long term long term persistent strengthening based recent patterns activity patterns activity produce long lasting increase signal transmission opposite long term depression produces long lasting decrease strength phenomena underlying ability chemical change strength memories thought modification strength widely considered major cellular mechanisms learning memory discovered rabbit remained popular subject research modern studies seek better understand basic biology aim draw link learning try develop methods enhancing improve learning memory subject clinical research example areas disease addiction medicine history early theories learning end 19th century scientists generally recognized number adult brain roughly billion increase significantly age giving good reason believe memories generally result new production realization came need explain memories form absence new spanish suggest mechanism learning require formation new lecture proposed memories instead formed strengthening connections existing improve effectiveness communication theory introduced echoed ideas proposing cells grow new connections undergo changes enhance ability communicate let assume persistence repetition activity trace tends induce lasting cellular changes add stability cell near cell repeatedly takes firing growth process change takes place cells efficiency cells firing increased theories memory formation established time late 19th early 20th century equipped techniques necessary biological learning animals skills come later half 20th century time discovery long term discovery observed oslo norway laboratory conducted series experiments rabbits explore role short term memory experiments focused connections experiments carried fibers recording responses collection cells expected single pulse electrical fibers caused cells unexpectedly observed cells response single pulse enhanced long period time delivered high frequency train fibers train applied subsequent single pulse stronger prolonged cell population phenomenon high frequency produce long lived cells response subsequent single pulse initially called long lasting joined laboratory collaborated published characterization long lasting rabbit bliss published similar report long lasting awake animal appeared issue bliss report douglas proposed long term new phenomenon long lasting suggested authors chose long term easily pronounced acronym models theory physical biological mechanism understood successful models developed studies spines protruding structures physically grow course minutes hours suggested relationship electrical resistance spine effective strength relationship calcium mathematical models depends calcium relation voltage gates developed 1980s modify traditional learning model biological experimental justification proposed arranging relationship regulation strength types original discovery rabbit observed variety structures including cerebral prominent researcher suggested occur brain different areas brain exhibit different forms specific type exhibited depends number factors factor age organism observed example molecular mechanisms immature differ mechanisms adult signalling pathways particular cell contribute specific type present example types depend depend depend altogether variety signaling pathways contribute wide distribution pathways brain reasons type exhibited depends location observed example dependent fiber independent activity required induce criteria classified broadly allows classification non anti mechanisms borrowing summarized maxim cells fire wire requires simultaneous induction type require simultaneous cells example occurs fiber special case non anti explicitly requires simultaneous relative induction owing predictable organization readily site study particular dependent adult widely studied type focus article properties dependent exhibits properties including input persistence input induced spread input specific long term propagated according rules input incomplete short distances model explain input presented morris called capture hypothesis refers observation weak single insufficient induction simultaneous strong induce pathways induced strong single weaker stimulated weakly produces insufficient induce contrast weak applied pathways converge single patch membrane individual generated collectively cell induce discussed later common mechanism underlying argues difference strictly persistence persistent lasting minutes months persistence separates forms early phase maintenance induction activation maintenance early form characterized persistent activation stage protein dependence calcium active consequently able carry events expression expression chemical reaction small group added change activity active use carry major mechanisms underlying expression importantly existing increase activity second additional membrane importantly delivery independent protein synthesis achieved having pool adjacent membrane appropriate inducing arrives rapidly membrane influence protein mentioned previously brain abundant majority activity increasing efficiency number future generate larger responses model describes entirely mechanisms induction maintenance expression additional component expression occur hypothesis persistent activity cell lead synthesis messenger discussed later according hypothesis newly synthesized messenger travels cell leading chain events facilitate response subsequent events include increase number probability release addition messenger underlying expression early messenger play role expression late late phase late natural extension unlike independent protein synthesis requires gene protein synthesis cell phases exist depends protein synthesis second depends gene protein synthesis phases occasionally called respectively referred nomenclature induction late induced changes gene expression protein synthesis brought persistent activation protein activated fact specifically signal regulated subfamily molecular link signaling involved including converge recent research shown induction depend molecular events activation calcium influx converge potent camp response element binding protein requirement molecular coincidence accounts perfectly nature presumably learning maintenance activation number nuclear molecules ultimately result protein synthesis morphological changes observed nuclear molecules include factors changes factor activity trigger synthesis proteins maintenance protein active synthesis increases following induction lacks regulatory remains active unlike active minutes following induction requirement maintenance late phase appears important persistence memory expected important maintenance long term memory administration rat results amnesia intact short term memory play role establishment short term memory recently shown maintenance directing trafficking reorganization proteins expression recently mice lacking demonstrate normal questioning necessity long term changes determined parallel increase structures spine density molecular level increase proteins shown expression identities proteins synthesized known regardless identities thought contribute increase spine number surface area sensitivity associated expression brought enhanced synthesis late associated synthesis increase number suggesting protein synthesis cells cells mentioned previously induction result protein synthesis communication cell occur synthesis messenger discussed later studies restricted events investigators determined location protein synthesis specifically unclear protein synthesis takes place cell body despite having observed major components protein synthesis machinery early 1960s prevailing wisdom cell body predominant site protein synthesis reasoning seriously challenged 1980s investigators reported observing protein synthesis connection cell body severed recently investigators demonstrated type local protein synthesis necessary types reason popularity local protein synthesis hypothesis provides possible mechanism associated specifically local protein synthesis spines receiving inducing undergo propagated adjacent contrast global protein synthesis occurs cell body requires proteins shipped area cell including received inducing local protein synthesis provides mechanism global protein synthesis directly compromise discussed later hypothesis successfully global protein synthesis signaling signaling hypothesis attempts explain induced expressed evidence suggests expressed hypothesis gets normal transmission directional proceeds cell induction occur partially expressed message travel cell cell reverse direction message presumably cascade events leads component expression increased probability release signaling currently contentious subject investigators believe cell contributes expression proponents hypothesis controversy identity messenger early thoughts focused recent evidence points cell proteins local protein synthesis hypothesis gained significant support general agreement protein synthesis underlying occurred cell body thought products synthesis shipped cell wide manner necessary explain protein synthesis occur cell body input hypothesis attempts solve cell difficult problem proteins cell body ensuring reach received inducing hypothesis proposes tag synthesized received inducing tag serve capture related proteins shipped cell wide cell body studies marine implicated mechanism input evidence given widely separated inducing drives signaling described previously gene expression cell nucleus local protein synthesis creates short lived hours tag products gene expression shipped globally cell captured express tag receiving inducing demonstrating input tag hypothesis account properties observed excited inducing separate weakly stimulated expect strongly stimulated undergo weak insufficient induce fact undergo weak unable induce protein synthesis cell body prompt synthesis tag simultaneous strong separate capable inducing cell body protein synthesis prompt production related proteins shipped cell wide expressing tag capture protein products resulting expression strongly stimulated weakly stimulated pathways observed activated weak incapable inducing stimulated individually simultaneous weak undergo cooperative fashion explain multiple weak result collective sufficient induce explained described previously explains ability weakly stimulated capable independently generating receive products protein synthesis initiated collectively accomplished synthesis local tag following weak described previously molecules classified calcium presence activity necessary generating nearly conditions contrast alter essential generation expression addition signaling pathways described altered variety example enhance driving subsequent spine growth additionally alter protein synthesis dependent late phase activity result subsequent activation similarly activation enhance camp signaling relationship memory long term cell culture provide elegant substrate learning memory contribution learning learning level organism simply studies reason considerable effort dedicated establishing requirement learning memory living animals plays crucial role fear processing spatial memory provided evidence required formation memories tested spatial memory rats modifying brain structure role spatial learning established rats trained morris water maze spatial memory task rats swim pool water locate platform hidden beneath surface exercise normal rats expected associate location hidden platform cues placed specific positions maze training group rats group served control groups subjected water maze spatial memory task rats control group able locate platform escape pool performance treated rats significantly impaired taken groups easily induced controls induced brains treated rats provided early evidence extension required types learning memory similarly demonstrated area crucial formation spatial memories living mice called place cells located region active rat particular location called place field environment place fields distributed environment interpretation groups place cells form maps accuracy maps determines rat learns environment navigate found specifically genetically removing region place fields generated substantially specific controls mice produced faulty spatial maps impaired expected mice performed poorly spatial tasks compared controls supporting role spatial learning avoidance colleagues reported series experiments provided strongest evidence role memory arguing conclude learning processes mimic employing avoidance learning researchers trained rats apparatus light dark chambers fitted device delivered foot shock rat entry analysis revealed avoidance training induced type seen avoidance training addition training experimental induced avoidance training response article colleagues remarked related experiments substantially advance case mechanism memory clinical significance role disease clear role basic mechanisms alterations contribute number diseases including depression disease pain impaired role disease drug addiction disease received attention study disease disease causes marked decline deterioration occurs association changes temporal lobe structures established role suggested decline seen individuals result impaired review literature proposed model affected appears result precursor protein app result abnormal processing accumulation fragments protein called exists forms app results accumulation according hypothesis lead decline seen early mechanisms distinct example study demonstrated marker critical importance maintenance late drug addiction research field addiction medicine recently turned focus owing hypothesis drug addiction represents powerful form learning memory addiction complex phenomenon involving parts brain ventral area nucleus studies demonstrated capable undergoing responsible behaviors characterize addiction
Long-term potentiation