A Good Memory or a Bad One? One Brain Molecule Decides.

When the brain encodes memories as positive or negative, one molecule determines which way they will go. Wecareaboutyourdata,andwe'dliketousecookiestogiveyouasmoothbrowsingexperience.Pleaseagreeandreadmoreaboutourprivacypolicy.AgreeAGoodMemoryoraBadOne?OneBrainMoleculeDecides.ReadLaterShareCopied!CommentsReadLaterReadLatermemoryAGoodMemoryoraBadOne?OneBrainMoleculeDecides.ByYaseminSaplakogluSeptember7,2022Whenthebrainencodesmemoriesaspositiveornegative,onemoleculedetermineswhichwaytheywillgo.ReadLaterWhenmemoriesareencodedaspositiveornegativeexperiences,therecordsaresetupindifferentpartsofthebrain.Researchersarenowlearningwhatdetermineswhichwaytheinformationgoes. JasonLyonforQuantaMagazine YaseminSaplakogluStaffWriterSeptember7,2022ViewPDF/PrintModebiologybrainsmemoryneuronsneuroscienceAlltopicsYou’reonthevacationofalifetimeinKenya,traversingthesavannaonsafari,withthetourguidepointingoutelephantstoyourrightandlionstoyourleft.Yearslater,youwalkintoaflorist’sshopinyourhometownandsmellsomethingliketheflowersonthejackalberrytreesthatdottedthelandscape.Whenyoucloseyoureyes,thestoredisappearsandyou’rebackintheLandRover.Inhalingdeeply,yousmileatthehappymemory. Nowlet’srewind.You’reonthevacationofalifetimeinKenya,traversingthesavannaonsafari,withthetourguidepointingoutelephantstoyourrightandlionstoyourleft.Fromthecornerofyoureye,younoticearhinotrailingthevehicle.Suddenly,itsprintstowardyou,andthetourguideisyellingtothedrivertohitthegas.Withyouradrenalinespiking,youthink,“ThisishowIamgoingtodie.”Yearslater,whenyouwalkintoaflorist’sshop,thesweetfloralscentmakesyoushudder. “Yourbrainisessentiallyassociatingthesmellwithpositiveornegative”feelings,saidHaoLi,apostdoctoralresearcherattheSalkInstituteforBiologicalStudiesinCalifornia.Thosefeelingsaren’tjustlinkedtothememory;theyarepartofit:Thebrainassignsanemotional“valence”toinformationasitencodesit,lockinginexperiencesasgoodorbadmemories. Andnowweknowhowthebraindoesit.AsLiandhisteamreportedrecentlyinNature,thedifferencebetweenmemoriesthatconjureupasmileandthosethatelicitashudderisestablishedbyasmallpeptidemoleculeknownasneurotensin.Theyfoundthatasthebrainjudgesnewexperiencesinthemoment,neuronsadjusttheirreleaseofneurotensin,andthatshiftsendstheincominginformationdowndifferentneuralpathwaystobeencodedaseitherpositiveornegativememories. Thediscoverysuggeststhatinitscreationofmemories,thebrainmaybebiasedtowardrememberingthingsfearfully—anevolutionaryquirkthatmayhavehelpedtokeepourancestorscautious. Thefindings“giveussignificantinsightsintohowwedealwithconflictingemotions,”saidTomásRyan,aneuroscientistatTrinityCollegeDublinwhowasnotinvolvedinthestudy.It“hasreallychallengedmyownthinkinginhowfarwecanpushamolecularunderstandingofbraincircuitry.” Italsoopensopportunitiestoprobethebiologicalunderpinningsofanxiety,addictionandotherneuropsychiatricconditionsthatmaysometimesarisewhenbreakdownsinthemechanismleadto“toomuchnegativeprocessing,”Lisaid.Intheory,targetingthemechanismthroughnoveldrugscouldbeanavenuetotreatment. “Thisisreallyanextraordinarystudy”thatwillhaveaprofoundimpactonpsychiatricconceptsaboutfearandanxiety,saidWenLi,anassociateprofessoratFloridaStateUniversitywhostudiesthebiologyofanxietydisordersandwasnotinvolvedinthestudy. DangerousBerries Neuroscientistsarestillfarfromunderstandingexactlyhowourbrainsencodeandremembermemories—orforgetthem,forthatmatter.Valenceassignmentisnonethelessseenasanessentialpartoftheprocessforformingemotionallychargedmemories. Theabilityofthebraintorecordenvironmentalcuesandexperiencesasgoodorbadmemoriesiscriticalforsurvival.Ifeatingaberrymakesusverysick,weinstinctivelyavoidthatberryandanythingthatlookslikeitthereafter.Ifeatingaberrybringsdelicioussatisfaction,wemayseekoutmore.“Tobeabletoquestionwhethertoapproachortoavoidastimulusoranobject,youhavetoknowwhetherthethingisgoodorbad,”HaoLisaid. SharethisarticleCopied!NewsletterGetQuantaMagazinedeliveredtoyourinboxSubscribenowRecentnewslettersTheneuroscientistsKayTyeandHaoLi,apostdoctoralresearcherinherlaboratoryattheSalkInstituteforBiologicalStudies,identifiedasmallpeptidemolecule,neurotensin,asthesignalthatdeterminedwhethermemorieswereencodedaspositive. SalkInstitute Memoriesthatlinkdisparateideas—like“berry”and“sickness”or“enjoyment”—arecalledassociativememories,andtheyareoftenemotionallycharged.Theyforminatinyalmond-shapedregionofthebraincalledtheamygdala.Thoughtraditionallyknownasthebrain’s“fearcenter,”theamygdalarespondstopleasureandotheremotionsaswell. Onepartoftheamygdala,thebasolateralcomplex,associatesstimuliintheenvironmentwithpositiveornegativeoutcomes.Butitwasnotclearhowitdoesthatuntilafewyearsago,whenagroupattheMassachusettsInstituteofTechnologyledbytheneuroscientistKayTyediscoveredsomethingremarkablehappeninginthebasolateralamygdalaofmice,whichtheyreportedinNaturein2015andinNeuronin2016. Tyeandherteampeeredintothebasolateralamygdalaofmicelearningtoassociateasoundwitheithersugarwateroramildelectricshockandfoundthat,ineachcase,connectionstoadifferentgroupofneuronsstrengthened.Whentheresearcherslaterplayedthesoundforthemice,theneuronsthathadbeenstrengthenedbythelearnedrewardorpunishmentbecamemoreactive,demonstratingtheirinvolvementintheassociatedmemory. ButTye’steamcouldn’ttellwhatwassteeringtheinformationtowardtherightgroupofneurons.Whatactedastheswitchoperator? Dopamine,aneurotransmitterknowntobeimportantinrewardandpunishmentlearning,wastheobviousanswer.Buta2019studyshowedthatalthoughthis“feel-good”moleculecouldencodeemotioninmemories,itcouldn’tassigntheemotionapositiveornegativevalue. Sotheteambeganlookingatthegenesexpressedinthetwoareaswherepositiveandnegativememorieswereforming,andtheresultsturnedtheirattentiontoneuropeptides,smallmultifunctionalproteinsthatcanslowlyandsteadilystrengthensynapticconnectionsbetweenneurons.Theyfoundthatonesetofamygdalaneuronshadmorereceptorsforneurotensinthantheother. Thisfindingwasencouragingbecauseearlierworkhadshownthatneurotensin,ameagermoleculejust13aminoacidslong,isinvolvedintheprocessingofrewardandpunishment,includingthefearresponse.Tye’steamsetouttolearnwhatwouldhappeniftheychangedtheamountofneurotensininthebrainsofmice. TinyMoleculeWithaBigPersonality Whatfollowedwereyearsofsurgicallyandgeneticallymanipulatingmouseneuronsandrecordingthebehaviorsthatresulted.“BythetimeIfinishedmyPh.D.,Ihaddoneatleast1,000surgeries,”saidPraneethNamburi,anauthoronbothofthepapersandtheleaderofthe2015one. Duringthattime,TyemovedhergrowinglabacrossthecountryfromMITtotheSalkInstitute.NamburistayedatMIT—henowstudieshowdancersandathletesrepresentemotionsintheirmovements—andHaoLijoinedTye’slabasapostdoc,pickingupNamburi’snotes.Theprojectwasstalledfurtherbythepandemic,butHaoLikeptitgoingbyrequestingessential-personnelstatusandbasicallymovingintothelab,sometimesevensleepingthere.“Idon’tknowhowhestayedsomotivated,”Tyesaid. Neuronsfromseveralregionsofthebrain’sthalamusextendaxonsintotheamygdala,butresearchersfoundthatonlytheparaventricularnucleusregion(green)dictatesvalence. NatsukoHitora-Imamura Theresearchersknewthattheneuronsintheamygdaladidnotmakeneurotensin,sotheyfirsthadtofigureoutwherethepeptidewascomingfrom.Whentheyscannedthebrain,theyfoundneuronsinthethalamusthatproducedalotofneurotensinandpokedtheirlongaxonsintotheamygdala. Tye’steamthentaughtmicetoassociateatonewitheitheratreatorashock.Theyfoundthatneurotensinlevelsincreasedintheamygdalaafterrewardlearninganddroppedafterpunishmentlearning.Bygeneticallyalteringthemice’sthalamicneurons,theywereabletocontrolhowandwhentheneuronsreleasedneurotensin.Activatingtheneuronsthatreleasedneurotensinintotheamygdalapromotedrewardlearning,whileknockingouttheneurotensingenesstrengthenedpunishmentlearning. Theyalsodiscoveredthattheassignmentofvalencestoenvironmentalcuespromotesactivebehavioralresponsestothem.Whentheresearcherspreventedtheamygdalafromreceivinginformationaboutpositiveornegativevalencebyknockingoutthethalamicneurons,themicewereslowertocollectrewards;inthreateningsituations,themicefrozeratherthanrunningaway. Sowhatdotheseresultssuggestwouldhappenifyourvalence-assignmentsystembrokedown—whileanangryrhinowaschargingyou,forexample?“Youwouldjustonlyslightlycare,”Tyesaid.Yourindifferenceinthemomentwouldberecordedinthememory.Andifyoufoundyourselfinasimilarsituationlaterinlife,yourmemorywouldnotinspireyoutotryurgentlytoescape,sheadded. However,thelikelihoodthatanentirebraincircuitwouldshutdownislow,saidJeffreyTasker,aprofessorinthebraininstituteatTulaneUniversity.It’smoreprobablethatmutationsorotherproblemswouldsimplypreventthemechanismfromworkingwell,insteadofreversingthevalence.“Iwouldbehard-pressedtoseeasituationwheresomebodywouldmistakeachargingtigerasaloveapproach,”hesaid. HaoLiagreedandnotedthatthebrainlikelyhasfallbackmechanismsthatwouldkickintoreinforcerewardsandpunishmentseveniftheprimaryvalencesystemfailed.Thiswouldbeaninterestingquestiontopursueinfuturework,headded. Onewaytostudydefectsinthevalencesystem,Taskernoted,mightbetoexaminetheveryrarepeoplewhodon’treportfeelingfear,eveninsituationsroutinelyjudgedasterrifying.Variousuncommonconditionsandinjuriescanhavethiseffect,suchasUrbach-Wiethesyndrome,whichcancausecalciumdepositstoformintheamygdala,dampeningthefearresponse. TheBrainIsaPessimist Thefindingsare“prettybigintermsofadvancingourunderstandingandthinkingofthefearcircuitandtheroleoftheamygdala,”WenLisaid.Wearelearningmoreaboutchemicalslikeneurotensinthatarelesswellknownthandopaminebutplaycriticalrolesinthebrain,sheadded. Theworkpointstowardthepossibilitythatthebrainispessimisticbydefault,HaoLisaid.Thebrainhastomakeandreleaseneurotensintolearnaboutrewards;learningaboutpunishmentstakeslesswork. Furtherevidenceofthisbiascomesfromthereactionofthemicewhentheywerefirstputintolearningsituations.Beforetheyknewwhetherthenewassociationswouldbepositiveornegative,thereleaseofneurotensinfromtheirthalamicneuronsdecreased.Theresearchersspeculatethatnewstimuliareassignedamorenegativevalenceautomaticallyuntiltheircontextismorecertainandcanredeemthem. “You’remoreresponsivetonegativeexperiencesversuspositiveexperiences,”HaoLisaid.Ifyoualmostgethitbyacar,you’llprobablyrememberthatforaverylongtime,butifyoueatsomethingdelicious,thatmemoryislikelytofadeinafewdays. Ryanismorewaryofextendingsuchinterpretationstohumans.“We’redealingwithlaboratorymicewhoarebroughtupinvery,veryimpoverishedenvironmentsandhaveveryparticulargeneticbackgrounds,”hesaid. Still,hesaid,itwouldbeinterestingtodetermineinfutureexperimentswhetherfearistheactualdefaultstateofthehumanbrain—andifthatvariesfordifferentspecies,orevenforindividualswithdifferentlifeexperiencesandstresslevels. Thefindingsarealsoagreatexampleofhowintegratedthebrainis,WenLisaid:Theamygdalaneedsthethalamus,andthethalamuslikelyneedssignalsfromelsewhere.Itwouldbeinterestingtoknowwhichneuronsinthebrainarefeedingsignalstothethalamus,shesaid. ArecentstudypublishedinNatureCommunicationsfoundthatasinglefearmemorycanbeencodedinmorethanoneregionofthebrain.Whichcircuitsareinvolvedprobablydependsonthememory.Forexample,neurotensinisprobablylesscrucialforencodingmemoriesthatdon’thavemuchemotionattachedtothem,suchasthe“declarative”memoriesthatformwhenyoulearnvocabulary. ForTasker,theclear-cutrelationshipthatTye’sstudyfoundbetweenasinglemolecule,afunctionandabehaviorwasveryimpressive.“It’sraretofindaone-to-onerelationshipbetweenasignalandabehavior,oracircuitandafunction,”Taskersaid. NeuropsychiatricTargets Thecrispnessoftherolesofneurotensinandthethalamicneuronsinassigningvalencemightmakethemidealtargetsfordrugsaimedattreatingneuropsychiatricdisorders.Intheory,ifyoucanfixthevalenceassignment,youmightbeabletotreatthedisease,HaoLisaid. It’snotclearwhethertherapeuticdrugstargetingneurotensincouldchangethevalenceofanalreadyformedmemory.Butthat’sthehope,Namburisaid. Pharmacologically,thiswon’tbeeasy.“Peptidesarenotoriouslydifficulttoworkwith,”Taskersaid,becausetheydon’tcrosstheblood-brainbarrierthatinsulatesthebrainagainstforeignmaterialsandfluctuationsinbloodchemistry.Butit’snotimpossible,anddevelopingtargeteddrugsisverymuchwherethefieldisheaded,hesaid. Ourunderstandingofhowthebrainassignsvalencestillhasimportantgaps.It’snotclear,forexample,whichreceptorstheneurotensinisbindingtoinamygdalaneuronstoflipthevalenceswitch.“Thatwillbothermeuntilitisfilled,”Tyesaid. Toomuchisalsostillunknownabouthowproblematicvalenceassignmentsmaydriveanxiety,addictionordepression,saidHaoLi,whowasrecentlyappointedasanassistantprofessoratNorthwesternUniversityandisplanningtoexploresomeofthesequestionsfurtherinhisnewlab.Beyondneurotensin,therearemanyotherneuropeptidesinthebrainthatarepotentialtargetsforinterventions,HaoLisaid.Wejustdon’tknowwhattheyalldo.He’salsocurioustoknowhowthebrainwouldreacttoamoreambiguoussituationinwhichitwasn’tclearwhethertheexperiencewasgoodorbad. ThesequestionslingerinHaoLi’sbrainlongafterhepacksupandgoeshomeforthenight.Nowthatheknowswhichnetworkofchattycellsinhisbraindrivestheemotionshefeels,hejokeswithfriendsabouthisbrainpumpingoutneurotensinorholdingitbackinresponsetoeverybitofgoodorbadnews. “It’sclearthatthisisbiology,ithappenstoeveryone,”hesaid.That“makesmefeelbetterwhenI’minabadmood.” YaseminSaplakogluStaffWriterSeptember7,2022ViewPDF/PrintModebiologybrainsmemoryneuronsneuroscienceAlltopicsSharethisarticleCopied!NewsletterGetQuantaMagazinedeliveredtoyourinboxSubscribenowRecentnewslettersTheQuantaNewsletterGethighlightsofthemostimportantnewsdeliveredtoyouremailinboxSubscribeRecentnewslettersCommentonthisarticleQuantaMagazinemoderatescommentsto facilitateaninformed,substantive,civilconversation.Abusive,profane,self-promotional,misleading,incoherentoroff-topiccommentswillberejected.Moderatorsarestaffedduringregularbusinesshours(NewYorktime)andcanonlyacceptcommentswritteninEnglish.  ShowcommentsNextarticleHowShannonEntropyImposesFundamentalLimitsonCommunication