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Genetically modified non-human primate models for research on neurodegenerative diseases

Zoological Research 2024年第2期45卷 263-274页

作者： Ming-Tian Pan Han Zhang Xiao-Jiang Li Xiang-Yu Guo Guangdong Key Laboratory of non-human primate Research Guangdong-Hongkong-Macao Institute of CNS RegenerationJinan UniversityGuangzhouGuangdong 510632China

Neurodegenerative diseases(NDs)are a group of debilitating neurological disorders that primarily affect elderly populations and include Alzheimer's disease(AD),Parkinson's disease(PD),Huntington's disease(HD),and amyotrophic lateral sclerosis(ALS).Currently,there are no therapies available that can delay,stop,or reverse the pathological progression of NDs in clinical settings.As the population ages,NDs are imposing a huge burden on public health systems and affected families.Animal models are important tools for preclinical investigations to understand disease pathogenesis and test potential treatments.While numerous rodent models of NDs have been developed to enhance our understanding of disease mechanisms,the limited success of translating findings from animal models to clinical practice suggests that there is still a need to bridge this translation gap.Old World nonhuman primates(NHPs),such as rhesus,cynomolgus,and vervet monkeys,are phylogenetically,physiologically,biochemically,and behaviorally most relevant to humans.This is particularly evident in the similarity of the structure and function of their central nervous systems,rendering such species uniquely valuable for neuroscience research.Recently,the development of several genetically modified NHP models of NDs has successfully recapitulated key pathologies and revealed novel mechanisms.This review focuses on the efficacy of NHPs in modeling NDs and the novel pathological insights gained,as well as the challenges associated with the generation of such models and the complexities involved in their subsequent analysis.

关键词： Neurodegeneration non-human primate Macaque monkey Animal model Gene modification

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A non-human primate derived anti-P-selectin glycoprotein ligand-1 antibody curtails acute pancreatitis by alleviating the inflammatory responses

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Acta Pharmaceutica Sinica B 2023年第11期13卷 4461-4476页

作者： Yuhan Li Xiangqing Ding Xianxian Wu Longfei Ding Yuhui Yang Xiaoliang Jiang Xing Liu Xu Zhang Jianrong Su Jianqing Xu Zhiwei Yang Institute of Laboratory Animal Science Chinese Academy of Medical Sciences(CAMS)&Comparative Medicine CentrePeking Union Medical College(PUMC)Beijing 100021China Department of Clinical Laboratory Beijing Friendship HospitalCapital Medical UniversityBeijing 100050China Shanghai Sinobay Biotechnology Company(Limited) Shanghai 201500China Shanghai Public Health Clinical Center Fudan UniversityShanghai 200083China Capital Medical University Beijing 100069China Department of Hepatobiliary Pancreatic Surgery Zhengzhou University People's HospitalHenan Provincial People's HospitalZhengzhou 450003China Chongqing Institutes for Life Science Innovation Chongqing 400715China

Acute pancreatitis(AP)is a devastating disease characterized by an inflammatory disorder of the pancreas.P-selectin glycoprotein ligand-1(PSGL-1)plays a crucial role in the initial steps of the adhesive at process to inflammatory sites,blockade of PSGL-1 might confer potent anti-inflammatory effects.In this study,we generated two non-human primate derived monoclonal antibodies capable of efficiently targeting human PSGL-1,RH001-6 and RH001-22,which were screened from immunized rhesus macaques.We found that RH001-6,can effectively block the binding of P-selectin to PSGL-1,and abolish the adhesion of leukocytes to endothelial cells in vitro.In vivo,we verified that RH001-6 relieved inflammatory responses and pancreatic injury in both caerulein and L-arginine induced AP models.We also evaluated the safety profile after RH001-6 treatment in mice,and verified that RH001-6 did not cause any significant pathological damages in vivo.Taken together,we developed a novel non-human primate derived PSGL-1 blocking antibody with high-specificity,named RH001-6,which can interrupt the binding of PSGL-1 and P-selectin and attenuate inflammatory responses during AP.Therefore,RH001-6 is highly potential to be further developed into therapeutics against acute inflammatory diseases,such as AP.

关键词： Acute pancreatitis PSGL-1 non-human primate Monoclonal antibody Therapeutic antibody RH001-6 Adhesion of leukocytes to endothelial cells Inflammatory responses Pancreatic injury

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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 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.

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

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Real-time simultaneous recording of electrophysiological activities and dopamine overflow in the deep brain nuclei of a non-human primate with Parkinson’s disease using nano-based microelectrode arrays

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Microsystems & Nanoengineering 2018年第1期4卷 541-549页

作者： Song Zhang Yilin Song Mixia Wang Guihua Xiao Fei Gao Ziyue Li Guoxian Tao Ping Zhuang Feng Yue Piu Chan Xinxia Cai State Key Laboratory of Transducer Technology Institute of ElectronicsChinese Academy of SciencesBeijing 100190China University of Chinese Academy of Sciences Beijing 100190China Wincon TheraCells Biotechnologies Co. Ltd.Nanning 530002China Department of Neurobiology Xuanwu HospitalCapital Medical UniversityThe Beijing Key Laboratory of Parkinson's DiseaseBeijing 100053China

Parkinson’s disease(PD)is characterized by a progressive degeneration of nigrostriatal dopaminergic neurons.The precise mechanisms are still unknown.Since the neuronal communications are inherently electrical and chemical in nature,dual-mode detection of PD-related neuroelectrical and neurochemical information is essential for PD research.Subthalamic nucleus(STN)highfrequency stimulation(HFS)can improve most symptoms of PD patients and decrease the dosage of antiparkinsonian drugs.The mechanism of STN-HFS for PD still remains elusive.In this study,a silicon-based dual-mode microelectrode array(MEA)probe was designed and fabricated,and systematic dual-mode detection methods were established.The recording sites were modified using Pt nanoparticles and Nafion to improve the signal-to-noise(SNR)ratio.To evaluate its applicability to PD research,in vivo electrophysiological and electrochemical detection was performed in normal and hemiparkinsonian models,respectively.Through comparison of the dual-mode signals,we demonstrated the following in a PD monkey:(1)the maximum dopamine concentration in the striatum decreased by 90%;(2)the spike firing frequency increased significantly,especially in the region of the cortex;(3)the spectrogram analysis showed that much power existed in the 0–10 Hz frequency band;and(4)following repeated subthalamic nucleus high-frequency stimulation trials,the level of DA in the striatum increased by 16.5μM,which led to a better elucidation of the mechanism of HFS.The dual-mode MEA probe was demonstrated to be an effective tool for the study of neurological disorders.

关键词： dual mode implantable MEA non-human primate Parkinson's disease STN-HFS

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Altered neurogenesis and disrupted expression of synaptic proteins in SHANK3 deficient non-human primate prefrontal cortex

Altered neurogenesis and disrupted expression of synaptic pr...

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中国神经科学学会第十二届全国学术会议

作者： Hui Zhao Zhuchi Tu Huijuan Xu Sen Yan Huanhuan Yan Yinghui Zheng Weili Yang Jiezhao Zheng Zhujun Li Rui Tian Youming Lu Xiangyu Guo Yong-hui Jiang Xiao-Jiang Li Yong Q.Zhang State Key Laboratory of Molecular Developmental Biology Institute of Genetics and Developmental Biology Chinese Academy of Sciences University of Chinese Academy of Sciences Guangdong-Hongkong-Macau Institute of CNS Regeneration Ministry of Education CNS Regeneration Collaborative Joint Laboratory Jinan University The Institute for Brain Research Collaborative Innovation Center for Brain Science Huazhong University of Science and Technology Department of human Genetics Emory University School of Medicine

Mutations in SHANK3 remained one of the best characterized and replicated genetic defects in autism spectrum disorders(ASD) in humans. Genetically modified Shank3 mutant mice have served as valuable tools to dissect the pathophysiology of SHANK3 causing ASD. However, the significant evolutional differences between mouse and human brain and behaviors pose many challenges to assess the translational value of the mouse models to humans and highlight the demand of developing non-human primate models. We found that the SHANK3 expression pattern in sub-regions of early developing brain in cynomolgus monkeys is significantly different from that in mouse brain. Using the CRISPR/Cas9 to target the SHANK3 gene in the embryos of cynomolgus monkeys, we successfully generated three mutant monkey offspring with various deleterious mutations in the SHANK3 gene. Of them, one miscarried close to the end of gestation(SHANK3 ), one lost due to a difficult labor(SHANK3 ), and one was alive(SHANK3 ). SHANK3 showed a complete loss and isoform-specific deficiency of SHANK3 in cerebral cortex and striatum, respectively. SHANK3 complete deficiency resulted in a significant reduction in postsynaptic proteins such as Glu N2 B, PSD95, m Glu R5 and increased cytosolic localization of Homer1 b/c. The number of mature neurons is markedly reduced but activated astrocytes are increased in the prefrontal cortex in SHANK3 monkey. The neuropathology caused by the complete loss of SHANK3 in monkey brain is much more severe than that in patients with heterozygous SHANK3 mutations and is also remarkably distinct from the findings reported from Shank3 knockout mice. Our findings indicate that SHANK3 is essential for the early development of primate brains and support the necessity and value of non-human primate model for SHANK3 and other genetic causing ASD in future studies.

关键词： autism non-human primate SHANK3

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EAE in non-human primate Animals

EAE in Non-human Primate Animals

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第九届中国实验动物科学年会（2010新疆）

作者：孙云霄华南灵长类研究中心

This review discusses non-human primate models of experimental autoimmune encephalomyelitis(EAE), which is the fittest model for related research of multiple sclerosis(MS) disease that is a progressive neurological disorder with a high unmet need for effective treatment.These models can bridge the gap between rodent EAE models and patients. non-human primates can offer unique models for translational research into autoimmune-mediated inflammatory disorders. This review introduces the preparation and usefulness of EAE model in nonhuman primate in recent years,and includes the mechanism of MS,choosing and applying of different monkey and antigens,immunization methods,related antigens,the use of adjuvants and clinical and pathological characteristics,etc.

关键词： EAE non-human primate Model Multiple Sclerosis

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Characterization of Changes and Driver Microbes in Gut Microbiota During Healthy Aging Using A Captive Monkey Model

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Genomics, Proteomics & Bioinformatics 2022年第2期20卷 350-365页

作者： Zhi-Yuan Wei Jun-Hua Rao Ming-Tian Tang Guo-An Zhao Qi-Chun Li Li-Ming Wu Shao-Qiang Liu Bi-Hai Li Bai-Quan Xiao Xing-Yin Liu Jian-Huan Chen Guangdong Key Laboratory of Animal Conservation and Resource Utilization Guangdong Public Laboratory of Wild Animal Conservation and UtilizationInstitute of ZoologyGuangdong Academy of SciencesGuangzhou 510260China Laboratory of Genomic and Precision Medicine Wuxi School of MedicineJiangnan UniversityWuxi 214122China Joint primate Research Center for Chronic Diseases Jiangnan University and Institute of ZoologyGuangdong Academy of SciencesWuxi School of MedicineJiangnan UniversityWuxi 214122China Department of Pathogen-Microbiology Division Nanjing Medical UniversityNanjing 211166China

Recent population studies have significantly advanced our understanding of how age shapes the gut microbiota.However,the actual role of age could be inevitably confounded due to the complex and variable environmental factors in human populations.A well-controlled environment is thus necessary to reduce undesirable confounding effects,and recapitulate age-dependent changes in the gut microbiota of healthy primates.Herein we performed 16S rRNA gene sequencing,characterized the age-associated gut microbial profiles from infant to elderly crab-eating macaques reared in captivity,and systemically revealed the lifelong dynamic changes of the primate gut microbiota.While the most significant age-associated taxa were mainly found as commensals such as Faecalibacterium,the abundance of a group of suspicious pathogens such as Helicobacter was exclusively increased in infants,underlining their potential role in host development.Importantly,topology analysis indicated that the network connectivity of gut microbiota was even more agedependent than taxonomic diversity,and its tremendous decline with age could probably be linked to healthy aging.Moreover,we identified key driver microbes responsible for such age-dependent network changes,which were further linked to altered metabolic functions of lipids,carbohydrates,and amino acids,as well as phenotypes in the microbial community.The current study thus demonstrates the lifelong age-dependent changes and their driver microbes in the primate gut microbiota,and provides new insights into their roles in the development and healthy aging of their hosts.

关键词： Age-dependent change non-human primate Healthy gut microbiota Network connectivity Driver microbe

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Genetic Approaches for Neural Circuits Dissection in non-human primates

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Neuroscience Bulletin 2023年第10期39卷 1561-1576页

作者： Ling Li Zhen Liu Institute of Neuroscience CAS Center for Excellence in Brain Science and Intelligence TechnologyCAS Key Laboratory of Primate NeurobiologyState Key Laboratory of NeuroscienceChinese Academy of SciencesShanghai 200031China Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology Shanghai 200031China University of Chinese Academy of Sciences Beijing 100049China

Genetic tools,which can be used for the morphology study of specific neurons,pathway-selective connectome mapping,neuronal activity monitoring,and manipulation with a spatiotemporal resolution,have been widely applied to the understanding of complex neural circuit formation,interactions,and functions in rodents.Recently,similar genetic approaches have been tried in non-human primates(NHPs)in neuroscience studies for dissecting the neural circuits involved in sophisticated behaviors and clinical brain disorders,although they are still very preliminary.In this review,we introduce the progress made in the development and application of genetic tools for brain studies on NHPs.We also discuss the advantages and limitations of each approach and provide a perspective for using genetic tools to study the neural circuits of NHPs.

关键词： Genetic tool Neural circuit non-human primate

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Representation of conspecific vocalizations in amygdala of awake marmosets

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National Science Review 2023年第11期10卷 8-19页

作者： Guoqiang Jia Siyi Bai Yingxu Lin Xiaohui Wang Lin Zhu Chenfei Lyu Guanglong Sun Kang An Anna Wang Roe Xinjian Li Lixia Gao Department of Neurology of the Second Affiliated Hospital and Interdisciplinary Institute of Neuroscience and Technology Zhejiang University School of Medicine Key Laboratory of Biomedical Engineering of Ministry of Education College of Biomedical Engineering and Instrument ScienceZhejiang University College of Information Mechanical and Electrical EngineeringShanghai Normal University MOE Frontier Science Center for Brain Science and Brain-Machine Integration School of Brain Science and Brain Medicine Zhejiang University Key Laboratory of Medical Neurobiology of Zhejiang Province Zhejiang University School of Medicine

human speech and animal vocalizations are important for social communication and animal survival.Neurons in the auditory pathway are responsive to a range of sounds, from elementary sound features to complex acoustic sounds. For social communication, responses to distinct patterns of vocalization are usually highly specific to an individual conspecific call, in some species. This includes the specificity of sound patterns and embedded biological information. We conducted single-unit recordings in the amygdala of awake marmosets and presented calls used in marmoset communication, calls of other species and calls from specific marmoset individuals. We found that some neurons(47/262) in the amygdala distinguished ’Phee’ calls from vocalizations of other animals and other types of marmoset vocalizations. Interestingly, a subset of Phee-responsive neurons(22/47) also exhibited selectivity to one out of the three Phees from two different ’caller’ marmosets. Our findings suggest that, while it has traditionally been considered the key structure in the limbic system, the amygdala also represents a critical stage of socially relevant auditory perceptual processing.

关键词： vocalization non-human primate marmoset amygdala

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Modulation of Neuronal Activity and Saccades at Theta Rhythm During Visual Search in non-human primates

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Neuroscience Bulletin 2022年第10期38卷 1183-1198页

作者： Jin Xie Ting Yan Jie Zhang Zhengyu Ma Huihui Zhou The Brain Cognition and Brain Disease Institute Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research InstitutionsShenzhen518055China University of Chinese Academy of Sciences Beijing100049China The Research Center for Artificial Intelligence Peng Cheng LaboratoryShenzhen518000China

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.

关键词： Visual search Saccade Theta rhythm FEF V4 non-human primate

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