基底神经节疾病优质课件

基底神经节疾病基底神经节疾病Outline1.IntroductionofbasalgangliaOverviewandfunction,structure,andconnections2.DisordersofbasalgangliaParkinson’sdiseaseHuntington’sdisease(symptomatology,pathology,pothogenesis,treatment…)Outline1.Introductionofbasal1.IntroductionofbasalgangliaOverviewandfunctionStructureConnections

1.IntroductionofbasalgangliThe

basalganglia

areagroupofnucleiinthebraininterconnectedwiththecerebralcortex,thalamusandbrainstem.

Functions:

motorcontrol,cognition,emotions,andlearning.Thebasalgangliaareagroup锥体系统锥体系统internalglobuspallidus(GPi)externalglobuspallidus(GPe)

internalglobuspallidus基底神经节疾病优质课件ConnectionsConnectionsCircuitofBasalGangliaDirectpathwayIndirectpathwayNigrostriatalpathwayCircuitofBasalGangliaDirectGlutamateGABA

Dopamine

GlutamateDirect:

Motorcortex→Putamen→GPi→Thalamus→Motorcortex

Indirect:

Motorcortex→Putamen→GPe→Subthalamicnucleus→GPi→Thalamus→MotorcortexNigrostriatalpathway:

Parscompacta→StriatumGluGABAGABAGluGluGABAGABAGluGABAGluDirect:Motorcortex→Putam2.DisordersofBasalGangliaDiminishedmovement:Parkinson’sdiseaseExcessivemovement:HuntingtondiseaseNeuropsychiatriccognitiveandbehavioraldisturbances2.DisordersofBasalGangliaParkinson’sdisease，PD"AnEssayontheShakingPalsy"EnglishphysicianJamesParkinson(1817)IntroductionPDisthemostcommonneurodegenerativedisorderafterAlzheimer'sdisease.Parkinson’sdisease，PD"AnEssaTheprevalenceis0.3inthewholepopulationinindustrializedcountries,risingto1%inthoseover60yearsofageandto4%ofthepopulationover80.Meanageofonsetisaround60years,although5-10%ofcasesareconsideredofyoungonset(theageof20and50).Theincidenceisbetween8and18per100.000person-years.EpidemiologyTheprevalenceis0.3inthewMonographbyJamesParkinson1817SymptomatologyMovementdisorders:restingtremormusclerigiditybradykinesiaandposturalinstability

ParkinsonismCognitiveandneurobehavioralproblems(dementia)Sensoryandsleepdifficulties

chronicandprogressiveMonographbyJamesParkinsonSyTherelationshipofthebasalgangliatothemajorcomponentsofthemotorsystem.

TherelationshipofthebasalOriginsandterminationsof(a)thecorticospinaltractand(b)therubrospinaltract.Originsandterminationsof(a正常年青人，黑质细胞数为42.5万

正常80岁老人，黑质细胞数减少到20.0万

PD病人黑质细胞数减少到少于10.0万

LewybodyPathology正常年青人，黑质细胞数为42.5万

正常80岁老人，黑质细胞Etiology

Etiology

PathogenesisCircuitdisorderofBasalGangliaGeneticDopamineoxidativestressToxinsOthersPathogenesisCircuitdisorderoCircuitdisorderofBasalGangliainhibitionofthedirectpathwayexcitationoftheindirectpathwayCircuitdisorderofBasalGang基底神经节疾病优质课件多巴胺神经元为何会发生黑质部选择性的退行性变呢？氧化应激损伤1、外源性毒物的侵入2、神经黑色素的存在3、DA的氧化应激代谢4、清除自由基的能力不全多巴胺神经元为何会发生黑质部选择性的退行性变呢？氧化应激损伤图31-5多巴胺在神经元中的酶代谢及其代谢产物引自金国章,脑内多巴胺的生物医学1998年Fe2+Fe3+O2O2·¯Fe2+Fe3+O2O2·¯H2O2多巴胺半醌多巴胺醌DAO2MAODOPACH2O2HVACOMTDopamineoxidativestress图31-5多巴胺在神经元中的酶代谢及其代谢产物Fe2+FeDopamineoxidativestressDopamineoxidativestressToxinsRotenone(aninsecticide)MPTP1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine（1-甲基-4-苯基-1,2,3,6-四氢吡啶）Paraquat(aherbicide)6-Hydroxydopamine(6-OHDA)

HeavymetalsToxinsRotenone(aninsecticideRotenoneRotenoneMPTPMPTPParaquatParaquat6-Hydroxydopamine,or6-OHDA

6-Hydroxydopamine,or6-OHDATheneurotoxinsusedinanimalmodelsofPDinducemitochondrialdysfunction.Theneurotoxinsusedinanimal一种理想的动物模型应该符合下列5种标准：

1.出生时，应有正常而完整的DAneurons，并在成年期开始逐渐退化丧失且超过50%。

2.具有容易检测的运动功能障碍。

3.Lewybodies的形成。

4.如模式是genetic，应以单一点突变为基础。

5.较短的时程，约数月。一种理想的动物模型应该符合下列5种标准：

1.出生时，应有基底神经节疾病优质课件Geneticmitochondrialdysfunction,oxidativedamage,abnormalproteinaccumulationandproteinphosphorylation

Geneticmitochondrialdysfuncti1.Synuclein(SNCA)/PARK1seenmainlyinpresynapticterminalsincludeα,βandγ-synucleinplayaroleinsynapticvesiclerecycling,storageandcompartmentalizationofneurotransmittersandassociateswithvesicularandmembranousstructures1.Synuclein(SNCA)/PARK1seenmSer129的磷酸化

-synuclein基因的倍增

Ser129的磷酸化

-synuclein基因的倍增Overviewofthea-synaggregationprocessintegratedwiththeoxidativestresspathwayandtheUPP.Overviewofthea-synaggregatParkinfunctionsasanE3ubiquitinproteinligasebytargetingmisfoldedproteinstotheubiquitnproteasomepathwayfordegradation,andthelossofitsE3ligaseactivityduetomutationsleadtoautosomalrecessiveearly-onsetPD.2.Parkin/PARK2ParkinfunctionsasanE3ubiqubiquitinproteasomesystem，UPS

ubiquitinproteasomesystem，UP3.PINK1(PTEN-inducedputativekinase1)/PARK6serine–threoninekinase(mitochondria)apivotalregulatorofmitochondrialquality3.PINK1(PTEN-inducedputative4.UCH-L1/PARK5utativekinase1(PINK1)Ubiquitincarboxyl-terminalhydrolaseL1neuron-specificproteinPGP9.5oneofthemostabundantproteinsinthebrain(2%)hydrolyticactivity,ligaseactivityandbindingmono-ub4.UCH-L1/PARK5utativekinase1PossibleroleofUCH-L1inPD.PossibleroleofUCH-L1inPD.基底神经节疾病优质课件基底神经节疾病优质课件Mechanismsofneurotoxicant-inducedproteasomedysfunctionanddopaminergicdegeneration.Mechanismsofneurotoxicant-inTransgenicanimalmodelalpha-synucleinA30P+A53T,LRRK2(R1441G),parkin,R621Csynphilin-1…mouse,C.elegans,Drosophila,zebrafish

Transgenicanimalmodelalpha-Inflammation

Neuroinflammationismediatedpredominatelybymicroglia,theresidentimmuno-competentandphagocyticcellswithintheCNS.Microglia,representing5−20%ofbraincellsMicroglialcelldensityintheSNis4−5timeshigherthaninotherregionsActivatedcellsalsoproducepro-inflammatorymoleculesInflammation

Neuroinflammation基底神经节疾病优质课件Schematicrepresentationoflipopolysaccharide(LPS)-inducedandglialactivation-mediateddopamine(DA)neurodegeneration.SchematicrepresentationoflKeymolecularmechanismsthatarewidelyacceptedtocontributetotheneurodegenerativeprocessindopaminergicneuronsinthesubstantianigrainParkinsondisease.KeymolecularmechanismsthatAtleasttwoofthethreemajorsymptomsarepresent.PossiblecausesforsymptomsResponsetolevodopaThemaintoolsusedtomakeadiagnosis:NeurologicalexaminationMotorphysiologytestsNeuro-imaging:PET(18-flurodopa),CT,MRI

Lewybodiesduringautopsy(goldstandard)

DiagnosisAtleasttwoofthethreemajo基底神经节疾病优质课件Treatment

ThereisnoknowncureforParkinson'sdisease.Treatmentisaimedatcontrollingthesymptoms.Medicationscontrolsymptomsprimarilybycontrollingtheimbalancebetweenthetransmitters.TreatmentThereisnoknownTherapeuticstrategyDirectlyimprovethefunctionofdopamineneurotransmissionIndirectlyimprovethefunctionofdopamineSurgeryanddeepbrainstimulationTherapeuticstrategyDirectlyidopamine↑inthebrain

PrecursorRate-limitingstep,decreaseinPDL-dopadopamine↑inthebrainPrecursPeripheralinhibitorsThecentralandperipheralmetabolismoflevodopaanditsmodificationbydrugs.PeripheralinhibitorsThecentreasilypassthroughtheblood-brainbarrieristransformedintodopamineinthedopaminergicneuronsbyDDCisoftenmetabolisedtoDAelsewhere,causingawidevarietyofsideeffectsCOMTinhibitors,MAO-BinhibitorsL-dopaeasilypassthroughtheblood-Long-termeffectsofL-DOPA：

On/offoscillationsDosefailure(drugresistance)DopaminedysregulationsyndromeLong-termeffectsofL-DOPA：Ach:

movementAchincreasesinhibitionoｆ

GABＡ．Adenosine:movementAdenosineincreasetheeffectsofAchontheGABAergicneurons;AdenosinecounterD2receptoractivity;AdenosinereducesGABArelease.Ach:movementEnkephalinDynorphinPeptidemodulationofstriatalinputtotheglobuspollidus.EnkephalinPeptidemodulationPallidotomyandSubthalamotomy

PallidotomyandSubthalamotomySurgeryisusedinpeoplewithadvancedPDforwhomdrugtherapyisnolongersufficient.Becausetheseprocedurescausepermanentdestructionofbraintissue,theyhavelargelybeenreplacedbydeepbrainstimulation(DBS)fortreatmentofParkinson'sdisease.SurgeryisusedinpeoplewithDBSisprimarilyusedtostimulateoneofthreebrainregions:thesubthalamicnucleus,theglobuspallidus,orthethalamus.DBSisprimarilyusedtostimuResearchdirections

Animalmodels

Genetherapy(virus)Neuroprotectivetreatments

(GDNF)Neuraltransplantation

Stemcellstransplantshaveraisedgreatrecentinterest.Whentransplantedintothebrainsofrodentsandmonkeystheysurviveandimprovebehavioralabnormalities.Neverthelesswhilefetalstemcellsaretheeasiesttomanipulatetheiruseiscontroversial.Suchcontroversymaybeovercomewiththeuseofinducedpluripotentstemcellsfromadults.

ResearchdirectionsAnimalmodAschemeofthegenerationofinducedpluripotentstem(iPS)cells.

(1)Isolateandculturedonorcells.(2)Transfectstemcell-associatedgenesintothecellsbyviralvectors.Redcellsindicatethecellsexpressingtheexogenousgenes.(3)HarvestandculturethecellsaccordingtoEScellculture,usingmitoticallyinactivatedfeedercells(lightgray).(4)AsmallsubsetofthetransfectedcellsbecomeiPScellsandgenerateES-likecolonies.

Aschemeofthegenerationof主要讲解的内容:1．

基底神经节的脑内组成的核团、它们的分布、主要通路的组成及其参与调节每条通路中的神经递质及其功能。2．

基底神经节（黑质）损伤后的主要临床表现及其病理表现的关系。3．PD脑内黑质多巴胺神经元退化的机制研究。4．Parkinson’sDisease(PD)的治疗方案及治疗基础。主要讲解的内容:思考题：1．Whatarethecomponentsofthebasalganglia?2．Howarethestructuresofthebasalgangliaconnected?3．Describethecorticostriatalprojections.4．Describetheconnectionsbetweensubthalamusandglobuspallidus.5．Describetheimportanceofthenigrastritalpathways.6．Whatistheroleofthebasalgangliainrelationtothemotorthalamus?7．Whataretheprincipalneurotransmittersandreceptorsassociatedwiththebasalganglia?8．Adisorderofthebasalgangliaisindicatedwhatsigns?9．CanadministrationofdopaminecureParkinson’sdisease?Why?10.DescribetheetiologyofneurodegenerationinthesubstantianigrainPD.11.WhydoselesioningtheSThnorGPreducethesymptomsofPD?

思考题：Huntington'sdisease(HD)In1872GeorgeHuntingtonthoroughlydescribedthedisorderinhisfirstpaper"OnChorea".IntroductionTheworldwideprevalenceofHDis5-10casesper100,000persons.

Itusuallyappearsinmiddleage(30-50years)EpidemiologyHuntington'sdisease(HD)IntroHD/chorea

isaninherited（autosomaldominantinheritance）progressiveneurodegenerativedisorder,whichaffectsmusclecoordinationandleadstocognitivedeclineanddementia.Ittypicallybecomesnoticeableinmiddleage.abnormalitiesinperipheraltissues(muscleatrophy,cardiacfailure,impairedglucosetolerance…)SymptomatologyHD/choreaisaninherited（aProminentcelllossandatrophyinstriatum.astrocytes↑PathologynuclearandcytoplasmicinclusionsProminentcelllossandatrophPathogenesisPathogenesisPathogenesisPathogenesisHttisexpressedinallmammaliancells.(brain)interactswithover100otherproteins,andappearstohavemultiplebiologicalfunctions.embryonicdevelopment,anti-apoptosis,controlingtheproductionofBDNF,facilitatingvesiculartransportandsynaptictransmission,andcontrolingneuronalgenetranscription.Pathogenesis1.LossofHttfunction

2.ToxicfunctionofmHttHttisexpressedinallmammal基底神经节疾病优质课件GlutamateGABA

Dopamine

GlutamateDiagnosis

typicalsymptomsafamilyhistoryofthediseasegenetictestingtohavetheexpandedtrinucleotiderepeatphysicalexamination,psychologicalexamination,Medicalimaging

DiagnosistypicalsymptomsThereisnoknowncureforHD.Treatmentisaimedatcontrollingthesymptoms.tetrabenazine(chorea)antipsychoticdrugs

TreatmentThereisnoknowncureforHD.Prognosis

Thelengthofthetrinucleotiderepeataccountsfor60%ofthevariationintheageofonsetandtherateofprogressionofsymptoms.Alongerrepeatresultsinanearlierageofonsetandafasterprogressionofsymptoms.

LifeexpectancyinHDisgenerallyaround20

yearsfollowingtheonsetofvisiblesymptoms.PrognosisThelengthofthetrResearchdirections

Appropriateanimalmodels(transgenicanimals)Geneticallyengineeredintrabodies(aninhibitionofmHttaggregation)havebeenshowntopreventmortalityduringthedevelopment

stagesofDrosophilamodels.Genesilencing(mHttisreduced)StemcelltherapyNumerousdrugsResearchdirectionsAppropriatThankyou！Thankyou！基底神经节疾病基底神经节疾病Outline1.IntroductionofbasalgangliaOverviewandfunction,structure,andconnections2.DisordersofbasalgangliaParkinson’sdiseaseHuntington’sdisease(symptomatology,pathology,pothogenesis,treatment…)Outline1.Introductionofbasal1.IntroductionofbasalgangliaOverviewandfunctionStructureConnections

1.IntroductionofbasalgangliThe

basalganglia

areagroupofnucleiinthebraininterconnectedwiththecerebralcortex,thalamusandbrainstem.

Functions:

motorcontrol,cognition,emotions,andlearning.Thebasalgangliaareagroup锥体系统锥体系统internalglobuspallidus(GPi)externalglobuspallidus(GPe)

internalglobuspallidus基底神经节疾病优质课件ConnectionsConnectionsCircuitofBasalGangliaDirectpathwayIndirectpathwayNigrostriatalpathwayCircuitofBasalGangliaDirectGlutamateGABA

Dopamine

GlutamateDirect:

Motorcortex→Putamen→GPi→Thalamus→Motorcortex

Indirect:

Motorcortex→Putamen→GPe→Subthalamicnucleus→GPi→Thalamus→MotorcortexNigrostriatalpathway:

Parscompacta→StriatumGluGABAGABAGluGluGABAGABAGluGABAGluDirect:Motorcortex→Putam2.DisordersofBasalGangliaDiminishedmovement:Parkinson’sdiseaseExcessivemovement:HuntingtondiseaseNeuropsychiatriccognitiveandbehavioraldisturbances2.DisordersofBasalGangliaParkinson’sdisease，PD"AnEssayontheShakingPalsy"EnglishphysicianJamesParkinson(1817)IntroductionPDisthemostcommonneurodegenerativedisorderafterAlzheimer'sdisease.Parkinson’sdisease，PD"AnEssaTheprevalenceis0.3inthewholepopulationinindustrializedcountries,risingto1%inthoseover60yearsofageandto4%ofthepopulationover80.Meanageofonsetisaround60years,although5-10%ofcasesareconsideredofyoungonset(theageof20and50).Theincidenceisbetween8and18per100.000person-years.EpidemiologyTheprevalenceis0.3inthewMonographbyJamesParkinson1817SymptomatologyMovementdisorders:restingtremormusclerigiditybradykinesiaandposturalinstability

ParkinsonismCognitiveandneurobehavioralproblems(dementia)Sensoryandsleepdifficulties

chronicandprogressiveMonographbyJamesParkinsonSyTherelationshipofthebasalgangliatothemajorcomponentsofthemotorsystem.

TherelationshipofthebasalOriginsandterminationsof(a)thecorticospinaltractand(b)therubrospinaltract.Originsandterminationsof(a正常年青人，黑质细胞数为42.5万

正常80岁老人，黑质细胞数减少到20.0万

PD病人黑质细胞数减少到少于10.0万

LewybodyPathology正常年青人，黑质细胞数为42.5万

正常80岁老人，黑质细胞Etiology

Etiology

PathogenesisCircuitdisorderofBasalGangliaGeneticDopamineoxidativestressToxinsOthersPathogenesisCircuitdisorderoCircuitdisorderofBasalGangliainhibitionofthedirectpathwayexcitationoftheindirectpathwayCircuitdisorderofBasalGang基底神经节疾病优质课件多巴胺神经元为何会发生黑质部选择性的退行性变呢？氧化应激损伤1、外源性毒物的侵入2、神经黑色素的存在3、DA的氧化应激代谢4、清除自由基的能力不全多巴胺神经元为何会发生黑质部选择性的退行性变呢？氧化应激损伤图31-5多巴胺在神经元中的酶代谢及其代谢产物引自金国章,脑内多巴胺的生物医学1998年Fe2+Fe3+O2O2·¯Fe2+Fe3+O2O2·¯H2O2多巴胺半醌多巴胺醌DAO2MAODOPACH2O2HVACOMTDopamineoxidativestress图31-5多巴胺在神经元中的酶代谢及其代谢产物Fe2+FeDopamineoxidativestressDopamineoxidativestressToxinsRotenone(aninsecticide)MPTP1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine（1-甲基-4-苯基-1,2,3,6-四氢吡啶）Paraquat(aherbicide)6-Hydroxydopamine(6-OHDA)

HeavymetalsToxinsRotenone(aninsecticideRotenoneRotenoneMPTPMPTPParaquatParaquat6-Hydroxydopamine,or6-OHDA

6-Hydroxydopamine,or6-OHDATheneurotoxinsusedinanimalmodelsofPDinducemitochondrialdysfunction.Theneurotoxinsusedinanimal一种理想的动物模型应该符合下列5种标准：

1.出生时，应有正常而完整的DAneurons，并在成年期开始逐渐退化丧失且超过50%。

2.具有容易检测的运动功能障碍。

3.Lewybodies的形成。

4.如模式是genetic，应以单一点突变为基础。

5.较短的时程，约数月。一种理想的动物模型应该符合下列5种标准：

1.出生时，应有基底神经节疾病优质课件Geneticmitochondrialdysfunction,oxidativedamage,abnormalproteinaccumulationandproteinphosphorylation

Geneticmitochondrialdysfuncti1.Synuclein(SNCA)/PARK1seenmainlyinpresynapticterminalsincludeα,βandγ-synucleinplayaroleinsynapticvesiclerecycling,storageandcompartmentalizationofneurotransmittersandassociateswithvesicularandmembranousstructures1.Synuclein(SNCA)/PARK1seenmSer129的磷酸化

-synuclein基因的倍增

Ser129的磷酸化

-synuclein基因的倍增Overviewofthea-synaggregationprocessintegratedwiththeoxidativestresspathwayandtheUPP.Overviewofthea-synaggregatParkinfunctionsasanE3ubiquitinproteinligasebytargetingmisfoldedproteinstotheubiquitnproteasomepathwayfordegradation,andthelossofitsE3ligaseactivityduetomutationsleadtoautosomalrecessiveearly-onsetPD.2.Parkin/PARK2ParkinfunctionsasanE3ubiqubiquitinproteasomesystem，UPS

ubiquitinproteasomesystem，UP3.PINK1(PTEN-inducedputativekinase1)/PARK6serine–threoninekinase(mitochondria)apivotalregulatorofmitochondrialquality3.PINK1(PTEN-inducedputative4.UCH-L1/PARK5utativekinase1(PINK1)Ubiquitincarboxyl-terminalhydrolaseL1neuron-specificproteinPGP9.5oneofthemostabundantproteinsinthebrain(2%)hydrolyticactivity,ligaseactivityandbindingmono-ub4.UCH-L1/PARK5utativekinase1PossibleroleofUCH-L1inPD.PossibleroleofUCH-L1inPD.基底神经节疾病优质课件基底神经节疾病优质课件Mechanismsofneurotoxicant-inducedproteasomedysfunctionanddopaminergicdegeneration.Mechanismsofneurotoxicant-inTransgenicanimalmodelalpha-synucleinA30P+A53T,LRRK2(R1441G),parkin,R621Csynphilin-1…mouse,C.elegans,Drosophila,zebrafish

Transgenicanimalmodelalpha-Inflammation

Neuroinflammationismediatedpredominatelybymicroglia,theresidentimmuno-competentandphagocyticcellswithintheCNS.Microglia,representing5−20%ofbraincellsMicroglialcelldensityintheSNis4−5timeshigherthaninotherregionsActivatedcellsalsoproducepro-inflammatorymoleculesInflammation

Neuroinflammation基底神经节疾病优质课件Schematicrepresentationoflipopolysaccharide(LPS)-inducedandglialactivation-mediateddopamine(DA)neurodegeneration.SchematicrepresentationoflKeymolecularmechanismsthatarewidelyacceptedtocontributetotheneurodegenerativeprocessindopaminergicneuronsinthesubstantianigrainParkinsondisease.KeymolecularmechanismsthatAtleasttwoofthethreemajorsymptomsarepresent.PossiblecausesforsymptomsResponsetolevodopaThemaintoolsusedtomakeadiagnosis:NeurologicalexaminationMotorphysiologytestsNeuro-imaging:PET(18-flurodopa),CT,MRI

Lewybodiesduringautopsy(goldstandard)

DiagnosisAtleasttwoofthethreemajo基底神经节疾病优质课件Treatment

ThereisnoknowncureforParkinson'sdisease.Treatmentisaimedatcontrollingthesymptoms.Medicationscontrolsymptomsprimarilybycontrollingtheimbalancebetweenthetransmitters.TreatmentThereisnoknownTherapeuticstrategyDirectlyimprovethefunctionofdopamineneurotransmissionIndirectlyimprovethefunctionofdopamineSurgeryanddeepbrainstimulationTherapeuticstrategyDirectlyidopamine↑inthebrain

PrecursorRate-limitingstep,decreaseinPDL-dopadopamine↑inthebrainPrecursPeripheralinhibitorsThecentralandperipheralmetabolismoflevodopaanditsmodificationbydrugs.PeripheralinhibitorsThecentreasilypassthroughtheblood-brainbarrieristransformedintodopamineinthedopaminergicneuronsbyDDCisoftenmetabolisedtoDAelsewhere,causingawidevarietyofsideeffectsCOMTinhibitors,MAO-BinhibitorsL-dopaeasilypassthroughtheblood-Long-termeffectsofL-DOPA：

On/offoscillationsDosefailure(drugresistance)DopaminedysregulationsyndromeLong-termeffectsofL-DOPA：Ach:

movementAchincreasesinhibitionoｆ

GABＡ．Adenosine:movementAdenosineincreasetheeffectsofAchontheGABAergicneurons;AdenosinecounterD2receptoractivity;AdenosinereducesGABArelease.Ach:movementEnkephalinDynorphinPeptidemodulationofstriatalinputtotheglobuspollidus.EnkephalinPeptidemodulationPallidotomyandSubthalamotomy

PallidotomyandSubthalamotomySurgeryisusedinpeoplewithadvancedPDforwhomdrugtherapyisnolongersufficient.Becausetheseprocedurescausepermanentdestructionofbraintissue,theyhavelargelybeenreplacedbydeepbrainstimulation(DBS)fortreatmentofParkinson'sdisease.SurgeryisusedinpeoplewithDBSisprimarilyusedtostimulateoneofthreebrainregions:thesubthalamicnucleus,theglobuspallidus,orthethalamus.DBSisprimarilyusedtostimuResearchdirections

Animalmodels

Genetherapy(virus)Neuroprotectivetreatments

(GDNF)Neuraltransplantation

Stemcellstransplantshaveraisedgreatrecentinterest.Whentransplantedintothebrainsofrodentsandmonkeystheysurviveandimprovebehavioralabnormalities.Neverthelesswhilefetalstemcellsaretheeasiesttomanipulatetheiruseiscontroversial.Suchcontroversymaybeovercomewiththeuseofinducedpluripotentstemcellsfromadults.

ResearchdirectionsAnimalmodAschemeofthegenerationofinducedpluripotentstem(iPS)cells.

(1)Isolateandculturedonorcells.(2)Transfectstemcell-associatedgenesintothecellsbyviralvectors.Redcellsindicatethecellsexpressingtheexogenousgenes.(3)HarvestandculturethecellsaccordingtoEScellculture,usingmitoticallyinactivatedfeedercells(lightgray).(4)AsmallsubsetofthetransfectedcellsbecomeiPScellsandgenerateES-likecolonies.

Aschemeofthegenerationof主要讲解的内容:1．

基底神经节的脑内组成的核团、它们的分布、主要通路的组成及其参与调节每条通路中的神经递质及其功能。2．

基底神经节（黑质）损伤后的主要临床表现及其病理表现的关系。3．PD脑内黑质多巴胺神经元退化的机制研究。4．Parkinson’sDisease(PD)的治疗方案及治疗基础。主要讲解的内容:思考题：1．Whatarethecomponentsofthebasalganglia?2．Howarethestructuresofthebasalgangliaconnected?3．Describethecorticostriatalprojections.4．Describetheconnectionsbetweensubthalamusandglobuspallidus.5．Describetheimportanceofthenigrastritalpathways.6．Whatistheroleofthebasalgangliainrelationtothemotorthalamus?7．Whataretheprincipalneurotransmittersandreceptorsassociatedwiththebasalganglia?8．Adisorderofthebasalgangliaisindicatedwhatsigns?9．Canadministrationofdopamine