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Somatostatin-Positive Neurons in the Rostral Zona Incerta Modulate Innate Fear-Induced Defensive Response in Mice

Neuroscience Bulletin 2023年第2期39卷 245-260页

作者： Shan Lin Meng-Yue Zhu Meng-Yu Tang Mi Wang Xiao-Dan Yu Yi Zhu Shi-Ze Xie Dan Yang Jiadong Chen Xiao-Ming Li Department of Neurobiology and Department of Neurology of the Second Afliated Hospital Zhejiang University School of MedicineHangzhou 310058China NHC and CAMS Key Laboratory of Medical Neurobiology MOE Frontier Science Center for Brain Research and Brain-Machine IntegrationSchool of Brain Science and Brian MedicineZhejiang UniversityHangzhou 310058China Center for brain Science and brain-Inspired intelligence Research Units for Emotion and Emotion DisordersChinese Academy of Medical SciencesChina/Guangdong-Hong Kong-Macao Greater Bay AreaJoint Institute for Genetics and Genome Medicine between Zhejiang University and the University of TorontoHangzhou 310058China

Defensive behaviors induced by innate fear or Pavlovian fear conditioning are crucial for animals to avoid threats and ensure survival.The zona incerta(ZI)has been demonstrated to play important roles in fear learning and fear memory,as well as modulating auditory-induced innate defensive behavior.However,whether the neuronal subtypes in the ZI and specific circuits can mediate the innate fear response is largely unknown.Here,we found that somatostatin(SST)-positive neurons in the rostral ZI of mice were activated by a visual innate fear stimulus.Optogenetic inhibition of SST-positive neurons in the rostral ZI resulted in reduced flight responses to an overhead looming stimulus.Optogenetic activation of SST-positive neurons in the rostral ZI induced fear-like defensive behavior including increased immobility and bradycardia.In addition,we demonstrated that manipulation of the GABAergic projections from SST-positive neurons in the rostral ZI to the downstream nucleus reuniens(Re)mediated fear-like defensive behavior.Retrograde trans-synaptic tracing also revealed looming stimulus-activated neurons in the superior colliculus(SC)that projected to the Re-projecting SST-positive neurons in the rostral ZI(SC-ZIrSST-Re pathway).Together,our study elucidates the function of SST-positive neurons in the rostral ZI and the SC-ZIrSST-Re tri-synaptic circuit in mediating the innate fear response.

关键词： Innate fear Zona incerta Somatostatinpositive neurons Looming stimulus Defensive behavior

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STON2风险变异通过影响Syt1转运和突触功能导致精神分裂症样行为

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Science Bulletin 2024年第10期69卷 1458-1471页

作者：马远林高凯孙晓璇王金鑫杨扬武建荧柴安平姚立刘楠郁昊苏怡卢天兰王力芳岳伟华章晓辉徐林张岱李俊 Peking University Sixth Hospital Peking University Institute of Mental HealthNHC Key Laboratory of Mental Health(Peking University)National Clinical Research Center for Mental Disorders(Peking University Sixth Hospital)Key Laboratory of Mental HealthChinese Academy of Medical SciencesBeijing 100191China The First Affiliated Hospital Chongqing Medical UniversityChongqing Key Laboratory of NeurologyChongqing 400016China Changping Laboratory Beijing 102206China d Chinese institute for brain research Beijing 102206China Laboratory of Learning and Memory Kunming Institute of ZoologyChinese Academy of SciencesKunming 650201China Shenzhen Key Laboratory of translational research for brain Diseases The Brain Cognition and Brain Disease InstituteShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research InstitutionsShenzhen 518055China State Key Laboratory of Cognitive Neuroscience and Learning IDG/McGovern Institute for Brain ResearchBeijing Normal UniversityBeijing 100875China PKU-IDG/McGovern institute for brain research Peking UniversityBeijing 100871China

Synaptic dysfunction is a core component of the pathophysiology of schizophrenia.However,the genetic risk factors and molecular mechanisms related to synaptic dysfunction are still not fully understood.The Stonin 2(STON2)gene encodes a major adaptor for clathrin-mediated endocytosis(CME)of synaptic vesicles.In this study,we showed that the C-C(307Pro-851Ala)haplotype of STON2 increases the susceptibility to schizophrenia and examined whether STON2 variations cause schizophrenia-like behaviors through the regulation of CME.We found that schizophrenia-related STON2 variations led to protein dephosphorylation,which affected its interaction with synaptotagmin 1(Syt1),a calcium sensor protein located in the presynaptic membrane that is critical for CME.STON2307Pro851Ala knockin mice exhibited deficits in synaptic transmission,short-term plasticity,and schizophrenia-like behaviors.Moreover,among seven antipsychotic drugs,patients with the C-C(307Pro-851Ala)haplotype responded better to haloperidol than did the T-A(307Ser-851Ser)carriers.The recovery of deficits in Syt1 sorting and synaptic transmission by acute administration of haloperidol effectively improved schizophrenia-like behaviors in STON2307Pro851Ala knockin mice.Our findings demonstrated the effect of schizophreniarelated STON2 variations on synaptic dysfunction through the regulation of CME,which might be attractive therapeutic targets for treating schizophrenia-like phenotypes.

关键词： STON2 variations Schizophrenia Synaptic dysfunction Syt1 Haloperidol

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Hexafluoropropylene oxide trimer acid,a perfluorooctanoic acid alternative,induces cardiovascular toxicity in zebrafish embryos

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Journal of Environmental Sciences 2024年第5期139卷 460-472页

作者： Sujie Sun Li Zhang Xue Li Lu Zang Ling Huang Junquan Zeng Zigang Cao Xinjun Liao Zilin Zhong Huiqiang Lu Jianjun Chen Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases Jiangxi Key Laboratory of Developmental Biology of OrgansCenter for Clinical Research Center of the Affiliated Hospital of Jinggangshan UniversityJi’an 343009China Translational Research Institute of Brain and Brain-like Intelligence Shanghai Key Laboratory of Anesthesiology and Brain Functional ModulationDepartment of PediatricsShanghai Fourth People’s HospitalSchool of MedicineTongji UniversityShanghai 200434China State Environmental Protection Key Laboratory of Environmental Health Impact Assessment of Emerging Contaminants School of Environmental Sciences and EngineeringShanghai Jiao Tong UniversityShanghai 200240China Department of Interventional and Vascular Surgery Affiliated Hospital of Jinggangshan UniversityJi’an 343009China Department of Internal Medicine and Hematology Affiliated Hospital of Jinggangshan UniversityJi’an 343009China

As an increasingly used alternative to perfluorooctanoic acid(PFOA),hexafluoropropylene oxide trimer acid(HFPO-TA)has been widely detected in global water environments.However,little is known regarding its toxic effects on cardiovascular development.Here,zebrafish embryos were treated with egg water containing 0,60,120,or 240 mg/L HFPO-TA.Results showed that HFPO-TA treatment led to a significant reduction in both larval survival percentage and heart rate.Furthermore,HFPO-TA exposure caused severe pericardial edema and elongation of the sinus venous to bulbus arteriosus distance(SV-BA)in Tg(myl7:GFP)transgenic larvae,disrupting the expression of genes involved in heart development and thus causing abnormal heart looping.Obvious sprouting angiogenesis was observed in the 120 and 240 mg/L exposed Tg(fli:GFP)transgenic larvae.HFPO-TA treatment also impacted the mRNA levels of genes involved in the vascular endothelial growth factor(VEGF)pathway and embryonic vascular development.HFPO-TA exposure significantly decreased erythrocyte number in Tg(gata1:DsRed)transgenic embryos and influenced gene expression associated with the heme metabolism pathway.HFPO-TA also induced oxidative stress and altered the transcriptional levels of genes related to cell cycle and apoptosis,inhibiting cell proliferation while promoting apoptosis.Therefore,HFPO-TA exposure may induce abnormal development of the cardiovascular and hematopoietic systems in zebrafish embryos,suggesting it may not be a suitable or safe alternative for PFOA.

关键词： Hexafluoropropylene oxide trimer acid Heart development Vascular development Hemopoiesis Zebrafish embryos

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Comparison of two vasopressor protocols for preventing hypotension post-spinal anesthesia during cesarean section: a randomized controlled trial

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Chinese Medical Journal 2021年第7期134卷 792-799页

作者： Qian-Qian Fan Yong-Hui Wang Jing-Wen Fu Hai-Long Dong Man-Ping Yang Duo-Duo Liu Xiao-Fan Jiang Zhi-Xin Wu Li-Ze Xiong Zhi-Hong Lu Department of Anesthesiology and Perioperative Medicine Xijing HospitalFourth Military Medical UniversityXi’anShaanxi 710032China Department of Gynecology and Obstetrics Xijing HospitalFourth Military Medical UniversityXi’anShaanxi 710032China Department of Neurosurgery Xijing HospitalFourth Military Medical UniversityXi’anShaanxi 710032China Department of Anesthesiology and Translational Research Institute of Brain and Brain-like Intelligence Shanghai Fourth People’s Hospital Affiliated to Tongji University School of MedicineShanghai 200081China.

Background:Norepinephrine infusion decreases hypotension after spinal anesthesia during cesarean section.This study aimed to compare the efficacy of norepinephrine infusion and ephedrine bolus against post-spinal hypotension in parturients.Methods:In this double-blinded,randomized controlled clinical trial,parturients scheduled for elective cesarean section were randomly allocated to receive norepinephrine infusion(0.05μg·kg^(-1)·min^(-1))just before spinal anesthesia continuing for 30 min or ephedrine bolus(0.15 mg/kg)just before spinal anesthesia.A rescue bolus(5μg norepinephrine for the norepinephrine group,and 5 mg ephedrine for the ephedrine group)was administered whenever hypotension occurred.Our primary outcome was the incidence of hypotension within 30 min of spinal anesthesia administration.Secondary outcomes included maternal and neonatal outcomes 30 min after spinal block,and neonatal cerebral oxygenation 10 min after birth.Results:In total,190 patients were enrolled;of these patients,177 were included in the final analysis.Fewer patients suffered hypotension in the norepinephrine group than in the ephedrine group(29.5%vs.44.9%,odds ratio[OR]:0.51,95%confidence interval[CI]:0.28-0.95,P=0.034).Moreover,the tachycardia frequency was lower in the norepinephrine group than in the ephedrine group(OR:0.22,95%CI:0.11-0.44,P<0.001),and patients suffered less nausea and vomiting(OR:0.28,95%CI:0.11-0.70,P=0.004).There was no difference in Apgar scores and umbilical arterial blood gas analysis between the two groups.However,neonatal cerebral regional saturations were significantly higher after birth in the norepinephrine group than in the ephedrine group(mean difference:2.0%,95%CI:0.55%-3.45%,P=0.008).Conclusion:In patients undergoing elective cesarean section with spinal anesthesia,norepinephrine infusion compared to ephedrine bolus resulted in less hypotension and tachycardia,and exhibited potential neonatal benefits.

关键词： Hypotension Spinal anesthesia Norepinephrine Ephedrine Cesarean section

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Sensation of pleasant touch:from molecules to circuits and behaviours

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Signal Transduction and Targeted Therapy 2022年第9期7卷 3187-3189页

作者： Ruining Hul Rongfeng K.Hu institute for translational brain research Fudan UniversityShanghai 200032China Department of Psychology Zhongshan HospitalInstitute for Translational Brain ResearchState Key Laboratory of Medical NeurobiologyMOE Frontiers Center for Brain ScienceFudan UniversityShanghai 200032China

A recent study by Liu et al.identifed a crucial role of the PROK2-PROKR2 signalling within the spinal circuit in pleasant touch sensation(Fig.1),providing the first evidence for the molecular and neural basis of how pleasant touch information is encoded and integrated from the skin to the spinal cord and highlighting the important role of neuropeptides in the processing of somatosensory information1(Fig.1).

关键词： sensation touch providing

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成年MECP2倍增小鼠中社交障碍相关神经集合的实时成像及功能挽救

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Science Bulletin 2020年第14期65卷 1192-1202,M0004页

作者：孙乐陈睿国李龙袁博宋坤潘娜程田林常世阳林坤章何晓斌吴倩徐富强仇子龙王晓群 State Key Laboratory of brain and Cognitive Science CAS Center for Excellence in Brain Science and Intelligence TechnologyInstitute of Brain-Intelligence Technology(Shanghai)Institute for Stem Cell and RegenerationInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China institute of Neuroscience CAS Key Laboratory of Primate NeurobiologyState Key Laboratory of NeuroscienceCAS Center for Excellence in Brain Science and Intelligence TechnologyChinese Academy of SciencesShanghai 200031China The College of Life Science University of Chinese Academy of SciencesBeijing 100049China The College of Life Science Hebei Normal UniversityShijiazhuang 050016China State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics Wuhan Institute of Physics and MathematicsCAS Center for Excellence in Brain Science and Intelligence TechnologyChinese Academy of SciencesWuhan 430071China Advanced Innovation Center for Human brain Protection Beijing Institute for Brain DisordersCapital Medical UniversityBeijing 100069China

人类男性中MECP2基因的倍增将导致严重的自闭症症状.过表达人源MECP2基因,会使转基因小鼠(MECP2-TG)表现出类似自闭症的行为,但这种社交行为缺陷相关的神经环路机制尚不明确.本文在小鼠海马体CA1区植入微型荧光透镜,观察MECP2-TG小鼠和... 详细信息

人类男性中MECP2基因的倍增将导致严重的自闭症症状.过表达人源MECP2基因,会使转基因小鼠(MECP2-TG)表现出类似自闭症的行为,但这种社交行为缺陷相关的神经环路机制尚不明确.本文在小鼠海马体CA1区植入微型荧光透镜,观察MECP2-TG小鼠和野生型小鼠的社交过程及相关的实时神经活动钙荧光信号,发现与社交行为紧密相关的神经活动在MECP2-TG小鼠中被削弱了.当使用CRISPR/Cas9技术,敲除成年MECP2-TG小鼠CA1区细胞中的过表达人源MECP2基因后,小鼠的社交障碍被缓解.这一数据提示了小鼠海马体中与社交行为相关的神经环路,并提出一种缓解成年自闭症患者社交障碍的潜在方法.

关键词：社交障碍自闭症神经活动神经环路社交行为实时成像 CA1区转基因小鼠

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3D-bioprinted cholangiocarcinoma-on-a-chip model for evaluating drug responses

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Bio-Design and Manufacturing 2023年第4期6卷 373-389页

作者： Qiong Liu Luis SMille Cesar Villalobos Ingrid Anaya Matthias Vostatek Sili Yi Wanlu Li Junlong Liao Huanghui Wu Yongteng Song Lize Xiong Yu Shrike Zhang Division of Engineering in Medicine Department of MedicineBrigham and Women’s HospitalHarvard Medical SchoolCambridgeMA 02139USA Translational Research Institute of Brain and Brain-like Intelligence Shanghai Fourth People’s HospitalSchool of MedicineTongji UniversityShanghai 200434China Shanghai Key Laboratory of Anesthesiology and brain Functional Modulation Shanghai 200434China Department of Bioengineering Stanford UniversityPalo AltoCA 94305USA Biotechnological Engineering Program Monterrey Institute of Technology and Higher Education64849 MonterreyNuevo LeónMexico Molecular Biotechnology University of Applied Sciences Campus Vienna1100 ViennaAustria Rapid Manufacturing Engineering Center School of Mechatronical Engineering and AutomationShanghai UniversityShanghai 200444China

Cholangiocarcinoma(CCA)is characterized by heterogeneous mutations and a refractory nature.Thus,the development of a model for effective drug screening is urgently needed.As the established therapeutic testing models for CCA are often ineffective,we fabricated an enabling three-dimensional(3D)-bioprinted CCA-on-a-chip model that to a good extent resembled the multicellular microenvironment and the anatomical microstructure of the hepato-vascular-biliary system to perform high-content antitumor drug screening.Specifically,cholangiocytes,hepatocytes,and vascular endotheliocytes were employed for 3D bioprinting of the models,allowing for a high degree of spatial and tube-like microstructural control.Interestingly,it was possible to observe CCA cells attached to the surfaces of the gelatin methacryloyl(GelMA)hydrogelembedded microchannels and overgrown in a thickening manner,generating bile duct stenosis,which was expected to be analogous to the in vivo configuration.Over 4000 differentially expressed genes were detected in the CCA cells in our 3D coculture model compared to the traditional two-dimensional(2D)monoculture.Further screening revealed that the CCA cells grown in the 3D traditional model were more sensitive to the antitumoral prodrug than those in the 2D monoculture due to drug biotransformation by the neighboring functional hepatocytes.This study provides proof-of-concept validation of our bioprinted CCA-on-a-chip as a promising drug screening model for CCA treatment and paves the way for potential personalized medicine strategies for CCA patients in the future.

关键词： Tumor-on-a-chip Biliary tumor 3D bioprinting Tumor microenvironment Drug screening

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Dynamic Variations in brain Glycogen are Involved in Modulating Isoflurane Anesthesia in Mice

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Neuroscience Bulletin 2020年第12期36卷 1513-1523页

作者： Ze Fan Zhihao Zhang Shiyi Zhao Yuanyuan Zhu Dong Guo Bo Yang Lixia Zhuo Jiao Han Rui Wang Zongping Fang Hailong Dong Yan Li Lize Xiong Department of Anesthesiology and Perioperative Medicine Xijing HospitalFourth Military Medical UniversityXi'an 710032ShaanxiChina College of Basic Medicine Fourth Military Medical UniversityXi'an 710032ShaanxiChina Department of Neurobiology Fourth Military Medical UniversityXi'an 710032ShaanxiChina Center for brain Science and Department of Anesthesiology The First Affiliated Hospital of Xi'an Jiaotong UniversityXi*an 710061ShaanxiChina Translational Research Institute of Brain and Brain-like Intelligence Department of Anesthesiology and Perioperative MedicineShanghai Fourth People's Hospital Affiliated to Tongji University School of MedicineShanghai 200081China

General anesthesia severely affects the metabolites in the brain.Glycogen,principally stored in astrocytes and providing the short-term delivery of substrates to neurons,has been implicated as an affected molecule.However,whether glycogen plays a pivotal role in modulating anesthesia-arousal remains unclear.Here,we demonstrated that isoflurane-anesthetized mice exhibited dynamic changes in the glycogen levels in various brain regions.Glycogen synthase(GS)and glycogen phosphorylase(GP),key enzymes of glycogen metabolism,showed increased activity after isoflurane exposure.Upon blocking glycogenolysis with 1,4-dideoxy-1,4-imino-Darabinitol(DAB),a GP antagonist,we found a prolonged time of emergence from anesthesia and an enhancedδfrequency in the EEG(electroencephalogram).In addition,augmented expression of glycogenolysis genes in glycogen phosphorylase,brain(Pygb)knock-in(PygbH11/H11)mice resulted in delayed induction of anesthesia,a shortened emergence time,and a lower ratio of EEG-δ.Our findings revealed a role of brain glycogen in regulating anesthesiaarousal,providing a potential target for modulating anesthesia.

关键词： Anesthesia-arousal brain glycogen General anesthesia Glycogen phosphorylase Glycogen synthetase Isoflurane

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Decreased peripheral mtDNA in methamphetamine use disorder

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Science China(Life Sciences) 2022年第3期65卷 648-650页

作者： Ling-Yan Su Yuan Li Qianjin Liu Lijin Jiao Jing Shen Lu-Xiu Yang Ti-Fei Yuan Yong-Gang Yao Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences&Yunnan Province and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesKunming Institute of ZoologyKunming 650204China Kunming College of Life Science University of Chinese Academy of SciencesKunming 650204China Shanghai Key Laboratory of Psychotic Disorders Shanghai Mental Health CenterShanghai Jiaotong University School of MedicineShanghai 200030China Hubei Shizishan Drug Rehabilitation Center Wuhan 426070China Co-innovation Center of Neuroregeneration Nantong UniversityNantong 226019China Translational Research Institute of Brain and Brain-like Intelligence Shanghai Fourth People’s Hospital Affiliated to Tongji University School of MedicineShanghai 200434China CAS Center for Excellence in brain Science and intelligence Technology Chinese Academy of SciencesShanghai 200031China

Dear Editor,Methamphetamine(METH)is the most prevalent addictive psychostimulant in China.METH use disorder(MUD)and its associated disorders constitute a significant burden to the affected individuals and their families(Paulus and Stewart,2020).Neurotransmitter system aberrations,mitochondrial dysfunction,oxidative stress,and inflammasome activation have been involved in METH-induced neurotoxicity(Shin et al.,2018;Wang et al.,2015;Wei et al.,2020).

关键词： China Stewart

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Bioinspired organic optoelectronic synaptic transistors based on cellulose nanopaper and natural chlorophyll-a for neuromorphic systems

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npj Flexible Electronics 2022年第1期6卷 286-295页

作者： Junyao Zhang Dapeng Liu Qianqian Shi Ben Yang Pu Guo Lu Fang Shilei Dai Lize Xiong Jia Huang Interdisciplinary Materials research Center School of Materials Science and EngineeringFrontiers Science Center for Intelligent Autonomous SystemsTongji UniversityShanghai 201804People’s Republic of China Translational Research Institute of Brain and Brain-like Intelligence Shanghai Fourth People’s Hospital Affiliated to Tongji UniversitySchool of Materials Science and EngineeringTongji UniversityShanghai 200434People’s Republic of China

Inspired by human brains,optoelectronic synapses are expected as one of significant steps for constructing neuromorphic systems.In addition,intensive attention has been paid to biodegradable and biocompatible materials for developing green electronics.In this regard,environmentally friendly organic optoelectronic synaptic transistors based on wood-derived cellulose nanopaper(WCN)as dielectric/substrate and nature chlorophyll-a as photoactive material are demonstrated.Both WCN and chlorophyll-a are biocompatible and biodegradable materials from natural organisms.Versatile synaptic behaviors have been well mimicked by the modulation of both electrical and optical signals.More significantly,optical wireless communication is experimentally emulated and the information processing capability is also verified in pattern recognition simulation.Furthermore,the flexible synaptic transistors exhibit no apparent synaptic performance degradation even when the bending radius is reduced to 1 mm.Our work may develop a promising approach for the development of green and flexible electronics in neuromorphic visual systems.

关键词： optoelectronic radius synaptic

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