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建立啮齿类酒精饮用动物模型的影响因素及研究进展

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中国药理学与毒理学杂志 2017年第6期31卷 607-614页

作者：刘欣张倩倩王圣霞张旺信张汉霆泰山医学院药理学研究所山东泰安271000 泰山医学院基础医学院医学心理学教研室山东泰安271000 泰山医学院脑科研究所山东泰安271000 泰安市中心医院眼科山东泰安271000 departments of behavioral medicine & psychiatry and physiology & pharmacology Blanchette Rockefeller Neurosciences InstituteWest Virginia University Health Sciences Center

酒精使用障碍(AUD)是威胁人类健康乃至生命的重要因素之一。世界卫生组织数据显示,全球每年因AUD而死亡的人数约330万。AUD已成为一个全球性公共卫生和社会性问题,但其神经行为学机制并未完全阐明。因此,建立有效和可靠的酒精饮用动物... 详细信息

酒精使用障碍(AUD)是威胁人类健康乃至生命的重要因素之一。世界卫生组织数据显示,全球每年因AUD而死亡的人数约330万。AUD已成为一个全球性公共卫生和社会性问题,但其神经行为学机制并未完全阐明。因此,建立有效和可靠的酒精饮用动物模型对AUD机制的探讨非常重要。本文从动物品系和造模方法等方面进行综述,探讨可能对造模结果造成偏差的相关影响因素,以期对AUD的动物行为学研究有所裨益。

关键词：酒精动物品系饮酒模型啮齿类动物

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AAV-9 Mediated Cdk5 Inhibitory Peptide Protects Neurons in p25 and APP/PS1 Transgenic Mouse Models

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神经药理学报 2019年第Z1期 24-25页

作者： HUANG Yao-wei HUANG Wei XU Miao-jing HUANG Ying-wei HE Yong SONG Ping-ping HE Yong-ni CHEN Xiao PAN Su-yue ZHANG Han-ting HU Ya-fang Department of Neurology Nanfang HospitalSouthern Medical University Department of Neurology the First people's Hospital of ShundeSouthern Medical University Dept.of Neurology the First Affiliated Hospital of Hainan Medical University Department of Neurology First People’s Hospital of Chenzhou Department of Neurology and Stroke Center The First Affiliated HospitalJinan University Department of Neurology Zhujiang HospitalSouthern Medical University departments of behavioral medicine & psychiatry Physiology & Pharmacologyand Neurosciencethe Rockefeller Neurosciences InstituteWest Virginia University Health Sciences Center

Objective:Cyclin-dependent kinase 5(Cdk5),which binds to and is activated by p35,phosphorylates multiple substrates which is essential for the brain development and function. However,p25,generated from p35 under stress conditions leads to the aberrant activation of Cdk5 and contributes to hyperphosphorylation of many substrates relating to the pathogenesis of neurodegenerative diseases including Alzheimer’s disease. Selective inhibition of aberrant Cdk5/p25 activity via genetic overexpression of Cdk5 inhibitory peptide(CIP) shows neuroprotection in p25-transgenic(Tg) mice. Here,we evaluated the neuroprotective effect of adeno-associated viral 9 mediated CIP in p25-Tg and APP/PS1-Tg mouse models. Methods:Injection of AAV9-CIP or control virus via intracerebroventricular(i.c.v.) was performed in p25-Tg 8-wk-old mice while the expression of p25 was trigged or APP/Ps-Tg 3-mo-old mice. Pathologic and Western blot analysis,behavioral change assessment were performed after 5,12 or 16 weeks treatment. Results:Administration of AAV9-CIP after p25 induction significantly reduced tau phosphorylation,inflammation and neuronal apoptosis,thus,inhibited the brain atrophy,loss of neurons in the hippocampus,and alleviated the impairment of spatial orientation in p25 Tg mice. Similarly,in APP/PS1 mice,treatment with AAV9-CIP reduced pathologic changes,including t hyperphosphorylation,(Ab) deposit,astrocytosis,and microgliosis,which were correlated with the reversal of memory loss and anxiety-like behavior observed. The neuroprotection effect of AAV9-GFP-CIP lasted an additional 7 mo—the end point of the study. Conclusion:AAV9-CIP is a potential protectant for the treatment of p25 related-aging diseases,including Alzheimer’s disease.

关键词： Cyclin-dependent kinase 5(Cdk5) Cdk5 inhibitory peptide(CIP) Adenoassociated virus 9(AAV9) Neurodegeneration

The Effect of PDE4B1 Overexpression on Ethanol Drinking Behavior in C57BL/6J Mice

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神经药理学报 2019年第4期 56-56页

作者： XU Bing-bing ZHOU Yan-meng ZHANG Han-ting Shandong First Medical University & Shandong Academy of Sciences departments of behavioral medicine & psychiatry Physiology & Pharmacologyand NeuroscienceThe Rockefeller Neuroscience InstituteWest Virginia University Health Sciences Center

Objective:To observe the effects of high expression of PDE4 B1 in the striatum on ethanol drinking behavior and the cAMP-CREB signaling pathway in mice. Methods:Thirtytwo adult male C57 BL/6 J mice were used and divided into 4 groups:three of the groups were microinfused with lentiviral vectors containing full-length PDE4 B1 or negative control( NC) sequence,or normal saline into bilateral striata( 0.7 μL/side,8×108 TU·mL-1) according to the following coordinates:AP,-2.5 mm from bregma;ML,±0.5 mm from the midline;DV,-2.7 mm from the dura;the forth group of mice was infused with the same volume of lentiPDE4 B1 into bilateral prefrontal cortices( PFC;AP,-1.5 mm from bregma;ML,±0.5 mm from the midline;DV-1.2 mm from the dura). Two weeks later,alcohol consumption and preference were determined using the two-bottle choice test,followed 30 min later by the open-field test for spontaneous activity. The striatum and cerebral cortex were dissected for biochemical assays,including Western blotting for expressions of PDE4 B1 and its downstream signaling molecules such as CREB/pCREB/BDNF/NPY,and ELISA for cAMP levels. Results:Compared to the NCor saline-treated animals,lenti-PDE4 B1-treated mice displayed overexpression of PDE4 B1 in the striatum and PFC,but only the former showed significant increases in alcohol consumption and preference,in addition to an early increase in locomotor activity. Western blotting also revealed that the expression of the signaling molecules such as pCREB,CREB,BDNF,and NPY was reduced in the striatum,but not significantly changed in the PFC. Consistently,the cAMP levels were reduced in the striatum of lenti-PDE4 B1-treated mice. Conclusion:The results provide additional demonstration that PDE4 B,in particular its PDE4 B1 isoform,plays a unique role in the regulation of ethanol consumption.

关键词： phosphodiesterase-4B1(PDE4B1) alcohol consumption cAMP signaling mice

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大麻的成瘾性和潜在的药用价值

中国药物依赖性杂志 2017年第5期26卷 330-336页

作者：苑佳玉李俊旭张汉霆周文华宁波大学医学院宁波315020 Department of pharmacology and Toxicology University at Buffalo School of MedicineThe State University of New York 泰山医学院药理研究所泰安271016 departments of behavioral medicine & psychiatry and physiology & pharmacology West Virginia University Health Sciences Center 宁波戒毒研究中心宁波315010

大麻是全世界被滥用最多的精神活性物质,滥用人数快速增长。本文系统回顾了大麻的种植历史;重点介绍了大麻以及主要活性成分四氢大麻酚的成瘾潜力以及大麻成瘾、中毒和戒断的临床诊断标准;总结了内源性大麻和大麻受体的生理功能和药理... 详细信息

大麻是全世界被滥用最多的精神活性物质,滥用人数快速增长。本文系统回顾了大麻的种植历史;重点介绍了大麻以及主要活性成分四氢大麻酚的成瘾潜力以及大麻成瘾、中毒和戒断的临床诊断标准;总结了内源性大麻和大麻受体的生理功能和药理作用如镇痛、抗惊厥和抗恶心作用,并系统介绍了大麻在多发性硬化症、青光眼和恶性神经胶质瘤等疾病中的治疗作用。总之,对于大麻的成瘾性和危害性值得高度关注,以利于减少大麻危害;同时有必要深入探索和发掘大麻的潜在药物价值,为人类健康服务。

关键词：大麻成瘾性镇痛治疗作用

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Site-specific Proteasome Phosphorylation Controls Cell Proliferation and Tumorigenesis

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Site-specific Proteasome Phosphorylation Controls Cell Proli...

中国生物化学与分子生物学会2016年全国学术会议

作者： Xing Guo Xiaorong Wang Zhiping Wang Sourav Banerjee Jing Yang Lan Huang Jack E.Dixon Department of pharmacology University of California-San Diego Life Sciences Institute Zhejiang University departments of physiology and Biophysics and of Developmental and Cell Biology University of California Division of Biological Sciences University of California-San Diego Department of Neurobiology Zhejiang University School of Medicine departments of Cellular and Molecular medicine and of Chemistry and Biochemistry University of California-San Diego

Despite the fundamental importance of proteasomal degradation in cells,little is known about whether and how the 26S proteasome itself is regulated in coordination with various physiological *** we show that the prote... 详细信息

关键词： Proteasome Phosphorylation DYRK2 Cell Cycle Tumorigenesis CRISPR/Cas9

NP-17 Icariin Facilitates Amyloid-βRemoval in Astrocytes via increased Autophagy by Up-Regulating Sirt6 Expression

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神经药理学报 2018年第4期8卷 115-115页

作者： ZHANG Feng ZHANG Fang-fang LI Bing-long GAO Yong-feng ZHANG Ji-guo ZHANG Han-ting Institute of pharmacology Taishan Medical UniversityTaian271016China departments of behavioral medicine&psychiatry and physiology Pharmacology&Neurosciencethe Rockefeller Neurosciences InstituteWest Virginia University Health Sciences CenterMorgantownWV 26506USA

Background:Amyloid-β(Aβ)metabolic imbalance is the pivotal pathogenesis leading to Alzheimer’s disease(AD).In sporadic AD,decreased clearance of Aβimportantly contributes to the onset and ***,the most abundant cell type in the brain,are mainly responsible for maintaining neuronal *** recently,it has been demonstrated that astrocytes play an important role in regulating Aβ***(ICA),a flavonoid glucoside extracted from the traditional Chinese herb Epimedium brevicornu,has been shown to produce protective effects against AD by decreasing Aβ***,it remains unclear whether ICA regulates cellular Aβclearance in the ***:To examine the regulatory effects of ICA on Aβremoval by astrocytes and explore the mechanisms of its ***:Uptake and subsequent degradation of Aβby astrocytes were evaluated using a combination of enzyme-linked immunosorbent assay(ELISA)and laser confocal *** effects of oligomer Aβ(oAβ1-42)and/or ICA on the expressions of sirt6 in the primary astrocytes were examined using western blotting and q-PCR *** expression of autophagy markers including P62 and LC3-Ⅱ,and phosphorylated-mTOR were measured by western *** order to determine whether sirt6 is involved in the intracellular Aβmetabolism,sirt6 was knocked down using lentiviral vectors containing sirt6-shRNAs and autophagy levels were assessed by western ***:①In primary astrocytes,ICA not only significantly increased Aβinternalization but also obviously accelerated its degradation in a concentration-dependent manner.②Treatment of astrocytes with Aβ1-42 at 1μmol·L-1 significantly down-regulated the expression of sirt6,which was rescued by *** addition,ICA at 20μmol·L-1 significantly increased the expression of LC3-Ⅱand markedly decreased the expression of P62 and phosphorylated-mTOR in primary astrocytes.③Sirt6 knockdown in primary astrocytes resulted in decreased cellular Aβuptak

关键词： icariin(ICA) amyloid-β(Aβ) astrocytes autophagy sirt6

A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export

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A neuroligin-4 missense mutation associated with autism impa...

中国神经科学学会第十届全国学术会议

作者： Chen Zhang Jeff M Milunsky Stephanie Newton Jaewon Ko Geping Zhao Tom A Maher Helen Tager-Flusberg Marc F Bolhger Alice S Carter Antony A Boucard Craig M Powell Thomas C Sudhof Department of Molecular and Cellular physiology Stanford University departments of Neuroscience The University of Texas Southwestern Medical Center Center for Human Genetics Boston University School of Medicine Department of Pediatrics/Genetics and Genomics Boston University School of Medicine Human Development Program Boston University School of Medicine departments of Neurology The University of Texas Southwestern Medical Center departments of psychiatry The University of Texas Southwestern Medical Center Howard Hughes Medical Institute Stanford University departments of Molecular Genetics The University of Texas Southwestern Medical Center departments of Howard Hughes Medical Institute The University of Texas Southwestern Medical Center

Neuroligins（NLs） are postsynaptic cell-adhesion molecules essential for normal synapse *** in neuroligin-4（NL4）（gene symbol:NLGN4） have been reported in some patients with autism spectrum disorder（ASD）and other neurodevelopmental ***,the low frequency of NL4 mutations and the limited information about the affected patients and the functional consequences of their mutations cast doubt on the causal role of NLA mutations in these ***,we describe two brothers with classical ASD who carry a single amino-acid substitution in NL4（R87W）.This substitution was absent from the brothers’ asymptomatic parents,suggesting that it arose in the maternal germ line.R87 is conserved in all NL isoforms,and the R87W substitution is not observed in control *** the protein level,the R87W substitution impaired glycosylation processing of NL4 expressed in HEK293 and COS cells,destabilized NL4,caused NL4 retention in the endoplasmic reticulum in non-neuronal cells and neurons,and blocked NLA transport to the cell *** a result,the R87Wsubstitution inactivated the synapse-formation activity of NLA and abolished the functional effect ofNLA on synapse *** together,these observations suggest that a point mutation in NLA can cause ASD by a loss-of-function mechanism.

关键词： neuroligins synapse autism spectrum disorder

Circuitry-dependent and independent phenotypes of MeCP2-deficient human neurons derived from ESCs and Rett syndrome specific iPSCs

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Circuitry-dependent and independent phenotypes of MeCP2-defi...

中国神经科学学会第十届全国学术会议

作者： Xiao-Ying Chen Xu Han Bruno CF Blanchi Yi Eve Sun Yong-Chun Yu Translational Center for Stem Cell Research Tongji HospitalStem Cell Research CenterTongji University School of Medicine Institute of Neurobiology Institute of Brain Science and State Key Laboratory of Medical NeurobiologyFudan University Intellectual and Developmental Disabilities Research Center Departments of Psychiatry & Behavioral Sciences and Molecular & Medical PharmacologySemel Institute for NeuroscienceDavid Geffen School of Medicine at University of California Los Angeles635 Charles E.Young Dr.South

It becomes increasingly acknowledged that changes in synaptic transmission and/or neural network properties are regional- and circuitry-specific in many neurological *** feature poses a huge challenge for using patient-specific induced pluripotent stem cells（hiPSCs） to model neurological disorders,because currently,scientists have limited control over the context of the various neural networks formed in such "disease-in-a-dish" ***,we report that neurons derived from Rett syndrome（RTT） hiPSCs exhibit variable spontaneous postsynaptic currents and variable ratios between excitation-inhibition from culture to *** alterations of circuitry contents using a ventralizing agent changed neural transmission phenotype,suggesting a circuitry-specific nature of such *** contrast,cell-intrinsic electrophysiological and morphological properties of RTT neurons demonstrate consistent changes,regardless of the type of circuitries *** findings demonstrate that "disease-in-a-dish" models using hiPSC-derived neurons,while may capture cell-intrinsic properties of diseased neurons,could be rather limited for assessing neural-circuitry-dependent phenotypes.

关键词： circuitry rett syndrome hiPSCs

CaMKH binding to GluN2B is critical for memory consolidation

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CaMKH binding to GluN2B is critical for memory consolidation

中国生理学会第23届全国会员代表大会暨生理学学术大会

作者： Amy R.Halt R.F.Dallapiazza J.W.Hell Alcino J.Silva departments of pharmacology and psychiatry and Neurosurgery Roy J.and Lucille A.Carver College of MedicineUniversity of IowaIowa CityIA 52242USA Department of Neurobiology Semel InstituteDepartment of PsychologyBrain Research InstituteUniversity of CaliforniaLos AngelesCalifornia90095USA

Memory is essential for our normal daily lives and our sense of ***,our knowledge of molecular and cellular mechanisms of memory formation and retention is *** influx through the NMDA-type glutamate receptor(NMDAR) and the ensuing activation of the Ca and calmodulin-dependent protein kinase(CaMKII) are required for memory formation and its physiological correlate,long-term potentiation(LTP).The Ca influx induces CaMKII binding to the NMDAR to strategically recruit CaMKII to synapses that are undergoing potentiation. We show that mice with two point mutations that impair CaMKII binding to the NMDAR GluN2B subunit initially learn the Morris water maze and acquire contextual fear conditioning under standard conditions to the same degree as wild type mice but show deficiency during the period of early memory consolidation in these ***, the activity-driven interaction of CaMKII with the NMDAR is important for imprinting memory traces.

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