal of Molecular Cell Biology 2024年第1期16卷 43-53页

作者： Xiaozhen Song Ruixing Hu Yi Chen Man Xiao Hong Zhang Shengnan Wu Qing Lu Molecular Diagnostic laboratory Shanghai Children’s HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200040China Bio-X institutes Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders(Ministry of Education)Shanghai Jiao Tong UniversityShanghai 200030China laboratory of Development and Diseases and State key laboratory for Medical genomics Shanghai Institute of HematologyRuĳin HospitalShanghai JiaoTong University School of MedicineShanghai 200025China

TRAF7 serves as a crucial intracellular adaptor and E3 ubiquitin ligase involved in signal transduction pathways,contributing to immune responses,tumor progression,and embryonic *** mutations within the coiled-coil(CC)domain and WD40 repeat domain of TRAF7 could cause brain tumors,while germline pathogenic mutations contribute to severe developmental ***,the precise molecular mechanism underlying TRAF7 involvement in embryonic development remains *** this study,we employed zebrafish as an in vivo model ***7 knock down caused defects in zebrafish embryonic *** determined the crystal structure of TRAF7 CC domain at 3.3Åresolution and found that the CC region trimerization was essential for TRAF7 functionality during zebrafish embryonic ***,disease-causing mutations in TRAF7 CC region could impair the trimer formation,consequently impacting early embryonic development of ***,our study sheds light on the molecular mechanism of TRAF7 CC trimer formation and its pivotal role in embryonic development.

关键词： TRAF7 coiled-coil domain crystal structure trimerization embryonic development

Comparative transcriptome analysis between rhesus macaques(Macaca mulatta) and crab-eating macaques(M. fascicularis)

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Zoological Research 2024年第2期45卷 299-310页

作者： Yu-Xiang Mao Yamei Li Zikun Yang Ning Xu Shilong Zhang Xuankai Wang Xiangyu Yang Qiang Sun Yafei Mao institute of Neuroscience State Key Laboratory of NeuroscienceCenter for Excellence in Brain Science&Intelligence TechnologyChinese Academy of SciencesShanghai 200031China shanghai Center for brain Science and brain-Inspired Intelligence Technology Shanghai 201210China University of Chinese Academy of Sciences Beijing 100049China key laboratory of Genetic Evolution&Animal Models Chinese Academy of SciencesKunmingYunnan 650201China Bio-X institutes Key Laboratory for the Genetics of Developmental and Neuropsychiatric DisordersMinistry of EducationShanghai Jiao Tong UniversityShanghai 200030China Zhiyuan College Shanghai Jiao Tong UniversityShanghai 200240China Center for Genomic Research International Institutes of MedicineFourth Affiliated HospitalZhejiang UniversityYiwuZhejiang 322000China

Understanding gene expression variations between species is pivotal for deciphering the evolutionary diversity in phenotypes. Rhesus macaques(Macaca mulatta, MMU)and crab-eating macaques(M. fascicularis, MFA) serve as crucial nonhuman primate biomedical models with different phenotypes. To date, however, large-scale comparative transcriptome research between these two species has not yet been fully explored. Here, we conducted systematic comparisons utilizing newly sequenced RNA-seq data from84 samples(41 MFA samples and 43 MMU samples)encompassing 14 common tissues. Our findings revealed a small fraction of genes(3.7%) with differential expression between the two species, as well as 36.5% of genes with tissue-specific expression in both macaques. Comparison of gene expression between macaques and humans indicated that 22.6% of orthologous genes displayed differential expression in at least two tissues. Moreover,19.41% of genes that overlapped with macaque-specific structural variants showed differential expression between humans and macaques. Of these, the FAM220A gene exhibited elevated expression in humans compared to macaques due to lineage-specific duplication. In summary,this study presents a large-scale transcriptomic comparison between MMU and MFA and between macaques and humans. The discovery of gene expression variations not only enhances the biomedical utility of macaque models but also contributes to the wider field of primate genomics.

关键词： Crab-eating macaques Rhesus macaques Comparative transcriptomics Biomedical models Nonhuman primates RNA-seq Duplicated genes

维普期刊数据库