Hippocampus

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The

Brain:Hippocampus

Thehippocampusislocatedinthemedialtemporallobeofthebrain.Inthislateralviewofthehuman brain,thefrontallobeisatleft,theoccipitallobeatright,andthetemporalandparietallobeshavelargely beenremovedtorevealthehippocampusunderneath. Partof MeSH NeuroLex ID Temporallobe Hippocampus(http://www.nlm.nih.gov/cgi/mesh/2007/MB_cgi?mode=&term=Hippocampus) birnlex_721(http://www.neurolex.org/wiki/birnlex_721) NeuroNames hier164(http://braininfo.rprc.washington.edu/Scripts/hiercentraldirectory.aspx?ID=164)

hippocampusisamajorcomponentofthebrainsofhumansand othervertebrates.Itbelongstothelimbicsystemandplays importantrolesintheconsolidationofinformationfromshortterm memorytolongtermmemoryandspatialnavigation.Humansand othermammalshavetwohippocampi,oneineachsideofthe brain.Thehippocampusisapartofthecerebralcortex,andin primatesislocatedinthemedialtemporallobe,underneaththe corticalsurface.Itcontainstwomaininterlockingparts:Ammon's horn[1]andthedentategyrus. InAlzheimer'sdisease,thehippocampusisoneofthefirstregions ofthebraintosufferdamagememoryproblemsanddisorientation appearamongthefirstsymptoms.Damagetothehippocampus canalsoresultfromoxygenstarvation(hypoxia),encephalitis,or medialtemporallobeepilepsy.Peoplewithextensive,bilateral hippocampaldamagemayexperienceanterogradeamnesiathe inabilitytoformorretainnewmemories.

MRIcoronalviewofahippocampus showninred

Inrodents,thehippocampushasbeenstudiedextensivelyaspartofabrainsystemresponsibleforspatial memoryandnavigation.Manyneuronsintheratandmousehippocampusrespondasplacecells:thatis, theyfireburstsofactionpotentialswhentheanimalpassesthroughaspecificpartofitsenvironment. Hippocampalplacecellsinteractextensivelywithheaddirectioncells,whoseactivityactsasaninertial compass,andwithgridcellsintheneighboringentorhinalcortex. Sincedifferentneuronalcelltypesareneatlyorganizedintolayersinthehippocampus,ithasfrequently beenusedasamodelsystemforstudyingneurophysiology.Theformofneuralplasticityknownaslong

termpotentiation(LTP)wasfirstdiscoveredtooccurinthehippocampusandhasoftenbeenstudiedinthis structure.LTPiswidelybelievedtobeoneofthemainneuralmechanismsbywhichmemoryisstoredin thebrain.

Contents
1Name 2Functions 2.1Roleinmemory 2.2Roleinspatialmemoryandnavigation 3Anatomy 4HippocampalFormation 5Physiology 5.1Thetarhythm 5.2Sharpwaves 5.3Longtermpotentiation 6Pathology 6.1Aging 6.2Stress 6.3Epilepsy 6.4Schizophrenia 6.5Transientglobalamnesia 7Evolution 8Notes 9References 10Furtherreading 10.1Journals 10.2Books 11Externallinks

Name
Theearliestdescriptionoftheridgerunningalongthefloorofthe temporalhornofthelateralventriclecomesfromtheVenetian anatomistJuliusCaesarAranzi(1587),whoinitiallylikenedittoa seahorse,usingtheLatin:hippocampus(fromGreek:, "horse"andGreek:,"seamonster")oralternativelytoa silkworm.TheGermananatomistDuvernoy(1729),thefirstto illustratethestructure,alsowaveredbetween"seahorse"and "silkworm.""Ram'shorn"wasproposedbytheDanishanatomist JacobWinslwin1732andadecadelaterhisfellowParisian,the surgeondeGarengeot,used"cornuAmmonis"hornof(the ancientEgyptiangod)Amun.[2] Anothermythologicalreferenceappearedwiththetermpes hippocampi,whichmaydatebacktoDiemerbroeckin1672,

TheHungarianneuroscientistLszl Seress'1980preparationofthe humanhippocampusandfornix comparedwithaseahorse.

introducingacomparisonwiththeshapeofthefoldedbackforelimbsandwebbedfeetoftheClassical hippocampus(Greek:),aseamonsterwithahorse'sforequartersandafish'stail.The hippocampuswasthendescribedaspeshippocampimajor,withanadjacentbulgeintheoccipitalhorn, thecalcaravis,beingnamedpeshippocampiminor.[2]Therenamingofthehippocampusashippocampus major,andthecalcaravisashippocampusminor,hasbeenattributedtoFlixVicqd'Azyrsystematising nomenclatureofpartsofthebrainin1786.Mayermistakenlyusedthetermhippopotamusin1779,and wasfollowedbysomeotherauthorsuntilKarlFriedrichBurdachresolvedthiserrorin1829.In1861the hippocampusminorbecamethecentreofadisputeoverhumanevolutionbetweenThomasHenryHuxley andRichardOwen,satirisedastheGreatHippocampusQuestion.Thetermhippocampusminorfellfrom useinanatomytextbooks,andwasofficiallyremovedintheNominaAnatomicaof1895.[3] Today,thestructureiscalledthehippocampusratherthanhippocampusmajor,withpeshippocampioften beingregardedassynonymouswithDeGarengeot's"cornuAmmonis",[2]atermwhichsurvivesinthe namesofthefourmainhistologicaldivisionsofthehippocampus:CA1,CA2,CA3andCA4.[4]

Functions
Historically,theearliestwidelyheldhypothesiswasthatthe hippocampusisinvolvedinolfaction.Thisideawascastinto doubtbyaseriesofanatomicalstudiesthatdidnotfindanydirect projectionstothehippocampusfromtheolfactorybulb.[5] However,laterworkdidconfirmthattheolfactorybulbdoes projectintotheventralpartofthelateralentorhinalcortex,and fieldCA1intheventralhippocampussendsaxonstothemain olfactorybulb,[6]theanteriorolfactorynucleus,andtotheprimary olfactorycortex.Therecontinuestobesomeinterestin hippocampalolfactoryresponses,particularlytheroleofthe hippocampusinmemoryforodors,butfewpeoplebelievetoday thatolfactionisitsprimaryfunction.[7][8] Overtheyears,threemainideasofhippocampalfunctionhave dominatedtheliterature:inhibition,memory,andspace.The behavioralinhibitiontheory(caricaturedbyO'KeefeandNadelas"slamonthebrakes!")[9]wasvery popularuptothe1960s.Itderivedmuchofitsjustificationfromtwoobservations:first,thatanimalswith hippocampaldamagetendtobehyperactivesecond,thatanimalswithhippocampaldamageoftenhave difficultylearningtoinhibitresponsesthattheyhavepreviouslybeentaught,especiallyiftheresponse requiresremainingquietasinapassiveavoidancetest.JeffreyGraydevelopedthislineofthoughtintoa fullfledgedtheoryoftheroleofthehippocampusinanxiety.[10]Theinhibitiontheoryiscurrentlytheleast popularofthethree.[11] Thesecondmajorlineofthoughtrelatesthehippocampustomemory.Althoughithadhistorical precursors,thisideaderiveditsmainimpetusfromafamousreportbyScovilleandBrendaMilner[12] describingtheresultsofsurgicaldestructionofthehippocampus(inanattempttorelieveepileptic seizures),inHenryMolaison,[13]knownuntilhisdeathin2008aspatientH.M.Theunexpectedoutcome ofthesurgerywassevereanterogradeandpartialretrogradeamnesia:Molaisonwasunabletoformnew episodicmemoriesafterhissurgeryandcouldnotrememberanyeventsthatoccurredjustbeforehis surgery,butretainedmemoriesforthingsthathappenedyearsearlier,suchashischildhood.Thiscase producedsuchenormousinterestthatMolaisonreportedlybecamethemostintensivelystudiedmedical subjectinhistory.[14]Intheensuingyears,otherpatientswithsimilarlevelsofhippocampaldamageand
Hippocampus(Animation)

amnesia(causedbyaccidentordisease)havebeenstudiedaswell,andthousandsofexperimentshave studiedthephysiologyofactivitydrivenchangesinsynapticconnectionsinthehippocampus.Thereis nowalmostuniversalagreementthatthehippocampusplayssomesortofimportantroleinmemory however,theprecisenatureofthisroleremainswidelydebated.[15][16] Thethirdimportanttheoryofhippocampalfunctionrelatesthehippocampustospace.Thespatialtheory wasoriginallychampionedbyO'KeefeandNadel,whowereinfluencedbyE.C.Tolman'stheoriesabout "cognitivemaps"inhumansandanimals.O'KeefeandhisstudentDostrovskyin1971discoveredneurons intherathippocampusthatappearedtothemtoshowactivityrelatedtotherat'slocationwithinits environment.[17]Despiteskepticismfromotherinvestigators,O'Keefeandhiscoworkers,especiallyLynn Nadel,continuedtoinvestigatethisquestion,inalineofworkthateventuallyledtotheirveryinfluential 1978bookTheHippocampusasaCognitiveMap.[18]Aswiththememorytheory,thereisnowalmost universalagreementthatspatialcodingplaysanimportantroleinhippocampalfunction,butthedetailsare widelydebated.[19]

Roleinmemory
Seealso:Amnesia Psychologistsandneuroscientistsgenerallyagreethatthehippocampushasanimportantroleinthe formationofnewmemoriesaboutexperiencedevents(episodicorautobiographicalmemory).[16][20]Part ofthisroleishippocampalinvolvementinthedetectionofnovelevents,placesandstimuli.[21]Some researchersviewthehippocampusaspartofalargermedialtemporallobememorysystemresponsiblefor generaldeclarativememory(memoriesthatcanbeexplicitlyverbalizedthesewouldinclude,for example,memoryforfactsinadditiontoepisodicmemory).[15] Duetobilateralsymmetrythebrainhasahippocampusinbothcerebralhemispheres,soeverynormal brainhastwoofthem.Ifdamagetothehippocampusoccursinonlyonehemisphere,leavingthestructure intactintheotherhemisphere,thebraincanretainnearnormalmemoryfunctioning.[22]Severedamageto thehippocampusinbothhemispheresresultsinprofounddifficultiesinformingnewmemories (anterogradeamnesia),andoftenalsoaffectsmemoriesformedbeforethedamage(retrogradeamnesia). Althoughtheretrogradeeffectnormallyextendssomeyearsbeforethebraindamage,insomecasesolder memoriesremainthissparingofoldermemoriesleadstotheideathatconsolidationovertimeinvolves thetransferofmemoriesoutofthehippocampustootherpartsofthebrain.[23] Damagetothehippocampusdoesnotaffectsometypesofmemory,suchastheabilitytolearnnewskills (playingamusicalinstrument,orsolvingcertaintypesofpuzzles,forexample).Thisfactsuggeststhat suchabilitiesdependondifferenttypesofmemory(proceduralmemory)anddifferentbrainregions. Furthermore,amnesicpatientsfrequentlyshow"implicit"memoryforexperiencesevenintheabsenceof consciousknowledge.Forexample,apatientaskedtoguesswhichoftwofacestheyhaveseenmost recentlymaygivethecorrectanswerthemajorityofthetime,inspiteofstatingthattheyhaveneverseen eitherofthefacesbefore.Someresearchersdistinguishbetweenconsciousrecollection,whichdependson thehippocampus,andfamiliarity,whichdependsonportionsofthemedialtemporalcortex.[24]

Roleinspatialmemoryandnavigation
Mainarticle:Placecell Studiesconductedonfreelymovingratsandmicehaveshownthatmanyhippocampalneuronshave "placefields",thatis,theyfireburstsofactionpotentialswhenaratpassesthroughaparticularpartofthe

environment.Evidenceforplacecellsinprimatesislimited,perhapsinpartbecauseitisdifficulttorecord brainactivityfromfreelymovingmonkeys.Placerelatedhippocampalneuralactivityhasbeenreportedin monkeysmovingaroundinsidearoomwhileseatedinarestraintchair[26]ontheotherhand,Edmund Rollsandhiscolleaguesinsteaddescribedhippocampalcellsthat fireinrelationtotheplaceamonkeyislookingat,ratherthanthe placeitsbodyislocated.[27]Inhumans,cellswithlocationspecific firingpatternshavebeenreportedinastudyofpatientswithdrug resistantepilepsywhowereundergoinganinvasiveprocedureto localizethesourceoftheirseizures,withaviewtosurgical resection.Thepatientshaddiagnosticelectrodesimplantedintheir hippocampusandthenusedacomputertomovearoundina virtualrealitytown.[28] Placeresponsesinratsandmicehavebeenstudiedinhundredsof Spatialfiringpatternsofsevenplace experimentsoverfourdecades,yieldingalargequantityof cellsrecordedfromasingleelectrode information.[19]Placecellresponsesareshownbypyramidalcells inthedorsalCA1layerofarat.The inthehippocampusproper,andgranulecellsinthedentategyrus. ratranseveralhundredlapsclockwise Theseconstitutethegreatmajorityofneuronsinthedensely aroundanelevatedtriangulartrack, packedhippocampallayers.Inhibitoryinterneurons,whichmake stoppinginthemiddleofeacharmto upmostoftheremainingcellpopulation,frequentlyshow eatasmallportionoffoodreward. significantplacerelatedvariationsinfiringrate,butmuchweaker Blackdotsindicatepositionsofthe thanthatshownbypyramidalorgranulecells.Thereislittleifany rat'sheadcoloreddotsindicateplaces spatialtopographyintherepresentation:cellslyingnexttoeach whereactionpotentialsoccurred, otherinthehippocampusgenerallyhaveuncorrelatedspatialfiring usingadifferentcolorforeach patterns.Placecellsaretypicallyalmostsilentwhenaratis cell. [25] movingaroundoutsidetheplacefield,butreachsustainedratesas highas40Hzwhentheratisnearthecenter.Neuralactivity sampledfrom3040randomlychosenplacecellscarriesenoughinformationtoallowarat'slocationtobe reconstructedwithhighconfidence.Thesizeofplacefieldsvariesinagradientalongthelengthofthe hippocampus,withcellsatthedorsalendshowingthesmallestfields,cellsnearthecentershowinglarger fields,andcellsattheventraltipfieldsthatcovertheentireenvironment.[19]Insomecases,thefiringrate ofrathippocampalcellsdependsnotonlyonplacebutalsoonthedirectionaratismoving,thedestination towardwhichitistraveling,orothertaskrelatedvariables.[29] Thediscoveryofplacecellsinthe1970sledtoatheorythatthehippocampusmightactasacognitivemap aneuralrepresentationofthelayoutoftheenvironment.[30]Severallinesofevidencesupportthe hypothesis.Itisafrequentobservationthatwithoutafullyfunctionalhippocampus,humansmaynot rememberwheretheyhavebeenandhowtogetwheretheyaregoing:gettinglostisoneofthemost commonsymptomsofamnesia.[31]Studieswithanimalshaveshownthatanintacthippocampusis requiredforinitiallearningandlongtermretentionofsomespatialmemorytasks,particularlyonesthat requirefindingthewaytoahiddengoal.[32][33][34][35]The"cognitivemaphypothesis"hasbeenfurther advancedbyrecentdiscoveriesofheaddirectioncells,gridcells,andbordercellsinseveralpartsofthe rodentbrainthatarestronglyconnectedtothehippocampus.[19][36] Brainimagingshowsthatpeoplehavemoreactivehippocampiwhencorrectlynavigating,astestedina computersimulated"virtual"navigationtask.[37]Also,thereisevidencethatthehippocampusplaysarole infindingshortcutsandnewroutesbetweenfamiliarplaces.Forexample,London'staxidriversmustlearn alargenumberofplacesandthemostdirectroutesbetweenthem(theyhavetopassastricttest,The Knowledge,beforebeinglicensedtodrivethefamousblackcabs).AstudyatUniversityCollegeLondon byMaguire,etal..(2000)[38]showedthatpartofthehippocampusislargerintaxidriversthaninthe

generalpublic,andthatmoreexperienceddrivershavebiggerhippocampi.Whetherhavingabigger hippocampushelpsanindividualtobecomeacabdriver,oriffindingshortcutsforalivingmakesan individual'shippocampusgrowisyettobeelucidated.However,inthatstudyMaguire,etal..examined thecorrelationbetweensizeofthegreymatterandlengthoftimethathadbeenspentasataxidriver,and foundapositivecorrelationbetweenthelengthoftimeanindividualhadspentasataxidriverandthe volumeoftherighthippocampus.Itwasfoundthatthetotalvolumeofthehippocampusremained constant,fromthecontrolgroupvs.taxidrivers.Thatistosaythattheposteriorportionofataxidriver's hippocampusisindeedincreased,butattheexpenseoftheanteriorportion.Therehavebeennoknown detrimentaleffectsreportedfromthisdisparityinhippocampalproportions.[38]

Anatomy
Mainarticle:Hippocampusanatomy Anatomically,thehippocampusisanelaborationoftheedge ofthecerebralcortex.[39]Thestructuresthatlinetheedgeof thecortexmakeupthesocalledlimbicsystem(Latinlimbus =border):theseincludethehippocampus,cingulatecortex, olfactorycortex,andamygdala.PaulMacLeanonce suggested,aspartofhistriunebraintheory,thatthelimbic structurescomprisetheneuralbasisofemotion.Some neuroscientistsnolongerbelievethattheconceptofaunified "limbicsystem"isvalid,though.[40]However,the hippocampusisanatomicallyconnectedtopartsofthebrain thatareinvolvedwithemotionalbehaviortheseptum,the hypothalamicmammillarybody,andtheanteriornuclear complexinthethalamussoitsroleasalimbicstructure cannotbecompletelydismissed.

Nisslstainedcoronalsectionofthebrain ofamacaquemonkey,showing hippocampus(circled).Source: brainmaps.org

Thehippocampusasawholehastheshapeofacurvedtube, whichhasbeenanalogizedvariouslytoaseahorse,aram'shorn(CornuAmmonis,hencethesubdivisions CA1throughCA4),orabanana.[39]Itcanbedistinguishedasazonewherethecortexnarrowsintoa singlelayerofdenselypackedpyramidalneurons36cellsdeepinrats,whichcurlintoatightUshape oneedgeofthe"U,"fieldCA4,isembeddedintoabackwardfacingstronglyflexedVshapedcortex,the dentategyrus.Itconsistsofventralanddorsalportions,bothofwhichsharesimilarcompositionbutare partsofdifferentneuralcircuits.[41]Thisgenerallayoutholdsacrossthefullrangeofmammalianspecies, fromhedgehogtohuman,althoughthedetailsvary.Intherat,thetwohippocampiresembleapairof bananas,joinedatthestemsbythehippocampalcommissurethatcrossesthemidlineundertheanterior corpuscallosum.Inhumanormonkeybrains,theportionofthehippocampusdownatthebottom,nearthe baseofthetemporallobe,ismuchbroaderthanthepartatthetop.Oneoftheconsequencesofthis complexgeometryisthatcrosssectionsthroughthehippocampuscanshowavarietyofshapes,depending ontheangleandlocationofthecut. Theentorhinalcortex(EC),locatedintheparahippocampalgyrus,isconsideredtobepartofthe hippocampalregionbecauseofitsanatomicalconnections.TheECisstronglyandreciprocallyconnected withmanyotherpartsofthecerebralcortex.Inaddition,themedialseptalnucleus,theanteriornuclear complexandnucleusreuniensofthethalamusandthesupramammillarynucleusofthehypothalamus,as wellastheraphenucleiandlocuscoeruleusinthebrainstemsendaxonstotheEC.Themainoutput pathway(perforantpath,firstdescribedbyRamonyCajal)ofECaxonscomesfromthelargestellate pyramidalcellsinlayerIIthat"perforate"thesubiculumandprojectdenselytothegranulecellsinthe

dentategyrus,apicaldendritesofCA3getalessdenseprojection,andtheapicaldendritesofCA1geta sparseprojection.Thus,theperforantpathestablishestheECasthemain"interface"betweenthe hippocampusandotherpartsofthecerebralcortex.Thedentategranulecellaxons(calledmossyfibers) passontheinformationfromtheEConthornyspinesthatexitfromtheproximalapicaldendriteofCA3 pyramidalcells.Then,CA3axonsexitfromthedeeppartofthecellbody,andloopupintotheregion wheretheapicaldendritesarelocated,thenextendallthewaybackintothedeeplayersoftheentorhinal cortextheShaffercollateralscompletingthereciprocalcircuitfieldCA1alsosendsaxonsbacktothe EC,butthesearemoresparsethantheCA3 projection.Withinthehippocampus,theflowof informationfromtheECislargelyunidirectional, withsignalspropagatingthroughaseriesoftightly packedcelllayers,firsttothedentategyrus,thento theCA3layer,thentotheCA1layer,thentothe subiculum,thenoutofthehippocampustotheEC, mainlyduetocollateralizationoftheCA3axons. Eachoftheselayersalsocontainscomplexintrinsic circuitryandextensivelongitudinalconnections.[39] Basiccircuitofthehippocampus,asdrawnby Severalotherconnectionsplayimportantrolesin hippocampalfunction.[39]Beyondtheoutputtothe EC,additionaloutputpathwaysgotoothercortical areasincludingtheprefrontalcortex.Averyimportantlargeoutputgoestothelateralseptalareaandtothe mammillarybodyofthehypothalamus.Thehippocampusreceivesmodulatoryinputfromtheserotonin, norepinephrine,anddopaminesystems,andfromnucleusreuniensofthethalamustofieldCA1.Avery importantprojectioncomesfromthemedialseptalarea,whichsendscholinergicandGABAergicfibersto allpartsofthehippocampus.Theinputsfromtheseptalareaplayakeyroleincontrollingthe physiologicalstateofthehippocampus:destructionoftheseptalareaabolishesthehippocampaltheta rhythm,andseverelyimpairscertaintypesofmemory.[42] Thecorticalregionadjacenttothehippocampusisknowncollectivelyastheparahippocampalgyrus(or parahippocampus).[43]ItincludestheECandalsotheperirhinalcortex,whichderivesitsnamefromthe factthatitliesnexttotherhinalsulcus.Theperirhinalcortexplaysanimportantroleinvisualrecognition ofcomplexobjects,butthereisalsosubstantialevidencethatitmakesacontributiontomemorywhichcan bedistinguishedfromthecontributionofthehippocampus,andthatcompleteamnesiaoccursonlywhen boththehippocampusandtheparahippocampusaredamaged.[43]
SantiagoRamonyCajal.DG:dentategyrus.Sub: subiculum.EC:entorhinalcortex

HippocampalFormation
Varioussectionsofthehippocampalformationareshowntobefunctionallyandanatomicallydistinct.The dorsal(DH),ventral(VH),andintermediateregionsofthehippocampalformationservedifferent functions,projectwithdifferingpathways,andhavevaryingdegreesofplacefieldneurons(Fanselow& Dong,2009).Thedorsalregionofthehippocampalformationservesforspatialmemory,verbalmemory, andlearningofconceptualinformation.UsingtheradialarmmazePothuizenetal.(2004),foundlesionsin theDHtocausespatialmemoryimpairmentwhileVHlesionsdidnot.Itsprojectingpathwaysincludethe medialseptalcomplex,andsupramammillarynucleus.Thedorsalhippocampalformationalsohasmore placefieldneuronsthanboththeventralandintermediatehippocampalformation(Jungetal.,1994).The intermediatehippocampushasoverlappingcharacteristicswithboththeventralanddorsalhippocampus (Fanselow&Dong,2009).UsingPHALanterogradetracingmethods,CenquizcaandSwanson(2007) locatedthemoderateprojectionstotwoprimaryolfactorycorticalareasandprelimbicareasofthemPFC. Thisregionhastheleastamountofplacefieldneurons.Theventralhippocampusfunctionsinfear

conditioningandaffectiveprocesses.Anagnostarasetal.(2002)showedthatalterationstotheventral hippocampusreducedtheamountofinformationsenttotheamygdalabythedorsalandventral hippocampus,consequentiallyalteringfearconditioninginrats.

Physiology
Thehippocampusshowstwomajor"modes"of activity,eachassociatedwithadistinctpatternof neuralpopulationactivityandwavesofelectrical activityasmeasuredbyanelectroencephalogram (EEG).ThesemodesarenamedaftertheEEG patternsassociatedwiththem:thetaandlargeirregular activity(LIA).Themaincharacteristicsdescribed belowarefortherat,whichistheanimalmost extensivelystudied.[44] Thethetamodeappearsduringstatesofactive,alert behavior(especiallylocomotion),andalsoduring REM(dreaming)sleep.[45]Inthethetamode,the EEGisdominatedbylargeregularwaveswitha frequencyrangeof69Hz,andthemaingroupsof hippocampalneurons(pyramidalcellsandgranule cells)showsparsepopulationactivity,whichmeans thatinanyshorttimeinterval,thegreatmajorityof cellsaresilent,whilethesmallremainingfractionfire atrelativelyhighrates,upto50spikesinonesecond forthemostactiveofthem.Anactivecelltypically staysactiveforhalfasecondtoafewseconds.Asthe ratbehaves,theactivecellsfallsilentandnewcells becomeactive,buttheoverallpercentageofactive cellsremainsmoreorlessconstant.Inmany situations,cellactivityisdeterminedlargelybythe spatiallocationoftheanimal,butotherbehavioral variablesalsoclearlyinfluenceit.

ExamplesofrathippocampalEEGandCA1neural activityinthetheta(awake/behaving)andLIA (slowwavesleep)modes.Eachplotshow20 secondsofdata,withahippocampalEEGtraceat thetop,spikerastersfrom40simultaneously recordedCA1pyramidalcellsinthemiddle(each rasterlinerepresentsadifferentcell),andaplotof runningspeedatthebottom.Thetopplotrepresents atimeperiodduringwhichtheratwasactively searchingforscatteredfoodpellets.Forthebottom plot,theratwasasleep.

TheLIAmodeappearsduringslowwave(nondreaming)sleep,andalsoduringstatesofwaking immobility,suchasrestingoreating.[45]IntheLIAmode,theEEGisdominatedbysharpwaves,which arerandomlytimedlargedeflectionsoftheEEGsignallastingfor200300ms.Thesesharpwavesalso determinethepopulationneuralactivitypatterns.Betweenthem,pyramidalcellsandgranulecellsarevery quiet(butnotsilent).Duringasharpwave,asmanyas510%oftheneuralpopulationmayemitaction potentialsduringaperiodof50msmanyofthesecellsemitburstsofseveralactionpotentials. Thesetwohippocampalactivitymodescanbeseeninprimatesaswellasrats,withtheexceptionthatit hasbeendifficulttoseerobustthetarhythmicityintheprimatehippocampus.Thereare,however, qualitativelysimilarsharpwaves,andsimilarstatedependentchangesinneuralpopulationactivity.[46]

Thetarhythm
Mainarticle:Thetarhythm

Becauseofitsdenselypackedneurallayers,thehippocampusgeneratessomeofthelargestEEGsignalsof anybrainstructure.InsomesituationstheEEGisdominatedbyregularwavesat310Hz,often continuingformanyseconds.Thesereflectsubthresholdmembranepotentialsandstronglymodulatethe spikingofhippocampalneuronsandsynchroniseacrossthehippocampusinatravellingwavepattern.[47] ThisEEGpatternisknownasathetarhythm.[48]Thetarhythmicityisveryobviousinrabbitsandrodents, andalsoclearlypresentincatsanddogs.Whetherthetacanbeseeninprimatesisavexingquestion.[49]In rats(theanimalsthathavebeenthemostextensivelystudied),thetaisseenmainlyintwoconditions:first, whenananimaliswalkingorinsomeotherwayactivelyinteractingwithitssurroundingssecond,during REMsleep.[50]Thefunctionofthetahasnotyetbeenconvincinglyexplained,althoughnumeroustheories havebeenproposed.[44]Themostpopularhypothesishasbeentorelateittolearningandmemory.For example,thephasewithwhichthetaatthetimeofstimulationofaneuronshapestheeffectofthat stimulationuponitssynapsesandthereforemayaffectlearningandmemorydependentuponsynaptic plasticity.[51]Itiswellestablishedthatlesionsofthemedialseptumthecentralnodeofthethetasystem causeseveredisruptionsofmemory.However,themediumseptumismorethanjustthecontrollerof theta,itisalsothemainsourceofcholinergicprojectionstothehippocampus.[39]Ithasnotbeen establishedthatseptallesionsexerttheireffectsspecificallybyeliminatingthethetarhythm.[52]

Sharpwaves
Duringsleep,orduringwakingstateswhenananimalisrestingorotherwisenotengagedwithits surroundings,thehippocampalEEGshowsapatternofirregularslowwaves,somewhatlargerin amplitudethanthetawaves.Thispatternisoccasionallyinterruptedbylargesurgescalledsharpwaves.[53] Theseeventsareassociatedwithburstsofspikeactivity,lasting50100msec,inpyramidalcellsofCA3 andCA1.TheyarealsoassociatedwithshortlastinghighfrequencyEEGoscillationscalled"ripples", withfrequenciesintherange150200Hzinrats.Sharpwavesaremostfrequentduringsleep,whenthey occuratanaverageratearound1persecond(inrats),butinaveryirregulartemporalpattern.Sharpwaves arelessfrequentduringinactivewakingstates,andareusuallysmaller.Sharpwaveshavealsobeen observedinhumansandmonkeys.Inmacaques,sharpwavesarerobust,butdonotoccurasfrequentlyas inrats.[46] Oneofthemostinterestingaspectsofsharpwavesisthattheyappeartobeassociatedwithmemory. WilsonandMcNaughton1994,[54]andnumerouslaterstudies,reportedthatwhenhippocampalplacecells haveoverlappingspatialfiringfields(andthereforeoftenfireinnearsimultaneity),theytendtoshow correlatedactivityduringsleepfollowingthebehavioralsession.Thisenhancementofcorrelation, commonlyknownasreactivation,hasbeenfoundtooccurmainlyduringsharpwaves.[55]Ithasbeen proposedthatsharpwavesare,infact,reactivationsofneuralactivitypatternsthatwerememorizedduring behavior,drivenbystrengtheningofsynapticconnectionswithinthehippocampus.[56]Thisideaformsa keycomponentofthe"twostagememory"theory,advocatedbyBuzskiandothers,whichproposesthat memoriesarestoredwithinthehippocampusduringbehavior,andthenlatertransferredtotheneocortex duringsleep:sharpwavesaresuggestedtodriveHebbiansynapticchangesintheneocorticaltargetsof hippocampaloutputpathways.[57]

Longtermpotentiation
Mainarticle:Longtermpotentiation SinceatleastthetimeofRamonyCajal,psychologistshavespeculatedthatthebrainstoresmemoryby alteringthestrengthofconnectionsbetweenneuronsthataresimultaneouslyactive.[58]Thisideawas formalizedbyDonaldHebbin1948,[59]butformanyyearsthereafter,attemptstofindabrainmechanism

forsuchchangescameupempty.In1973,TimBlissandTerjeLmodescribedaphenomenoninthe rabbithippocampusthatappearedtomeetHebb'sspecifications:achangeinsynapticresponsiveness inducedbybriefstrongactivationandlastingforhours,days,orlonger.[60]Thisphenomenonwassoon referredtoaslongtermpotentiation,abbreviatedLTP.Asacandidatemechanismformemory,LTPhas beenstudiedintensivelyoverthefollowingyears,andagreatdealhasbeenlearnedaboutit. ThehippocampusisaparticularlyfavorablesiteforstudyingLTPbecauseofitsdenselypackedand sharplydefinedlayersofneurons,butsimilartypesofactivitydependentsynapticchangehavenowbeen observedinmanyotherbrainareas.[61]ThebeststudiedformofLTPoccursatsynapsesthatterminateon dendriticspinesandusethetransmitterglutamate.Severalofthemajorpathwayswithinthehippocampus fitthisdescription,andshowLTP.[62]Thesynapticchangesdependonaspecialtypeofglutamate receptor,theNMDAreceptor,whichhasthespecialpropertyofallowingcalciumtoenterthepostsynaptic spineonlywhenpresynapticactivationandpostsynapticdepolarizationoccuratthesametime.[63]Drugs thatinterferewithNMDAreceptorsblockLTPandalsohavemajoreffectsonsometypesofmemory, especiallyspatialmemory.Transgenicmice,geneticallymodifiedinwaysthatdisabletheLTPmechanism, alsogenerallyshowseverememorydeficits.[63]

Pathology
Aging
AgerelatedconditionssuchasAlzheimer'sdisease(forwhichhippocampaldisruptionisoneoftheearliest signs[64])haveasevereimpactonmanytypesofcognition,butevennormalagingisassociatedwitha gradualdeclineinsometypesofmemory,includingepisodicmemoryandworkingmemory.Becausethe hippocampusisthoughttoplayacentralroleinmemory,therehasbeenconsiderableinterestinthe possibilitythatagerelateddeclinescouldbecausedbyhippocampaldeterioration.[65]Someearlystudies reportedsubstantiallossofneuronsinthehippocampusofelderlypeople,butlaterstudiesusingmore precisetechniquesfoundonlyminimaldifferences.[65]Similarly,someMRIstudieshavereported shrinkageofthehippocampusinelderlypeople,butotherstudieshavefailedtoreproducethisfinding. Thereis,however,areliablerelationshipbetweenthesizeofthehippocampusandmemoryperformance meaningthatnotallelderlypeopleshowhippocampalshrinkage,butthosewhodotendtoperformless wellonsomememorytasks.[66]Therearealsoreportsthatmemorytaskstendtoproducelesshippocampal activationinelderlythaninyoungsubjects.[66]Furthermore,arandomizedcontrolstudypublishedin 2011foundthataerobicexercisecouldincreasethesizeofthehippocampusinadultsaged55to80and alsoimprovespatialmemory.[67] Inrats,wheredetailedstudiesofcellularphysiologyarepossible,agingdoesnotcausesubstantialcellloss inthehippocampus,butitalterssynapticconnectivityinseveralways.[68]Functionalsynapsesarelostin thedentategyrusandCA1region,andNMDAreceptormediatedresponsesarereduced.Thesechanges mayaccountfordeficitsininductionandmaintenanceoflongtermpotentiation,aformofsynaptic plasticitythathasbeenimplicatedinmemory.Therearealsoagerelateddeclinesinhippocampal expressionofseveralgenesassociatedwithsynapticplasticity.[69]Finally,therearedifferencesinthe stabilityof"placecell"representations.Inyoungrats,thearrangementofplacefieldsisusuallyalteredif theratismovedintoadifferentenvironment,butremainsthesameifaratisreturnedtoanenvironmentit hasvisitedpreviously.Inagedrats,theplacefieldsfrequentlyfailto"remap"whenaratismovedtoa differentenvironment,andalsofrequentlyfailtorestoretheoriginal"map"whentheratisreturnedtothe sameenvironment. A2011studybyresearchersattheDukeUniversityMedicalCenterfoundhippocampalatrophyis

associatedwitholderadultswhoreportlifechangingreligiousexperiences,aswellasthosewhoare "bornagainProtestants,Catholics,andthosewithnoreligiousaffiliation".[70] Ina2012study,ledbyneuroscientistsattheUniversityofBristol,itwasdiscoveredthatacellular mechanismknownassodiumchannelswasplayingadirectroleinthechangingofactivityofneurons, leadingtoacognitivedeclineofthehumanbrain.Inthestudy,afterresearchersrecordedelectricalsignals knownasactionpotentialsinsinglecellsofthehippocampusregion,itwasdiscoveredthatitbecame difficultforanagedbraintomakehippocampalneuronstogenerateactionpotentials.Thereasoningfor thiswasduetochangestotheactivationpropertiesofmembraneproteinscalledsodiumchannels.These proteinswouldthenintervenetherapidupstrokeofanactionpotential,thusallowingaflowofsodium ionsintoneurons.[71]

Stress
Thehippocampuscontainshighlevelsofglucocorticoidreceptors,whichmakeitmorevulnerabletolong termstressthanmostotherbrainareas.[72]Stressrelatedsteroidsaffectthehippocampusinatleastthree ways:first,byreducingtheexcitabilityofsomehippocampalneuronssecond,byinhibitingthegenesisof newneuronsinthedentategyrusthird,bycausingatrophyofdendritesinpyramidalcellsoftheCA3 region.Thereisevidencethathumanswhohaveexperiencedsevere,longlastingtraumaticstress,show atrophyofthehippocampus,morethanofotherpartsofthebrain.[73]Theseeffectsshowupinpost traumaticstressdisorder,[74]andtheymaycontributetothehippocampalatrophyreportedin schizophrenia[75]andseveredepression.[76]Arecentstudyhasalsorevealedatrophyasaresultof depression,butthiscanbestoppedwithantidepressants,eveniftheyarenoteffectiveinrelievingother symptoms.[77]HippocampalatrophyisalsofrequentlyseeninCushing'ssyndrome,adisordercausedby highlevelsofcortisolinthebloodstream.Atleastsomeoftheseeffectsappeartobereversibleifthestress isdiscontinued.Thereis,however,evidencemainlyderivedfromstudiesusingratsthatstressshortlyafter birthcanaffecthippocampalfunctioninwaysthatpersistthroughoutlife.[78] Sexspecificresponsestostresshavealsobeendemonstratedtohaveaneffectonthehippocampus.Recent researchhasrevealedadifferencebetweentheresponseofadultmaleandfemaleratstoacutestress.When adultmaleratsweresubjectedtoacutestressorstheirhippocampalneuronsbecamebushier(i.e.the numberofdendritesperneuronincreased).Inadultfemaleratstheoppositeoccurred(i.e.thenumberof dendritesperhippocampalneurondecreased).Thisstudysuggeststhatadultmaleratsarebetterableto copewithacutestressthanareadultfemalerats.[79]Researchonchronicstress,however,hasshowna differentsexspecificresponse.Duringsituationsinwhichadultmaleandfemaleratswereexposedto chronicstress,thefemaleswereshowntobebetterabletocope.Thiswasdemonstratedbyassessinghow vulnerabletokillingbyaneurotoxintheneuronsofthehippocampuswere.Themalerats'hippocampal neuronsshowedincreasedsusceptibilityafterexposuretochronicstresswhereastheadultfemalerats' hippocampalneuronsremainedlessaffectedbytheneurotoxin.Whilethemechanismsthatallowforthis neuronalprotectionareunclearithasbeenpostulatedthatsexspecifichormonesmayplayarole.[80]

Epilepsy
Thehippocampusisoftenthefocusofepilepticseizures:hippocampalsclerosisisthemostcommonly visibletypeoftissuedamageintemporallobeepilepsy.[81]Itisnotyetclear,though,whethertheepilepsy isusuallycausedbyhippocampalabnormalities,orthehippocampusisdamagedbycumulativeeffectsof seizures.[82]Inexperimentalsettingswhererepetitiveseizuresareartificiallyinducedinanimals, hippocampaldamageisafrequentresult:thismaybeaconsequenceofthehippocampusbeingoneofthe mostelectricallyexcitablepartsofthebrain.Itmayalsohavesomethingtodowiththefactthatthe

hippocampusisoneofveryfewbrainregionswherenewneuronscontinuetobecreatedthroughout life.[83]

Schizophrenia
Thecausesofschizophreniaarenotatallwellunderstood,butnumerousabnormalitiesofbrainstructure havebeenreported.Themostthoroughlyinvestigatedalterationsinvolvethecerebralcortex,buteffectson thehippocampushavealsobeendescribed.Manyreportshavefoundreductionsinthesizeofthe hippocampusinschizophrenicsubjects.[84]Thechangesprobablyresultfromaltereddevelopmentrather thantissuedamage,andshowupeveninsubjectswhohaveneverbeenmedicated.Severallinesof evidenceimplicatechangesinsynapticorganizationandconnectivity.[84]Itisunclearwhether hippocampalalterationsplayanyroleincausingthepsychoticsymptomsthatarethemostimportant featureofschizophrenia.AnthonyGraceandhiscoworkershavesuggested,onthebasisofexperimental workusinganimals,thathippocampaldysfunctionmightproduceanalterationofdopaminereleaseinthe basalganglia,therebyindirectlyaffectingtheintegrationofinformationintheprefrontalcortex.[85]Others havesuggestedthathippocampaldysfunctionmightaccountfordisturbancesinlongtermmemory frequentlyobservedinpeoplewithschizophrenia.[86]

Transientglobalamnesia
Acurrenthypothesisastoonecauseoftransientglobalamnesiaadramaticsuddentemporaryneartotal lossofshorttermmemoryisthatitmaybeduetovenouscongestionofthebrain,[87]leadingtoischemia ofstructures,suchasthehippocampus,thatareinvolvedwithmemory.[88]

Evolution
Thehippocampushasagenerallysimilarappearanceacrosstherangeofmammalspecies,from monotremessuchastheechidnatoprimatessuchashumans.[89]Thehippocampalsizetobodysizeratio broadlyincreases,beingabouttwiceaslargeforprimatesasfortheechidna.Itdoesnot,however,increase atanywhereclosetotherateoftheneocortextobodysizeratio.Therefore,thehippocampustakesupa muchlargerfractionofthecorticalmantleinrodentsthaninprimates.Inadulthumans,thevolumeofthe hippocampusoneachsideofthebrainisabout33.5cm3,ascomparedto320420cm3forthevolumeof theneocortex.[90] Thereisalsoageneralrelationshipbetweenthesizeofthehippocampusandspatialmemory.When comparisonsaremadebetweensimilarspecies,thosethathaveagreatercapacityforspatialmemorytend tohavelargerhippocampalvolumes.[91]Thisrelationshipalsoextendstosexdifferences:inspecieswhere malesandfemalesshowstrongdifferencesinspatialmemoryability,theyalsotendtoshowcorresponding differencesinhippocampalvolume.[92] Nonmammalianspeciesdonothaveabrainstructurethatlookslikethemammalianhippocampus,but theyhaveonethatisconsideredhomologoustoit.Thehippocampus,aspointedoutabove,isessentially themedialedgeofthecortex.Onlymammalshaveafullydevelopedcortex,butthestructureitevolved from,calledthepallium,ispresentinallvertebrates,eventhemostprimitiveonessuchasthelampreyor hagfish.[93]Thepalliumisusuallydividedintothreezones:medial,lateral,anddorsal.Themedialpallium formstheprecursorofthehippocampus.Itdoesnotresemblethehippocampusvisually,becausethelayers arenotwarpedintoanSshapeorenwrappedbythedentategyrus,butthehomologyisindicatedbystrong chemicalandfunctionalaffinities.Thereisnowevidencethatthesehippocampallikestructuresare involvedinspatialcognitioninbirds,reptiles,andfish.[94]

Inbirds,thecorrespondenceissufficientlywellestablishedthatmostanatomistsrefertothemedialpallial zoneasthe"avianhippocampus".[95]Numerousspeciesofbirdshavestrongspatialskills,particularly thosethatcachefood.Thereisevidencethatfoodcachingbirdshavealargerhippocampusthanother typesofbirds,andthatdamagetothehippocampuscausesimpairmentsinspatialmemory.[96] Thestoryforfishismorecomplex.Inteleostfish(whichmakeupthegreatmajorityofexistingspecies), theforebrainisdistortedincomparisontoothertypesofvertebrates:mostneuroanatomistsbelievethatthe teleostforebrainisessentiallyeverted,likeasockturnedinsideout,sothatstructuresthatlieintheinterior, nexttotheventricles,formostvertebrates,arefoundontheoutsideinteleostfish,andviceversa.[97]One oftheconsequencesofthisisthatthemedialpallium("hippocampal"zone)ofatypicalvertebrateis thoughttocorrespondtothelateralpalliumofatypicalfish.Severaltypesoffish(particularlygoldfish) havebeenshownexperimentallytohavestrongspatialmemoryabilities,evenforming"cognitivemaps" oftheareastheyinhabit.[91]Thereisevidencethatdamagetothelateralpalliumimpairsspatial memory.[98][99] Thus,theroleofthehippocampalregioninnavigationappearstobeginfarbackinvertebrateevolution, predatingsplitsthatoccurredhundredsofmillionsofyearsago.[100]Itisnotyetknownwhetherthe medialpalliumplaysasimilarroleinevenmoreprimitivevertebrates,suchassharksandrays,oreven lampreysandhagfish.Sometypesofinsects,andmolluscssuchastheoctopus,alsohavestrongspatial learningandnavigationabilities,buttheseappeartoworkdifferentlyfromthemammalianspatialsystem, sothereisasyetnogoodreasontothinkthattheyhaveacommonevolutionaryoriginnoristhere sufficientsimilarityinbrainstructuretoenableanythingresemblinga"hippocampus"tobeidentifiedin thesespecies.Somehaveproposed,though,thattheinsect'smushroombodiesmayhaveafunctionsimilar tothatofthehippocampus.[101]

Notes
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. ^Pearce,2001 ^ a b cDuvernoy,2005 ^Gross,1993 ^Wechsler,2004 ^Finger,p.183 ^citepmid690266 ^Eichenbaumetal.,1991 ^Vanderwolf,2001 ^Nadeletal.,1975 ^GrayandMcNaughton,2000 ^Best&White,1999 ^ScovilleandMilner,1957 ^N.Y.Times,12062008 ^Squire,2009 ^ a bSquire,1992 ^ a bEichenbaumandCohen,1993 ^O'KeefeandDostrovsky,1971 ^O'KeefeandNadel,1978 ^ a b c dMoseretal.,2008 ^SquireandSchacter,2002 ^VanElzakkeretal.,2008 ^DiGennaroG,GrammaldoLG,QuaratoPP,EspositoV,MasciaA,SparanoA,MeldolesiGN,PicardiA. Severeamnesiafollowingbilateralmedialtemporallobedamageoccurringontwodistinctoccasions.Neurol

23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70.

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Furtherreading

Journals
Hippocampus(Wiley)

Books
PerAndersen,RichardMorris,DavidAmaral,TimBlissandJohnO'Keefe,ed.(2007).The HippocampusBook.OxfordUniversityPress.ISBN9780195100273. HenriM.Duvernoy,F.Cattin(2005).TheHumanHippocampus:FunctionalAnatomy, Vascularization,andSerialSectionswithMRI.Springer.ISBN9783540231912. HowardEichenbaum(2002).TheCognitiveNeuroscienceofMemory.OxfordUniversityPressUS. ISBN9780195141757. editedbyPatriciaE.Sharp.(2002).PatriciaE.Sharp.ed.TheNeuralBasisofNavigation:Evidence fromSingleCellRecording.Springer.ISBN9780792375791. PhilippeTaupin(2007).TheHippocampus:NeurotransmissionandPlasticityintheNervous System.NovaPublishers.ISBN9781600219146. JohnHByrne,ed.(2008).LearningandMemory:Acomprehensivereference.Elsevier.ISBN978 0123705099.

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