神經(jīng)生物學(xué)的理論概述及神經(jīng)系統(tǒng)疾病的研究課件

神經(jīng)生物學(xué)

神經(jīng)生物學(xué)的理論概述及神經(jīng)系統(tǒng)疾病的研究學(xué)習(xí)方法英語教科書：是壓力，有后勁以學(xué)習(xí)名詞為主，要敢于發(fā)音綜合學(xué)科：multidisciplinary以功能為主，結(jié)合形態(tài)以基礎(chǔ)為主，結(jié)合臨床教科書內(nèi)容與講課內(nèi)容可能不完全一致， 但鼓勵看書（教科書），借機學(xué)習(xí)專業(yè)英語。百年來與神經(jīng)科學(xué)有關(guān)的諾貝爾獎獲得者選介(I)C.S.Sherrington(英)18571850190019502000C.Golgi(意)19261934神經(jīng)元染色方法18431852R.Cajal(西班牙)“神經(jīng)元學(xué)說”形態(tài)190619521932?“突觸”定名?“反射”概念?“交互”抑制反射學(xué)說生理電生理18891977?感覺神經(jīng)纖維電活動?傳入沖動大腦誘發(fā)電位?神經(jīng)控制骨骼肌運動機制E.D.Adrian(英)電生理O.Loewi(德英)196118731936（乙酰膽堿）神經(jīng)化學(xué)?蛙心灌流實驗?“迷走物質(zhì)”19681875H.Dale(英)?神經(jīng)末梢分泌?乙酰膽堿ACh神經(jīng)化學(xué)18741965194419631888J.Erlanger(美)H.S.Gasser(美)?陰極射線示波器?神經(jīng)纖維的分類ABC19731881W.R.Hess(瑞士)?腦立體定位儀hypothalamus方法學(xué)創(chuàng)新1949電生理OxfCambridge徒手切腦片銀染神經(jīng)元染出神經(jīng)末梢，發(fā)現(xiàn)神經(jīng)元之間無原生質(zhì)聯(lián)系生理科學(xué)進展2001，32：187神經(jīng)藥理學(xué)分子藥理學(xué)百年來與神經(jīng)科學(xué)有關(guān)的諾貝爾獎獲得者選介(II)1850190019502000J.C.Eccles(澳大利亞)191419031963A.L.Hodgkin(英)B.Katz(德英)1917A.F.Huxley(英)?細(xì)胞內(nèi)微電極?突觸后電位?抑制性遞質(zhì)突觸?電壓鉗技術(shù)?動作電位的離子學(xué)說?數(shù)學(xué)方程表述?NM終板電位?遞質(zhì)“量子釋放”1911動作電位機制19051983U.VonEuler(瑞典…)?交感神經(jīng)遞質(zhì)?去甲腎上腺素1970?兒茶酚胺代謝?影響CAs的藥物電生理1912J.Axelrod(美)（兒茶酚胺）神經(jīng)化學(xué)1913(左右腦)R.W.Sperry(美)1981“腦功能側(cè)化”D.Hubel(加美)19261924T.Wiesel(瑞典美)信息加工視皮層E.Neher(德)1991B.Sakmann(德)?大腦視覺信息加工?視覺系統(tǒng)發(fā)育的可塑性膜片鉗單通道方法學(xué)?膜片鉗技術(shù)?單個離子通道電流記錄1999英，澳CambridgeCambridgeLeviMontalcini1986NervegrowthFactor(NGF)(Italy)百年來與神經(jīng)科學(xué)有關(guān)的諾貝爾獎獲得者選介(3)1850190019502000192619232000P.Greengard(美)1930E.Kandel(美)A.Carlsson(瑞典)神經(jīng)系統(tǒng)中的信號轉(zhuǎn)導(dǎo)蛋白磷酸化慢突觸傳遞多巴胺(Schizophrenia)(Parkingson’sDisease)(DA)(cAMP)(PKA)SlowsynaptictransmmissionEffectslastforsecondstohoursShorttermmemory

lastsformin.tohrsLongtermmemory

lastsforweeksDenovo雜志:《生理學(xué)報》70%論文屬神經(jīng)生理 1927年創(chuàng)刊(上海生理所)《中國神經(jīng)科學(xué)雜志》1998年創(chuàng)刊(上海二軍大)《中國疼痛醫(yī)學(xué)雜志》1995年創(chuàng)刊(北醫(yī)大)《中國神經(jīng)解剖雜志》1985年創(chuàng)刊(四軍大解剖系）大型專著:《神經(jīng)科學(xué)綱要》1993年北醫(yī)大韓濟生主編 (156萬字)

《神經(jīng)科學(xué)原理》1999年北醫(yī)大韓濟生主編 (200萬字)學(xué)會:中國科學(xué)神經(jīng)學(xué)會(1994年成立),1995年會(上海),1997年會(西安),1999年會(北京),2001(香港）研究經(jīng)費:“攀登計劃”腦功能研究(1992-1997)400萬

國家自然科學(xué)基金重大課題2項(神經(jīng)肽,視覺信息 加工）200萬

國家自然科學(xué)基金委重點課題12項(每項50-90萬) 973項目兩項（1999-）（2000萬）(3400萬)差距:分子神經(jīng)生物學(xué),發(fā)育神經(jīng)生物學(xué) (美國2.5萬)(IBRO3萬會員,1999年以色列)北醫(yī)大神經(jīng)科學(xué)的發(fā)展神經(jīng)解剖:臧玉淦教授,許鹿希教授生理:崔宏,周佳音，顧蘊輝，于英心北醫(yī)大神經(jīng)痛與鎮(zhèn)痛1965-(韓濟生,湯健,任民峰…)科學(xué)研究所海洛因成癮的機理與治療1992-(韓濟生,吳鎏楨…)

帕金森氏癥的基因治療1993-(王曉民,韓濟生…)一院小兒神經(jīng):癲癇的發(fā)病原理與治療(吳希如)神經(jīng)內(nèi)科:神經(jīng)肌肉病,腦血管意外,語言障礙(陳清棠)六院精神病學(xué):抑郁癥,酒精成癮(沈漁邨)神經(jīng)科學(xué)進展(2000海內(nèi)外中青年)神經(jīng)發(fā)育,衰老與再生(Neuraldevelopment,agingandregeneration)[18]離子通道與突觸傳遞(Ionchannelsandsynaptictransmission)[14]神經(jīng)系統(tǒng)疾病(Neuraldiseases,PD,AD,HD,Psych)[11]感覺系統(tǒng)(Sensorysystem,Pain,Visual)[7]神經(jīng)遞質(zhì),調(diào)質(zhì),轉(zhuǎn)運體和受體(Neurotransmitters,modulators,transportersandreceptors,5-HT,)[4]神經(jīng)免疫與神經(jīng)內(nèi)分泌(Neuroimmunologyandneuroendocrine)新技術(shù)(Newtechnology)[2]學(xué)習(xí)與記憶(Learningandmemory)[2]運動系統(tǒng)(Motorsystem)[2] [62] 神經(jīng)發(fā)育與再生神經(jīng)營養(yǎng)因子突觸發(fā)生及其可塑性(蒲慕明,魯白)神經(jīng)細(xì)胞遷移的分子生物學(xué)(饒毅)神經(jīng)干細(xì)胞的應(yīng)用潛力(王偉業(yè))脊髓損傷的修復(fù)(徐小明)視網(wǎng)膜結(jié)細(xì)胞軸突再生(蘇國輝)視神經(jīng)再生(陳東風(fēng))神經(jīng)移植的免疫學(xué)(段維明)同源盒基因(范明) 神經(jīng)系統(tǒng)疾病1.帕金森病(王曉民)2.老年癡呆(杜燕生)3.亨廷敦病(李曉江)4.星型膠質(zhì)細(xì)胞與腦缺氧(于常海)巴甫洛夫：非條件反射巴甫洛夫：條件反射復(fù)雜的操作式條件反射人的心理活動，學(xué)習(xí)記憶，計算，思維……肥胖癥能量代謝失衡對美食的渴求藥物成癮身體依賴：戒斷癥狀精神依賴：心癮痛與鎮(zhèn)痛感知功能情緒反應(yīng)疼痛的現(xiàn)代研究方法清醒動物神經(jīng)元單位放電

多通道記錄

多通道腦電與腦誘發(fā)電位研究人體功能磁共振成像(fMRI)………ABCSchematicdrawingofmicroarrays（微電極芯片）Microarraysmaybeone-,two-orthree-dimentionalMicrowiresaregroupedtogethertooccupyatargetarea-10-505100.02.55.07.510.0SI-10-505100.02.55.07.510.0VP外側(cè)通路

thelateralpathway：ContralateralbiasIpsilateralContralateralControlSurprise(-lnp)Time(Sec)

內(nèi)側(cè)通路

themedialpathway：

Bilateralunbiasedresponse

-10-50510ACC0.02.55.07.510.0-10-50510MD0.02.55.07.510.0IpsilateralContralateralControlSurprise(-lnp)Time(Sec)腦內(nèi)兩套痛覺編碼體系的

功能磁共振(fMRI)測試疼痛感覺

與情緒 的可分離性分別加以評分的可能選擇性地加以干預(yù)RainvillePHypnoticsuggestionsdissociatepainsensationandpainaffectRainvillePetal.1997,Science277:968-971.HofbauerRKetal.2001,JNeurophysiol86:402-411.不同品系小鼠電針鎮(zhèn)痛效果比較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<100?慢性疼痛的研究韓濟生北京大學(xué)神經(jīng)科學(xué)研究所合作者：張旭中科院神經(jīng)科學(xué)研究所重點項目結(jié)題驗收匯報2003年2月22-24日StudyonChronicPainMechanismsGenePeptideProteinIn

vitroInvivoCognitive(DRG)Painrelated11229ESTNovelGenesOFQNSTEMGDNFMuORDeltaORIhIonChannelHistochemstainingCellculturePatchclampingAcutePainChronicPaininflammatoryneuropathicnervelesion

fMNRPainrelatedbrainareasOptimalparametersforEAtreatmentTrendsinNeuroscience,2003;26:17-22FiringRateResponse/ReleaseTransmitterPeptidesThomasHokfelt,1991,Neuron7:867-879經(jīng)典神經(jīng)遞質(zhì)神經(jīng)肽阿片肽opioidpeptidesaaYearOpiodreceptor電針(Hz)μδκ腦啡肽Enkephalins51975

+++

2β-內(nèi)啡肽β-endorphin311976

+++2強啡肽Dynorphins171979++100孤啡肽OrphaninFQ171995

內(nèi)嗎啡肽Endomorphins41997++2內(nèi)源性阿片肽EndogenousOpioidPeptidesEffectsproducedbyEAofdifferentfrequencies2Hz100HzNaloxonereversibilityofEAanalgesia(ID50,mg/kg)0.5(mu,deltaOR)20(kappaOR)InductionofthereleaseofneuropeptidesinthespinalcordEnk,?-EP,EM,GalaninDynorphin,CCK-8Neuralpathwaysrevealedbylesion,stimulation,c-fosexpression,etc.ArcuateN.hypothalamusParabrachialN.ChronicInflammatoryPain（炎癥痛）++++++Neuropathicpain（神經(jīng)源性痛）++++Spinalspasticpain（肌痙攣痛）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

實驗研究結(jié)果的臨床驗證

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-肥胖癥能量代謝失衡對美食的渴求藥物成癮身體依賴：戒斷癥狀精神依賴：心癮痛與鎮(zhèn)痛感知功能情緒反應(yīng)7255786100010203040506070809010019901993199720002002

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

Acupoint

NerveStimulator(HANS)韓氏穴位神經(jīng)刺激儀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，終身想毒。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應(yīng)激引起復(fù)吸條件反射隨時間而消退DaysofobservationSuppressionofheroincraving

byHANSinhumans人體心癮觀察及HANS抗心癮作用Druguseover1year(aver4.6y);Detoxificationover1month;Male,Aver25y;n=29-30Cravingscore(VAS)30minperdayPre-HANSHANS-treatingPost-HANS102030100Hz2HzMock2/100Hz0012345Norelapseover1yearClinicalBaseMethodofDetox.HANSforRehabSuccessover1yearSuccessRateHainanHANSYes11/56Ca20%ShanghaiHANSandothersYes9/100Ca10%CantonHANSNotconstant9-20/500Ca2-4%Norelapseover1year一年不復(fù)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美國權(quán)威性“物質(zhì)濫用”教科書JoyceLowinson等主編第4版，2004“針刺戒毒”一章由韓濟生編寫肥胖癥能量代謝失衡對美食的渴求藥物成癮身體依賴：戒斷癥狀精神依賴：心癮痛與鎮(zhèn)痛感知功能情緒反應(yīng)肥胖的發(fā)展趨勢肥胖發(fā)病機理GenesEnvironmentalfactors

HANS治療肥胖癥：人體研究結(jié)果048121620242832-4-3-2-10

AHANSB

CHANSDn=16Time(week)ABCD-4-3-2-10******HANS(3time/week)Changeofbodyweight(kg)梁門，一對。天樞，一對。水道，一對。梁丘，公孫。頻率：2/100Hz每周3次每次30分鐘大鼠實驗結(jié)果（高能食物引起肥胖）

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