神经生物学的理论概述及神经系统疾病的研究课件

神经生物学

神经生物学的理论概述及神经系统疾病的研究学习方法英语教科书：是压力，有后劲以学习名词为主，要敢于发音综合学科：multidisciplinary以功能为主，结合形态以基础为主，结合临床教科书内容与讲课内容可能不完全一致， 但鼓励看书（教科书），借机学习专业英语。百年来与神经科学有关的诺贝尔奖获得者选介(I)C.S.Sherrington(英)18571850190019502000C.Golgi(意)19261934神经元染色方法18431852R.Cajal(西班牙)“神经元学说”形态190619521932•“突触”定名•“反射”概念•“交互”抑制反射学说生理电生理18891977•感觉神经纤维电活动•传入冲动大脑诱发电位•神经控制骨骼肌运动机制E.D.Adrian(英)电生理O.Loewi(德英)196118731936（乙酰胆碱）神经化学•蛙心灌流实验•“迷走物质”19681875H.Dale(英)•神经末梢分泌•乙酰胆碱ACh神经化学18741965194419631888J.Erlanger(美)H.S.Gasser(美)•阴极射线示波器•神经纤维的分类ABC19731881W.R.Hess(瑞士)•脑立体定位仪hypothalamus方法学创新1949电生理OxfCambridge徒手切脑片银染神经元染出神经末梢，发现神经元之间无原生质联系生理科学进展2001，32：187神经药理学分子药理学百年来与神经科学有关的诺贝尔奖获得者选介(II)1850190019502000J.C.Eccles(澳大利亚)191419031963A.L.Hodgkin(英)B.Katz(德英)1917A.F.Huxley(英)•细胞内微电极•突触后电位•抑制性递质突触•电压钳技术•动作电位的离子学说•数学方程表述•NM终板电位•递质“量子释放”1911动作电位机制19051983U.VonEuler(瑞典…)•交感神经递质•去甲肾上腺素1970•儿茶酚胺代谢•影响CAs的药物电生理1912J.Axelrod(美)（儿茶酚胺）神经化学1913(左右脑)R.W.Sperry(美)1981“脑功能侧化”D.Hubel(加美)19261924T.Wiesel(瑞典美)信息加工视皮层E.Neher(德)1991B.Sakmann(德)•大脑视觉信息加工•视觉系统发育的可塑性膜片钳单通道方法学•膜片钳技术•单个离子通道电流记录1999英，澳CambridgeCambridgeLeviMontalcini1986NervegrowthFactor(NGF)(Italy)百年来与神经科学有关的诺贝尔奖获得者选介(3)1850190019502000192619232000P.Greengard(美)1930E.Kandel(美)A.Carlsson(瑞典)神经系统中的信号转导蛋白磷酸化慢突触传递多巴胺(Schizophrenia)(Parkingson’sDisease)(DA)(cAMP)(PKA)SlowsynaptictransmmissionEffectslastforsecondstohoursShorttermmemory

lastsformin.tohrsLongtermmemory

lastsforweeksDenovo杂志:《生理学报》70%论文属神经生理 1927年创刊(上海生理所)《中国神经科学杂志》1998年创刊(上海二军大)《中国疼痛医学杂志》1995年创刊(北医大)《中国神经解剖杂志》1985年创刊(四军大解剖系）大型专著:《神经科学纲要》1993年北医大韩济生主编 (156万字)

《神经科学原理》1999年北医大韩济生主编 (200万字)学会:中国科学神经学会(1994年成立),1995年会(上海),1997年会(西安),1999年会(北京),2001(香港）研究经费:“攀登计划”脑功能研究(1992-1997)400万

国家自然科学基金重大课题2项(神经肽,视觉信息 加工）200万

国家自然科学基金委重点课题12项(每项50-90万) 973项目两项（1999-）（2000万）(3400万)差距:分子神经生物学,发育神经生物学 (美国2.5万)(IBRO3万会员,1999年以色列)北医大神经科学的发展神经解剖:臧玉淦教授,许鹿希教授生理:崔宏,周佳音，顾蕴辉，于英心北医大神经痛与镇痛1965-(韩济生,汤健,任民峰…)科学研究所海洛因成瘾的机理与治疗1992-(韩济生,吴鎏桢…)

帕金森氏症的基因治疗1993-(王晓民,韩济生…)一院小儿神经:癫痫的发病原理与治疗(吴希如)神经内科:神经肌肉病,脑血管意外,语言障碍(陈清棠)六院精神病学:抑郁症,酒精成瘾(沈渔邨)神经科学进展(2000海内外中青年)神经发育,衰老与再生(Neuraldevelopment,agingandregeneration)[18]离子通道与突触传递(Ionchannelsandsynaptictransmission)[14]神经系统疾病(Neuraldiseases,PD,AD,HD,Psych)[11]感觉系统(Sensorysystem,Pain,Visual)[7]神经递质,调质,转运体和受体(Neurotransmitters,modulators,transportersandreceptors,5-HT,)[4]神经免疫与神经内分泌(Neuroimmunologyandneuroendocrine)新技术(Newtechnology)[2]学习与记忆(Learningandmemory)[2]运动系统(Motorsystem)[2] [62] 神经发育与再生神经营养因子突触发生及其可塑性(蒲慕明,鲁白)神经细胞迁移的分子生物学(饶毅)神经干细胞的应用潜力(王伟业)脊髓损伤的修复(徐小明)视网膜结细胞轴突再生(蘇国辉)视神经再生(陈东风)神经移植的免疫学(段维明)同源盒基因(范明) 神经系统疾病1.帕金森病(王晓民)2.老年痴呆(杜燕生)3.亨廷敦病(李曉江)4.星型胶质细胞与脑缺氧(于常海)巴甫洛夫：非条件反射巴甫洛夫：条件反射复杂的操作式条件反射人的心理活动，学习记忆，计算，思维……肥胖症能量代谢失衡对美食的渴求药物成瘾身体依赖：戒断症状精神依赖：心瘾痛与镇痛感知功能情绪反应疼痛的现代研究方法清醒动物神经元单位放电

多通道记录

多通道脑电与脑诱发电位研究人体功能磁共振成像(fMRI)………ABCSchematicdrawingofmicroarrays（微电极芯片）Microarraysmaybeone-,two-orthree-dimentionalMicrowiresaregroupedtogethertooccupyatargetarea-10-505100.02.55.07.510.0SI-10-505100.02.55.07.510.0VP外侧通路

thelateralpathway：ContralateralbiasIpsilateralContralateralControlSurprise(-lnp)Time(Sec)

内侧通路

themedialpathway：

Bilateralunbiasedresponse

-10-50510ACC0.02.55.07.510.0-10-50510MD0.02.55.07.510.0IpsilateralContralateralControlSurprise(-lnp)Time(Sec)脑内两套痛觉编码体系的

功能磁共振(fMRI)测试疼痛感觉

与情绪 的可分离性分别加以评分的可能选择性地加以干预RainvillePHypnoticsuggestionsdissociatepainsensationandpainaffectRainvillePetal.1997,Science277:968-971.HofbauerRKetal.2001,JNeurophysiol86:402-411.不同品系小鼠电针镇痛效果比较Wanetal.Pain

2001Painthresholdandtheeffectof2HzEAanalgesiainB10andB6mice

1.0-1.5mALowrespondersHighrespondersHereditorydifferencebetweenB6andB10miceH9(chromosomeX)

Igh2(chromosome12)

Lv

(chromosome4)Festing,199259-67cMsegmentonchromosome4

McCliveetal,19944lociand2segmentsonchromosomes2,11,13and16

Slingsbyetal,1995Pain/analgesia-relatedgenesinB10andB6miceOprd1

δOR(Chr464.8cM)Htr65-HT6R(Chr464.9cM)Htr1d5-HT1DR(Chr466.0cM)Htr1da5-HT1DαR

(Chr466.2cM)Htr1db5-HT1D

βR

(Chr466.2cM)Adra1bNAα1b

R

(Chr1119.0cM)Gabra1GABAAα1R

(Chr1119.0cM)Gabrg1GABAAγ1

R

(Chr1119.0cM)

DeviL.A.OligomerizationofOpioidReceptors2002Bioluminesenceresonanceenergytransfer(BRET)techniquefortestingthedistancebetweentwomolecules<100Å慢性疼痛的研究韩济生北京大学神经科学研究所合作者：张旭中科院神经科学研究所重点项目结题验收汇报2003年2月22-24日StudyonChronicPainMechanismsGenePeptideProteinIn

vitroInvivoCognitive(DRG)Painrelated11229ESTNovelGenesOFQNSTEMGDNFMuORDeltaORIhIonChannelHistochemstainingCellculturePatchclampingAcutePainChronicPaininflammatoryneuropathicnervelesion

fMNRPainrelatedbrainareasOptimalparametersforEAtreatmentTrendsinNeuroscience,2003;26:17-22FiringRateResponse/ReleaseTransmitterPeptidesThomasHokfelt,1991,Neuron7:867-879经典神经递质神经肽阿片肽opioidpeptidesaaYearOpiodreceptor电针(Hz)μδκ脑啡肽Enkephalins51975

+++

2β-内啡肽β-endorphin311976

+++2强啡肽Dynorphins171979++100孤啡肽OrphaninFQ171995

内吗啡肽Endomorphins41997++2内源性阿片肽EndogenousOpioidPeptidesEffectsproducedbyEAofdifferentfrequencies2Hz100HzNaloxonereversibilityofEAanalgesia(ID50,mg/kg)0.5(mu,deltaOR)20(kappaOR)InductionofthereleaseofneuropeptidesinthespinalcordEnk,ß-EP,EM,GalaninDynorphin,CCK-8Neuralpathwaysrevealedbylesion,stimulation,c-fosexpression,etc.ArcuateN.hypothalamusParabrachialN.ChronicInflammatoryPain（炎症痛）++++++Neuropathicpain（神经源性痛）++++Spinalspasticpain（肌痉挛痛）0+++0281624485d0102030hrcontrolneedling2Hz100Hzn=11-12****************TimeafterEANumberofPawLiftsfromcoldplate/5minTheCumulativeEffectofElectroacupunctureonCold-inducedNeuropathicPain3735Hzm215100EM/ENK/βEP

dDYNAntinociceptionandTreatmentofdrugaddictionFrequencyofelectroacupunctureNeuropeptidesreleasedinCNSOpioidreceptorsPhysiologicalandtherapeuticeffectsNeurochemicalBasisofAcupunctureEffectsDREAMPeptidereleasedinCNSEnkDynEnk+DynAB2Hz2Hz100Hz100Hz30691215s2Hz100Hz

Hamza,M.A.etal.(1999)Effectofthefrequencyoftranscutaneouselectricalnervestimulationonthepostoperativeopioidanalgesicrequirementandrecoveryprofile.Anesthesiology91,1232-8Wang,B.G.etal.(1997)Effectofthe

intensityoftranscutaneous

acupointelectricalstimulationonthepostoperativeanalgesicrequirement.Anesth.Analg.85,406-13El-sayed,A.etal.(1999)Percutaneouselectricalnervestimulationforlowback

pain.Arandomizedcrossoverstudy.JAMA281,818-823

Hamza,M.A.etal.(1999)Effectofthedurationofelectricalstimulationontheanalgesicresponseinpatientswithlowbackpain.Anesthesiology91,1622-7

Hamza,M.A.,etal.(2000)Percutaneouselectricalnervestimulation:anovelanalgesictherapyfordiabeticneuropathicpain.DiabeticCare23,365-370

实验研究结果的临床验证

Clinicalverificationofbasicresearch11NervepathwaysforlowandhighfrequencyEAanalgesia100Hz2Hz-endEnkDynPBNArcuateN.Hypoth.PAGMedullaDHNR.PrimaryMotorArea(R-MI)R.SupplementaryMotorArea(R-SMA)

BrainareasinvolvedinAA:fMRIstudiesinhumansPositivecorrelation4341R.Hippocampus(R-Hi)L.Hippocampus(L-Hi)44BrainareasinvolvedinAA:fMRIstudiesinhumansNegativecorrelation42RightPrimaryMotorAreaRightSupplementaryMotorAreaLeftSecondarySomatosensoryAreaLeftInsulaRightSecondarySomatosensoryAreaLeftSuperiorTemporalGyrusRightThalamusRightAnteriorCingulateCortexRightHippocampusRightHippocampusRightPrimarySomatosensoryAreaRightInsulaEffectsof2HzEAonthebrainfMRISummaryBrainAreas2Hz100HzR-SensoryII++L-SensoryII++R-BroadmanArea24++R-Thalamus++L-Insular++R-PrimaryMotorArea+R-SupplementoryMA+L-SuperiorTemporalGyrus+R-BroadmanArea40+L-BroadmanArea24+L-NucleusAccumbens+PONS+R-Hippocampus-L-Hippocampus-R-Amygdala-肥胖症能量代谢失衡对美食的渴求药物成瘾身体依赖：戒断症状精神依赖：心瘾痛与镇痛感知功能情绪反应7255786100010203040506070809010019901993199720002002

HeroinaddictsinChina(tenthousand)80%-85%heroinaddictsHeroinaddiction:canacupuncturehelp?针刺是否能戒除海洛因成瘾？H.A.N.SHan’s

Acupoint

NerveStimulator(HANS)韩氏穴位神经刺激仪Threshold(mA)ofafferentfibersactivatedbyEA(HANS)atdifferentfrequenciesAα012345672Hz 0.6ms15Hz 0.3ms100Hz 0.2msTypesofnervefibers*

Thresholdofexcitation

(mA)AβAδCEffectofHANSon

heartrate

of

heroinaddictsDayoftreatment1234567891060708090100110120130Control2Hz2/100Hz100Hzn=13-16*********HeartRate(beat/min)ThedoseofBPNneededbyHeroinAddictsduringdetoxificationBPNDose(mg/d)1234567891011121314DaysofTreatment(n=14)0.00.51.01.52.02.5**********Buprenorphine

HANS+BPN**P<0.001,comparedwithBPNgroupCRAVING:themostdifficultissue一朝吸毒，终身想毒。1Month050100RelapseRate(%)***P<0.05,comparedwithBPNgroup92%78%57%71%100%100%

HANSDecreasesHeroinRelapseRateoftheHeroinaddicts2Month3MonthBPN(n=12)HANS+BPN(n=14)*Theauto-trackconditionedplacepreference(CPP)instrumentMorphine-inducedconditionedplacepreference(CPP)Dose-dependenteffect*p<0.05,**p<0.01,***p<0.001;comparedwith0mg/kggroupIndexofpreference=TimeMor/(TimeMor+Timesaline)Morphine-inducedCPPLineardoseeffectrelationship-2-1010100200n=9-12LgofMorDose(mg/kg)difference(s)EASuppressionofCPPforMorphineControlRestrainFootshockNeedle100Hz2Hz2/100Hz0.02.55.07.510.0******TimeSpentintheDrug-pairingSide(min)n=18~20EffectofEAofDifferentFrequenciesEffectofEAReversedbyNaloxonen=8~9Needle2/100Hz2Hz0.02.55.07.510.0******2/100Hz+NX(5mg/kg)2Hz+NX(1mg/kg)Reinstatementofmorphine’sCPPonratsbystress

TimeSpentintheDrug-pairingSide(min)FadingofMorphine’sCPPwithTimeTimefromLastDrug-pairing(days)0.02.55.07.510.01357*******FootShock2Hz2Hz+0.02.55.07.510.0NX1mg/kgn=12RelapseInducedbyIntermittentFootshock(9daysafterlastdrug-pairing)SalineMorphine(4mg/kg)n=12***Ordrugpriming100Hz应激引起复吸条件反射随时间而消退DaysofobservationSuppressionofheroincraving

byHANSinhumans人体心瘾观察及HANS抗心瘾作用Druguseover1year(aver4.6y);Detoxificationover1month;Male,Aver25y;n=29-30Cravingscore(VAS)30minperdayPre-HANSHANS-treatingPost-HANS102030100Hz2HzMock2/100Hz0012345Norelapseover1yearClinicalBaseMethodofDetox.HANSforRehabSuccessover1yearSuccessRateHainanHANSYes11/56Ca20%ShanghaiHANSandothersYes9/100Ca10%CantonHANSNotconstant9-20/500Ca2-4%Norelapseover1year一年不复吸Aim:HANSdetox.+HANSreadyinthepocket30＋%successover1yearOpiatecravingSuppressionofdrugcravingbyHANSCocainecraving2Hz>100Hz100Hz>2HzElectroacupuncturetreatmentfordrugaddictionVTAOpiateGABANAcDADATCocaineEuphoriaEnkDynElectroacupuncture2Hz100HzPresynapticinhibitionSubstitutionμκμμA100bp2000bp1000bp750bp500bp250bpDL2000

NSCPP2Hz100HzrestrainGAPDH(532bp)PPD(250bp)Effectof100HzEAonthelevelofPPDmRNAinNAcofCPPratsB0.00.51.01.5Greyscaleratios(PPD/GAPDH)Treatment*#n=4NSCPP2Hz100HzrestrainEffectof2HzEAonthelevelofPPEmRNA

inNAcofCPPratsGreyscaleratios(PPE/GAPDH)0.000.250.500.751.00NSCPP*#2Hz100Hzrestrainn=42000bp1000bp750bp500bp250bp100bpDL2000CPP2Hz100HzrestrainGAPDH（532bp）PPE（402bp）NS美国权威性“物质滥用”教科书JoyceLowinson等主编第4版，2004“针刺戒毒”一章由韩济生编写肥胖症能量代谢失衡对美食的渴求药物成瘾身体依赖：戒断症状精神依赖：心瘾痛与镇痛感知功能情绪反应肥胖的发展趋势肥胖发病机理GenesEnvironmentalfactors

HANS治疗肥胖症：人体研究结果048121620242832-4-3-2-10

AHANSB

CHANSDn=16Time(week)ABCD-4-3-2-10******HANS(3time/week)Changeofbodyweight(kg)梁门，一对。天枢，一对。水道，一对。梁丘，公孙。频率：2/100Hz每周3次每次30分钟大鼠实验结果（高能食物引起肥胖）

Diet-inducedObesity(DIO)After14weeks02468101214160100200300400500600700Highenergydiet(n=80)Normaldiet(n=20)************************Time(week)Bodyweight(g)ControlDRDIO0100200300400500600700800***#HighenergydietBodyweight(