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Human Hippocampal Neurogenesis Persists throughout Aging
Article??in??Cell stem cell · April 2018
DOI: 10.1016/j.stem.2018.03.015
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HumanHippocampalNeurogenesisPersiststhroughoutAging
GraphicalAbstract
Highlights
d
Poolsofquiescentstemcellsaresmallerinagedhumanhippocampaldentategyri
d
Proliferatingprogenitorandimmatureneuronpoolsarestablewithaging
dAngiogenesisandneuroplasticitydeclineinolderhumansd
Granuleneurons,glia,anddentategryusvolumeareunchangedwithaging
Boldrinietal.,2018,CellStemCell22,1–11April5,2018a2018ElsevierInc.
https://doi.org/10.1016/j.stem.2018.03.015
Authors
MauraBoldrini,CamilleA.Fulmore,AlexandriaN.Tartt,...,
AndrewJ.Dwork,Rene
′Hen,J.JohnMann
Correspondence
mb928@cumc.columbia.edu
InBrief
Boldrinietal.?ndpersistentadult
neurogenesisinhumansintotheeighthdecadeoflife,despitedeclinesin
quiescentstemcellpools,angiogenesis,andneuroplasticity.Overa65-yearagespan,proliferatingneuralprogenitors,immatureandmaturegranuleneurons,glia,anddentategryusvolumewereunchanged.
Pleasecitethisarticleinpressas:Boldrinietal.,HumanHippocampalNeurogenesisPersiststhroughoutAging,CellStemCell(2018),https://doi.org/10.1016/j.stem.2018.03.015CellStemCellShortArticleHumanHippocampalNeurogenesisPersiststhroughoutAging
MauraBoldrini,1,5,9,10,*CamilleA.Fulmore,5AlexandriaN.Tartt,5LaikaR.Simeon,5InaPavlova,6VericaPoposka,8′Hen,1,3,4,6GorazdB.Rosoklija,1,5,7AleksandarStankov,8VictoriaArango,1,5AndrewJ.Dwork,1,2,5,7Rene
andJ.JohnMann1,51Department2Department
ofPsychiatry,ColumbiaUniversity,NewYork,NY10027,USA
ofPathologyandCellBiology,ColumbiaUniversity,NewYork,NY10027,USA
3DepartmentofNeuroscience,ColumbiaUniversity,NewYork,NY10027,USA4DepartmentofPharmacology,ColumbiaUniversity,NewYork,NY10027,USA
5DivisionofMolecularImagingandNeuropathology,NYSPsychiatricInstitute,NewYork,NY10032,USA6DivisionofIntegrativeNeuroscience,NYSPsychiatricInstitute,NewYork,NY10032,USA
7MacedonianAcademyofSciences&Arts,2,Ss.Cyril&MethodiusUniversity,Skopje1000,RepublicofMacedonia8InstituteforForensicMedicine,Ss.Cyril&MethodiusUniversity,Skopje1000,RepublicofMacedonia9Twitter:@DrMauraBoldrini10LeadContact
*Correspondence:mb928@cumc.columbia.eduhttps://doi.org/10.1016/j.stem.2018.03.015
SUMMARY
Adulthippocampalneurogenesisdeclinesinagingrodentsandprimates.Aginghumansarethoughttoexhibitwaningneurogenesisandexercise-inducedangiogenesis,witharesultingvolumetricdecreaseintheneurogenichippocampaldentategyrus(DG)region,althoughconcurrentchangesintheseparam-etersarenotwellstudied.Hereweassessedwhole-autopsyhippocampifromhealthyhumanindividualsrangingfrom14to79yearsofage.WefoundsimilarnumbersofintermediateneuralprogenitorsandthousandsofimmatureneuronsintheDG,compara-blenumbersofgliaandmaturegranuleneurons,andequivalentDGvolumeacrossages.Nevertheless,olderindividualshavelessangiogenesisandneuro-plasticityandasmallerquiescentprogenitorpoolinanterior-midDG,withnochangesinposteriorDG.Thus,healthyoldersubjectswithoutcognitiveimpairment,neuropsychiatricdisease,ortreatmentdisplaypreservedneurogenesis.Itispossiblethatongoinghippocampalneurogenesissustainshu-man-speci?ccognitivefunctionthroughoutlifeandthatdeclinesmaybelinkedtocompromisedcogni-tive-emotionalresilience.
INTRODUCTION
Healthyagingiscrucialinagrowingolderpopulation(UnitedStatesCensusBureau,2017).Theabilitytoseparatesimilarmemorypatterns(Sahayetal.,2011)andrecoverfromstress(Schloesseretal.,2010)maydependonadulthippocampalneu-rogenesis(AHN),whichisreportedtodeclinewithaginginnonhumanprimates(Leuneretal.,2007)andmice(BenAbdallahetal.,2007).Newneuronsaregeneratedinthedentategyrus
(DG)oftheadulthumanhippocampus,evenaftermiddleage(Erikssonetal.,1998),buttheextenttowhichneurogenesisoc-cursinhumansishighlydebatedandquantitativestudiesarescarce.
Phylogeneticdifferencesbetweenhumansandrodentsmandateassessmentofthedifferentstagesofneuronalmatura-tioninthehumanDG.Forexample,striatalneurogenesisisfoundonlyinhumans(Bergmannetal.,2015),whileolfactorybulbneurogenesisisabsentinhumans(Bergmannetal.,2012)butpresentinothermammals.PreviousanalysesofhumanAHNdidnotaddresstheeffectsofaging,althoughstudieshaveexaminedAHNinolderpopulations(Erikssonetal.,1998).Thedensityofdoublecortin-positive(DCX+)cellswerere-portedtodeclinefrombirthintothetenthdecadeoflife(Knothetal.,2010)inparallelwith14C-determinedneuronturnover(Bergmannetal.,2015);however,medicationanddruguse,whichaffectAHN(Boldrinietal.,2014),werenotaddressed(Knothetal.,2010;Sorrellsetal.,2018;Spaldingetal.,2013).Usinghistologicaltechniquesthatcouldnotdistinguishmatureandimmatureneurons,severalgroupsestimatedthatDGneu-??ronsdidnotdeclineinaginghumans(Hardingetal.,1998;Simic
etal.,1997;Westetal.,1994).
Invivobrainimagingstudiesreportedcon?icting?ndingsregardingage-relatedchangesinspeci?chippocampalregions.Whilesomestudiesobservedage-relateddeclinesinanteriorhippocampalvolume(Malykhinetal.,2008),othersfoundnovol-umechange(Headetal.,2005),oralteredhippocampalshaperatherthanvolume(Yangetal.,2013).EffortstoevaluateAHNinvivofacelimitationsduetoinadequatespatialresolutionandtheinabilitytoaccuratelydifferentiatehippocampalsub-regions(Hoetal.,2013;Manganasetal.,2007;Rammetal.,2009).AHNandangiogenesisareco-regulated(Boldrinietal.,2012;Heineetal.,2005;Thoredetal.,2007;Warner-SchmidtandDu-man,2007).Exerciseenhancescerebralbloodvolume,whichre-sultsinmoreAHNinmiceandbettercognitiveperformanceinhumans(Pereiraetal.,2007),butitmayhaveareducedimpactinolderpeople(Maassetal.,2015).Thus,wequanti?edAHN,angiogenesis,andDGvolumeandtheirrelationshipinpeople
CellStemCell22,1–11,April5,2018a2018ElsevierInc.1
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Pleasecitethisarticleinpressas:Boldrinietal.,HumanHippocampalNeurogenesisPersiststhroughoutAging,CellStemCell(2018),https://doi.org/10.1016/j.stem.2018.03.015ABCD
EFGHIJKL
M
Sox2-IR cell numberN
Nestin-IR cell numberO
Ki67-IR cell numberAge (years)Age (years)Age (years)
(legendonnextpage)
2CellStemCell22,1–11,April5,2018
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Pleasecitethisarticleinpressas:Boldrinietal.,HumanHippocampalNeurogenesisPersiststhroughoutAging,CellStemCell(2018),https://doi.org/10.1016/j.stem.2018.03.015ofdifferentages,hypothesizingthattheywouldconcurrentlydecreasewithagingandcorrelatewitheachother.
GiventhedifferentfunctionsoftherostralandcaudalDG(WuandHen,2014),weassessedtheanterior,mid,andposteriorhippocampuspostmortemfrom28womenandmen14to79yearsofage.Ineachregion,wecharacterizedandquanti?edangiogenesis,volume,andcellsatdifferentmaturationalstagesintheDGneurogenicniche,usingunbiasedstereologicalmethods(West,1993).Toavoidconfounders,subjectsstudiedhadnoneuropsychiatricdiseaseortreatment.
Healthyelderlypeoplehavethepotentialtoremaincognitivelyandemotionallymoreintactthancommonlybelieved,duetothepersistenceofAHNintotheeighthdecadeoflife.However,reducedcognitive-emotionalresiliencemaybecausedbyavarietyoffactorssuchasasmallerquiescentneuralprogenitorpool,diminishedangiogenesis,ordecreasingneuroplasticityintheanteriorDG.RESULTS
ThegenerationofnewneuronsintheDGneurogenicnichestartsfromquiescentradial-glia-liketypeIneuralprogenitorcells(QNPs)expressingglial?brillaryacidprotein(GFAP),sexdeterminingregionY-box2(Sox2),brainlipid-bindingprotein(BLBP),andnestin(Encinasetal.,2011).QNPsundergoasym-metricdivisionsandgenerateamplifying,ortypeII,intermediateneuralprogenitors(INPs)expressingKi-67andnestin(Encinasetal.,2011).AstypeIIINPsdifferentiateintoneuroblasts,ortypeIIIINPs,theylosetheexpressionofSox2andGFAPwhilegainingexpressionofDCXandpolysialylatedneuralcelladhe-sionmolecule(PSA-NCAM),whichisalsoexpressedbyimma-tureandmaturegranuleneurons(GNs)(Encinasetal.,2011).GNsarethe?nalproductofthedifferentiationcascadeandex-pressneuronalnuclearmarker(NeuN),Prox-1,calbindin,andbIII-tubulin(Encinasetal.,2011).Inanterior,mid,andposteriorDG,wecharacterizedandquanti?edthefollowing:QNPsex-pressingGFAP,Sox2,andnestin;typeIandIIINPsexpressingKi-67andnestin;neuroblasts,ortypeIIIINPs,andimmatureGNsexpressingDCXandPSA-NCAM;and?nally,matureGNsexpressingNeuN.TheanteriorDGwasde?nedastheportionfromthemostrostralappearanceoftheDGtothestartofthelateralgeniculate(visibleincoronalbrainsections);themidDGspannedthelateralgeniculate;andtheposteriorDGwentfromtheendofthelateralgeniculatetothecaudalendoftheDG.QNPsDeclinebutINPsAreStableduringHumanAgingWeassessedthe?rststepsofneurogenesis,speci?callytheabundanceofQNPandtypeI-IIINPcellsintheanterior,mid,
andposteriorDGof28males(n=17)andfemales(n=11)be-tween14and79yearsofage.ExpressionoftranscriptionfactorSox2,requiredformaintenanceofmultipotentneuralstemcells(D’AmourandGage,2003),labeledQNPsanddeclinedwithagingselectivelyinanterior-midDG,regardlessofgender;GFAPalsolabeledQNPs,showingthetypicalradial-glia-likemorphology,withapicalprocesses(Figures1A–1E,1M,andS1A;VideoS1).Sox2/nestin+typeI-IIINPs(Yuetal.,2014)showeddistinctperikaryonandmultipolarprocesses,contact-′etal.,2008;Salehiingnestin+remodelingcapillaries(Mokry
etal.,2008)intheneurogenicnicheofthesubgranularzone(SGZ,Figures1E–1JandFigures4A–4C),aswereportedearlier(Boldrinietal.,2009,2012),anddidnotdeclinewithageinhu-mananterior,mid,orposteriorDGinmalesorfemales.Nestin+proliferatingtypeIIINPsalsoco-labeledwithKi-67,amarkerofactivecellcycle(ScholzenandGerdes,2000),andwerefoundintheSGZasseeninmice,andinthegranulecelllayer(GCL)(Figures1Fand1I–1L),aswehaveshowninhumans(Boldrinietal.,2012)andasothershavefoundinnonhumanprimates(Gouldetal.,1999;KornackandRakic,1999).Ki-67+cellswerestablebetween14and79yearsofageinhumananterior,mid,andposteriorDGinbothsexes(Figures1N,1O,S1B,andS1C).
Insummary,theSox2+QNPpoolwassmallerintheanterior-midDGofolderpeopleandcomprisedapproximately1,000cellsperDGregion(anterior,mid,orposterior),whilenestin+andSox2/nestin+INPtypeI-IIcells,intherangeofthousandsperDGregion,werenotfewerinolderhumansinanterior,mid,orposteriorDG.Ki-67+cells,unchangedbetween14and79yearsofage,wereintheorderof10,000perDGregion,likelyincludingdividingcellsofnon-neuronallineage(likelyendothelialandglialcells).
ImmatureGNsArePreservedbutNeuroplasticityMightDeclineinOlderIndividuals
Totestage-relatedchangesintypeII-IIIINPsandimmatureGNs,aswellasactivity-dependentneuroplasticityormigration,weusedmarkersspeci?cforthismaturationalphase.
PSA-NCAMwasdetectedinneuralcellswithimmature,bipolar,andpyramidalmorphologyandisconsideredamarkerofneuroblastsorimmatureGNsonlywhenco-labeledwithDCX(Songetal.,2012);however,whenfoundaloneandoncellsofdifferentmorphologies,itisconsideredamarkerofneuroplasticity(VarbanovandDityatev,2017).
WefoundthatPSA-NCAM+cellsinhumanSGZ,showingmorphologiesofINPsandimmatureGNs,andPSA-NCAM+matureGNswereallfewerinanteriorDGwitholderage,in
Figure1.FewerQuiescentNeuralProgenitorsandStableProliferatingIntermediateNeuralProgenitorsinAgingHumanDentateGyrus
(AandB)Co-expressionofsexdeterminingregionY-box2(Sox2)andnestininQNPs;4’,6-diamidino-2-phenylindole(DAPI)stainednuclei.(C)Sox2+typeIQNPsinthesubgranularzone(SGZ)withapicalprocessescrossingthegranulecelllayer(GCL)intothemolecularlayer(ML).(D)Sox2+typeIIINPsinSGZ.
(E)Glial?brillaryacid(GFAP)+QNPswithapicalprocess(whitearrow)andhilarastrocytesandnestin+INP(yellowarrow).(F)Nestin/Ki-67+INP.
(GandH)Nestin+INPs(blackarrows)andcapillaries(redarrows);INPprocessestouchremodelingcapillariesoftubularmorphology.(IandJ)Nestin/Ki-67+INPs(yellowsarrows)andcapillary(greenarrow).
(KandL)Ki-67+cellsinSGZ/GCLanddifferentialinterferencecontrastimageofKi-67+nuclei.(M)Sox2+celldeclineinanterior-midDGwithaging.
(NandO)Nestin+andKi-67+cellsdonotdeclinewitholderageinanterior,mid,orposteriorDG.
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Human Hippocampal Neurogenesis Persists throughout Aging
