光遗传技术比较好的一篇nature综述_精品文档.pdf

光遗传技术比较好的一篇nature综述_精品文档.pdf

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298VOLUME15|NUMBER2|FEBRUARY2012natureneurOSCIenCeartICleSRetinalganglioncell（RGC）projectionstothebrainformstereo-typicmapsforeyeoforiginandretinotopiclocation,makingthemanidealmodelsystemtostudythedevelopmentandplasticityofpreciselypatternedneuralcircuits1,2.Theinitialformationofthesevisualcircuitsisthoughttobeguidedbymolecularcues3,whereastherefinementandmaintenance46oftheseconnectionsseemstobeactivitydependent7.Substantialevidencesupportsageneralroleforactivity-dependentbinocularcompetitioninretinofugalmapdevel-opment.Forinstance,arelativeincreaseinactivityinoneeyeleadstotheexpansionofthateyestargetterritoryinthedorsallateralgenicu-latenucleus（dLGN）8,9,indicatingthatthemoreactiveeyemakesandfurtherstrengthensmoretargetsynapseswhenitisatacompeti-tiveadvantage.Hebbiansynapticlearningrulesthatmaymediatetheactivity-dependentdevelopmentofvisualmapshavebeenobservedinavarietyofretinofugalsystems,includingspike-timingdependentplasticityatretinotectalsynapsesintadpolesinvivo10andbursttimingdependentplasticityatretinogeniculate11andretinocollicular12synapsesinrodentsinvitro.Theseobservationssuggestthatsynapticconnectionsarefunctionallystrengthenedwhencellsaresynchronouslyactiveandweakenedwhencellsareasynchronouslyactiveovertimewindowsthataredistinctindifferentmodelsystems13.Ithaslongbeenpostulatedthatthetimingofspontaneouswave-likeactivityinRGCs14iscriticalfortheestablishmentandmaintenanceofeye-specificsegregationthroughaHebb-basedsynapticlearningrule11,13beforetheonsetofvision.Theshortdurationofretinalwavesrelativetotheintervalbetweenwavesisthoughttoasynchronouslyactivatethetwoeyes,resultingintherefinementofeye-specificdomains15.Evidenceforthistimingmodelforbinocularcompetitionislimited,withtheonlydirectexperimentalsupportcomingfromclassiccatexperimentsinwhichartificiallyasynchronousstimulationoftheopticnervesproducedneuronsthatrespondedpredominantlytoonlyoneeye,whereasstimulationoftheoptictract,whichsynchro-nouslyactivatesRGCafferentsfrombotheyes,causedmostcellsinvisualcortextobecomefunctionallybinocular16.Similarly,alternat-ingmonocularocclusionincatsresultsinreducedcorticalbinocular-ityanddisrupteddepthdiscrimination17.However,theseexperimentswererestrictedtoaphysiologicalanalysisofbinocularityinthecortexandmanipulatedRGCactivityaftertheonsetofnormalvisualexperi-ence,wheneyesegregationinthedLGNandvisualcortexhasalreadyemerged2,18.Becauseithasbeendifficulttopreciselymanipulateneo-natalRGCactivityinmammalsinvivo,theroleoftimingintheinitialdevelopmentofvisualmapsremainsunexplored.Wechronicallymanipulatedretinalactivityinmicebeforetheonsetofvisionoverarangeoftimescalesinvivobyexpressingthelight-gatedcationchannelChannelrhodopsin-2（ChR2）19directlyinRGCsusingtransgenicandviraltransfectionmethods20,21.Light-drivenactivationofChR2-expressingRGCstriggeredpreciselytimedpost-synapticcalciumsignalsinthesuperiorcolliculus,demonstratingthatoptogenetictechniquescanreliablydriveneuronalresponseevenearlyinvisualdevelopment.Whenthetwoeyesweresynchronouslystimu-lated,wefoundthattheinitialemergenceofeye-specificdomainswasdisrupted,whereasasynchronousstimulationimprovedsegregation.Aftereye-specificdomainswerealreadyestablishedinthesuperiorcolliculusanddLGN,asynchronousstimulationhadnoeffect,butsyn-chronousstimulationcauseddomainstodesegregate.Thedisruptiveeffectofoptogeneticstimulationoneyesegregationwanedasthetimedifferencebetweenstimulationoftheeyesincreasedbeyond100ms,whichsuggestsasub-secondtimewindowforbinocularcompeti-tion.Ofnote,whensynchronousstimulationdisruptedeye-specific1DepartmentofNeurobiology,YaleUniversity,NewHaven,Connecticut,USA.2DepartmentofOphthalmology&VisualSciences,YaleUniversity,NewHaven,Connecticut,USA.CorrespondenceshouldbeaddressedtoM.C.C.（michael.crairyale.edu）.Received8September;accepted9November;publishedonline18December2011;doi:

10.1038/nn.3007VisualmapdevelopmentdependsonthetemporalpatternofbinocularactivityinmiceJiayiZhang1,JamesBAckman1,Hong-PingXu1&MichaelCCrair1,2Binocularcompetitionisthoughttodriveeye-specificsegregationinthedevelopingvisualsystem,potentiallythroughHebbiansynapticlearningrulesthataresensitivetocorrelationsinafferentactivity.Alteringretinalactivitycandisrupteye-specificsegregation,butlittleisknownaboutthetemporalfeaturesofbinocularactivitythatmodulatevisualmapdevelopment.Weusedoptogenetictechniquestodirectlymanipulateretinalactivityinvivoandidentifiedacriticalperiodbefor