Adult-Generated Hippocampal Neurons Allow the Flexible Use of Spatially Precise Learning Strategies 英文参考文献.docVIP

Adult-GeneratedHippocampalNeuronsAllowthe FlexibleUseofSpatiallyPreciseLearningStrategies AlexanderGarthe1,JoachimBehr2,GerdKempermann1* 1CRTD–CenterforRegenerativeTherapiesDresden,Dresden,Germany,2DepartmentofPsychiatry,Charite′ UniversityMedicine,Berlin,Germany Abstract Despiteenormousprogressinthepastfewyearsthespecificcontributionofnewlyborngranulecellstothefunctionofthe adulthippocampusisstillnotclear.Wehypothesizedthatinordertosolvethisquestionparticularattentionhastobepaid tothespecificdesign,theanalysis,andtheinterpretationofthelearningtesttobeused.Wethusdesignedabehavioral experiment along hypotheses derived from a computational model predicting that new neurons might be particularly relevant for learning conditions, in which novel aspects arise in familiar situations, thus putting high demands on the qualitative aspects of (re-)learning. In the reference memory version of the water maze task suppression of adult neurogenesiswithtemozolomide(TMZ)causedahighlyspecificlearningdeficit.Miceweretestedinthehiddenplatform versionoftheMorriswatermaze(6trialsperdayfor5dayswithareversaloftheplatformlocationonday4).Testingwas doneat4weeksaftertheendoffourcyclesoftreatmenttominimizethenumberofpotentiallyrecruitablenewneuronsat thetimeoftesting.ThereductionofneurogenesisdidnotalterlongtermpotentiationinCA3andthedentategyrusbut abolishedthepartofdentategyrusLTPthatisattributedtothenewneurons.TMZdidnothaveanyovertsideeffectsatthe time of testing, and both treated mice and controls learned to find the hidden platform. Qualitative analysis of search strategies, however, revealedthattreated mice did notadvance tospatiallyprecise search strategies, in particularwhen learning a changed goal position (reversal). New neurons in the dentate gyrus thus seem to be necessary for adding flexibilitytosomehippocampus-dependentqualitativeparametersoflearning. Ourfindingthatalackofadult-generated granule cells specifically results in the animal’s inability to precisely locat