神經生物學的理論概述及神經系統(tǒng)疾病的研究課件

神經生物學

神經生物學的理論概述及神經系統(tǒng)疾病的研究學習方法英語教科書：是壓力，有后勁以學習名詞為主，要敢于發(fā)音綜合學科：multidisciplinary以功能為主，結合形態(tài)以基礎為主，結合臨床教科書內容與講課內容可能不完全一致， 但鼓勵看書（教科書），借機學習專業(yè)英語。百年來與神經科學有關的諾貝爾獎獲得者選介(I)C.S.Sherrington(英)18571850190019502000C.Golgi(意)19261934神經元染色方法18431852R.Cajal(西班牙)“神經元學說”形態(tài)190619521932?“突觸”定名?“反射”概念?“交互”抑制反射學說生理電生理18891977?感覺神經纖維電活動?傳入沖動大腦誘發(fā)電位?神經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）神經化學?蛙心灌流實驗?“迷走物質”19681875H.Dale(英)?神經末梢分泌?乙酰膽堿ACh神經化學18741965194419631888J.Erlanger(美)H.S.Gasser(美)?陰極射線示波器?神經纖維的分類ABC19731881W.R.Hess(瑞士)?腦立體定位儀hypothalamus方法學創(chuàng)新1949電生理OxfCambridge徒手切腦片銀染神經元染出神經末梢，發(fā)現神經元之間無原生質聯系生理科學進展2001，32：187神經藥理學分子藥理學百年來與神經科學有關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)?細胞內微電極?突觸后電位?抑制性遞質突觸?電壓鉗技術?動作電位的離子學說?數學方程表述?NM終板電位?遞質“量子釋放”1911動作電位機制19051983U.VonEuler(瑞典…)?交感神經遞質?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）神經化學1913(左右腦)R.W.Sperry(美)1981“腦功能側化”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?膜片鉗技術?單個離子通道電流記錄1999英，澳CambridgeCambridgeLeviMontalcini1986NervegrowthFactor(NGF)(Italy)百年來與神經科學有關的諾貝爾獎獲得者選介(3)1850190019502000192619232000P.Greengard(美)1930E.Kandel(美)A.Carlsson(瑞典)神經系統(tǒng)中的信號轉導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:《生理學報》70%論文屬神經生理 1927年創(chuàng)刊(上海生理所)《中國神經科學雜志》1998年創(chuàng)刊(上海二軍大)《中國疼痛醫(yī)學雜志》1995年創(chuàng)刊(北醫(yī)大)《中國神經解剖雜志》1985年創(chuàng)刊(四軍大解剖系）大型專著:《神經科學綱要》1993年北醫(yī)大韓濟生主編 (156萬字)

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

國家自然科學基金重大課題2項(神經肽,視覺信息 加工）200萬

國家自然科學基金委重點課題12項(每項50-90萬) 973項目兩項（1999-）（2000萬）(3400萬)差距:分子神經生物學,發(fā)育神經生物學 (美國2.5萬)(IBRO3萬會員,1999年以色列)北醫(yī)大神經科學的發(fā)展神經解剖: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)大神經痛與鎮(zhèn)痛1965-(韓濟生,湯健,任民峰…)科學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:癲癇的發(fā)病原理與治療(吳希如)神經內科:神經肌肉病,腦血管意外,語言障礙(陳清棠)六院精神病學:抑郁癥,酒精成癮(沈漁邨)神經科學進展(2000海內外中青年)神經發(fā)育,衰老與再生(Neuraldevelopment,agingandregeneration)[18]離子通道與突觸傳遞(Ionchannelsandsynaptictransmission)[14]神經系統(tǒng)疾病(Neuraldiseases,PD,AD,HD,Psych)[11]感覺系統(tǒng)(Sensorysystem,Pain,Visual)[7]神經遞質,調質,轉運體和受體(Neurotransmitters,modulators,transportersandreceptors,5-HT,)[4]神經免疫與神經內分泌(Neuroimmunologyandneuroendocrine)新技術(Newtechnology)[2]學習與記憶(Learningandmemory)[2]運動系統(tǒng)(Motorsystem)[2] [62] 神經發(fā)育與再生神經營養(yǎng)因子突觸發(fā)生及其可塑性(蒲慕明,魯白)神經細胞遷移的分子生物學(饒毅)神經干細胞的應用潛力(王偉業(yè))脊髓損傷的修復(徐小明)視網膜結細胞軸突再生(蘇國輝)視神經再生(陳東風)神經移植的免疫學(段維明)同源盒基因(范明) 神經系統(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.星型膠質細胞與腦缺氧(于常海)巴甫洛夫：非條件反射巴甫洛夫：條件反射復雜的操作式條件反射人的心理活動，學習記憶，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疼痛的現代研究方法清醒動物神經元單位放電

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外側通路

thelateralpathway：ContralateralbiasIpsilateralContralateralControlSurprise(-lnp)Time(Sec)

內側通路

themedialpathway：

Bilateralunbiasedresponse

-10-50510ACC0.02.55.07.510.0-10-50510MD0.02.55.07.510.0IpsilateralContralateralControlSurprise(-lnp)Time(Sec)腦內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神經科學研究所合作者：張旭中科院神經科學研究所重點項目結題驗收匯報2003年2月22-24日StudyonChronicPainMechanismsGenePeptideProteinIn

vitroInvivoCognitive(DRG)Painrelated11229ESTNovelGenesOFQNSTEMGDNFMuORDeltaORIhIonChannelHistochemstainingCellculturePatchclampingAcutePainChronicPaininflammatoryneuropathicnervelesion

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

+++

2β-內啡肽β-endorphin311976

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

內嗎啡肽Endomorphins41997++2內源性阿片肽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應激引起復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美國權威性“物質濫用”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分鐘大鼠實驗結果（高能食物引起肥胖）

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