Shadlen Neuronsinthelateralintraparietalareaarespatiallyselectiveandpersistentlyfireinthe timebetweenthestimulusandtheactionifamonkeyisaskedtodoanactionafter seeingacueanddelay Monkeyseesasequenceofshapesandwhenthemonkeyisreadyhechoosesoneof twotargets.Therewardisatoneofthetwotargetsandtheprobabilitythatashape appearsisdeterminedbywhichoneisthecorrecttarget. ThestrengthoftheinformationisdeterminedbylogLR(likelihoodratio) Whenlog(LR)ishigh(above2),monkeysareverygoodatchoosingthecorrect target Monkeystypicallypickatargetafter5shapes IftheyrecordfromtheLIPduringthepresentationofshapes,theyseethattheneural firingrateincreasesasevidenceaccumulatesfortargetanddecreasesasevidence accumulatesagainstthetarget.So,asevidenceaccumulates,theneuronfiresfaster andfaster.

aster. Andsinceeachshapeasadifferentprobabilityofrelatingtoatarget,theshapes withhighestprobabilitywillincreasethefiringratethemost.Thespikesincrease 56spikesperminutewitheachunitofloginformation Iftheyalignthespikestowhenthemonkeymakesaselection,findthatthedifferencein spikerategoesaway.Thatis,oncethespikingreachessomelevel,themonkeywillthen choose Brody Harddecisionsareslowandeasydecisionsarefast.Thishappensacrossmodalities, suchassocialdecisions,valuedecision,economicdecisions,sensorydecisions,etc. Noisyaccumulationofevidencecanaccountforthis.Asevidenceisaccumulated,it reachesathresholdfasteriftheevidenceaccumulatesfaster Weakevidenceaccumulatesslowlyandstrongevidenceaccumulateswith higherslope Evidenceislikelytobeaccumulatedfromeverywhereinthebrain,buttheway thisworksisunknown. Poissonclickstask:ratsareplacedinroomwiththreenoseports.Whenthelightinthe middleturnon,heputshisnoseinthemiddle.Thenplayclicksfromleftandright speakersandbasedonwhichsideclicksmore,willputnoseinthenoseportonthat side. Cancontroldifficultyoftaskbychangingtheratioofclicksonthetwosides FoundstandardhallmarksofevidenceaccumulationinPPC(parietalcortex)andFOF (frontalcortex)firingincreasedasevidencewasaccumulated. Wantstobeabletoestimatetheaccumulatoratanygiventime. InPPC,foundastableandgraded(thefiringrateisafunctionofstrengthof representation)representationofaccumulatorvariable InFOf,foundstable,binaryrepresentationofa.Thatis,allthenegative representationsarefiringatthesamerateandallthepositiveonesarefiringat

anotherrate.Thatis,iftherathadtochooseimmediately,whichonewouldhe choose? InactivationofneuronsinFOFwithmuscimolcausesbiasinanimalchoise.But inactivationofPPCdoesnot.ThissuggeststhataccumulatorisupstreamofPPC Ifusedinactivationwithhalorhodopsin,foundthatfofinactivationonlyattheendofthe stimulussowhenthechoiceisbeingmadeimmediately Chklovskii Invisualsensorydetection,itswellknownthatthereisabuiltintimedelaysothata movingobjectthatpassesthroughtwovisualfieldswillreachthedownstreamneuron multiplieratthesametime Indrosophila,neuronsinthelamina(firstsynapseafterphotoreceptors)arenot directionsselectivebutthoseinthelobulaplatearedirectionselection.Bteweenthe laminaandthelobulaplateisthemedulla,sosomethinghappensinthemedullathat makesdirectionselectivity SothereforeusedEMtopographytoreconstructthecircuitin3D Seethatneuronarearrangedincolumns. Cansimulatemotionbystimulatingneuroninadjacentcolumns Becauseneuronmorphologyisstereotyped,usedmorphlogytoidentifyneuroncell types. ReconstructedstacksofEMimagesinto3Dshapesandthenidentifiedneurons andsynapses Creatednetworktoreconstructcircuit Sincecelltypesareidentified,eliminatedneuroncircuitsthatareforshapeand colorandfocusedonremainingcircuitstoidentifymotiondetection L1andL2neuronsinlaminaareknowntobenecessaryformotion.AndT4andT5 neuronsareknowntobeneededinthemedullaformotion.Theyaretheoutputneurons. Mi1andTm3havestrongconnectionbetweenL1andT4andarelikely responsibleforthemotiondetector.Mi1receivesinputfromitsowncolumnwhile Tm3receivesinputfromadjacentcolumns,makingitintegrator FortheL2pathway,Tm1andTm4arelikelytobethecellsmediatingthis. Differenceindelaysmaybeduetodifferentneurotransmitterreceptorsinmi1and Tm3 Seung Isinvestigatingdirectionselectivityintheretina FocusingontheJtypeofganglioncell,definedbyJamBexpression Cellsshareacommonfunction:motiondetectionwithpreferencetowardsdown ThedendritesinJtypecellspointdownsoisthiscorrelatedwithtsdirectional preference? Thishypthesiscomesfromthestarburstamacrinecell,whichhasdeindritesthat pointoutwardandeachdendriteprefersoutwardmotionalongthatdendrite. Apassivedendriteshouldbedirectionallyselective.Ifyoustimulatetwosynapses,the

currentfromthefartherdendritewillreachthesomaatalatertime Soifyoustimulatethetwosynapsesinsuccessionwiththefartheronefirstand thecloseronesecond,thesignalswillreachthesomatogether. Forthestarburstcells,theyaretheoutputsynapsesaredistaltothesoma.So thetwosignalsintegrateattheoutputsynapseifthesynapsethatisclosertothe outputsynapse(distaltosoma)isstimulatedsecond. Hausselt.showedalsothattheproximaldendriteisalsodepolarizedinthe preferreddirection,soitsnotjustinterationatthesynapse Hypthesis1:JandSACsharesimilardendriticbiophysics.TheJcellislikehalfa starburstcellthatonlypointsdown Jcellsareconnectedtostarburstcellsbysynapses IsaJcellmoreconnectedtosACdendriteswiththeoppositepreferreddirection? Asitturnsout,no.JSACsynapsenumbersareindiscriminate. ButthesAcinhibitionismoreproximaltoJsomathanbipolarcellexcitation Thissuggeststhattheexcitationcanbevetoedbyinhibitiononthepathwaytoth soma Sointhenulldirection,theexcitationhitsthebipolarcellfirstandtheSACinhibitsthe signalsonothinghappens.butinthepreferreddirection,theexcitationhitsaftertheSAC inhibition. Vosshall Mosquito(aedesaegypti)arehighlyhumanselective,sousesvisual,odor,carbon dioxide,andheatarecuesforher. CarbondioxideissensedbyGR3,agustoryreceptor,usingzincfingersthatcutoutthe geneandknockedinafluorescentmarker Inwildtypemosquitoes,mosquitoesgocrazyinthepresenceofCO2inthe knockout,thisbehaviorgoesaway Femalemosquitoesareattractedtoheat,butonlywhenactivatedbyCO2,andthis activatesbitingbehavior Maleshavethereceptors,butlackthisbehavior Similarly,femalemosquitosareinterestedtolacticacid,butonlyinthepresenceofCO2 Theknockoutslackthisbehavior Apieceofclothwithhumanodorswillattractfliesalittle(morethanlacticacid), butnotasmuchaswheninthepresenceofCO2 Ifpresentedwithamouse,mosquitoesusuallytargetthemice.ButGR3knockout mosquitoesdonot Currentlytestingthiswithhumanbait Orcomutantmalemosquitoesareimpairedinsensinghoneyodor Orcofemales,however,arecapableoffindinghumansandguineapigtargets Thisbehaviorisreplicatedbyanylonstockingthatsmellslikehumansonlyinthe presenceofCO2,butnotwithoutCO2 SotheorcopathwaycanpartiallycomplementtheGR3pathway Wildtypesshowextremepreferenceforhumansoverguineapigs,butorco

mutantsareimpaired. Baker Studyinginnatebehaviors,whichbydefinitionmustbeestablishedbygenes.Uses drosophilacourtshipasamodel. Thegenespartofthesexdeterminationpathway(fruitless,doublesex,etc.) determinethis.Fruitlessisbothnecessaryandsufficientdoublesexisneither. FruManddsxareexpressedinnonoverlappingsetsofneurons FruMnullmalesdoesntocourtfemale MultiplefruMnullmaleswillcourteachother ActivatingdsxneuronsusingdTrpA1willactivatecourtshipbehaviorinfruMnull malesevenwithoutanotherflyaround SofruMnullmalesarecapableofcourtship,butnotwithfemales ThedifferencebetweenthefruMmalewithfemalesandmalesisthewaytheyare housed.ThefruMmaleishousewithothermalesbeforetheassay,butnotwithfemales. IfyouputthefruMnullmalewithfemalesbeforetheassay,giveitfourdays,the mutantmalewillstartcourtingthefemale. Grouphousing/socialexperienceisimportantforcourtshipbehaviorinfruMnull dsxisacandidategeneresponsibleforthefruMindependentcourtshipbehavior ExpressingthemaledsxMspliceinfemalescausescourtshipbehaviorin femalesaftergrouphousingforseveraldays AfterthefruMnullmaleslearncourtshipingrouphousing,doesthebehaviorpersist? AfterhousingthefruMnullmaleswithfemalesforseveraldays,itwillcourta freshfemaleafter30minutesor7daysofisolation Sothelearningofcourtshipislongterm(evenlongerthanolfactorylearning paradigms) Thisisreminescentwithimpritinginduckswheretheducklingswilllearntofollow whoeverisaroundafterhatching IfthefliesarehousedwithD.mojavensis(anotherspecies),theywilllearntocourtD. mojavensisoverD.melanogaster. Sehgal Sleepisdrivenbyboththecircadiansystemthatisdrivenbylight(anddeterminestime ofsleep)andahomeostaticsystemthatdeterminestheamountofsleep Identifiedasleepless(sss)mutantthatsleepslessthanwildtype(eventhoughitfollows thelight/darkschedule) SssisatoxinlikemoleculethattargetsShaker.ItactivatesShaker,whichdepresses neuralactivityandresultsinsleep IdentifiedCG7433asamoleculethatisupregulatedinsssmutants.ThisislikelyaGABA transaminase,amitochondrialenzymethatbreaksdownGABA Mutantsofgabatshowincreaseddailysleep Mutantsofgabatsleepinlongerblocks,soeachboutofsleepislonger Mutantsofgabatshowincreasedarousalthreshold,soittakesabiggerstimulus

towakethemup Thegabatmutantcompletelysuppressesthesssphenotype Anothermutantofdopaminetransporteralsohaveshortersleep.Thegabat mutantisunabletosuppressthatphenotype Thisisnotcellautonomous,sinceexpressionofsssingabatcellsdoesnot rescue.However,expressioningad1cells(gabaergiccells)does. Puttinggabatinglialcellsrescuessssmutants Hermodelisthatknockoutofsssincreasesshakeractivity,whichcausesneuronsto usemoreenergy,whichcausesgabatactivationinmitochondriainglia,whichdrives sleep Rosbash Thecircadiangenesaresyncedacrossall75neuronsinvolvedinthefly AsetofMcellsworkinthedayandasetofEcellsworkintheevening.These twosetsofcellsoperateautonomously ScreenedforneuropeptidesandfoundthatsNPFinducessleepunderbothLDandDD conditions Noticesthatyoucangetnegativesleepreboundiffliesareforcedtosleeplongerthan usualbytemperatureshifts.Inthefuture,theysleepless Atthesametime,fliesalsochangetheirfeedingbehaviorasaresultof temperaturechanges.Butthisshiftisnotimmediate,unlikethsleepphenotype Whencellsaresortedbywhethertheyarelightarousalornot,sNPFishighlyexpressed incellsthatsurroundthelightarousalcells Inthearousalcells,Oamb,andDopR(dopaminereceptor)arehighlyexpressed sNPFhasasleepinhibitoryeffectonthelightarousalneurons Rubin GEnerated7000linesusingenhancerfragmentstotrytolabelsinglecelltypes Unfortunately,almostallenhancersareexpressedinmanycelltypes,sousingthe splitGal4system,labeledsinglecellsattheintersectionoftwoenhancers Usingthissystem,testedfliesonanarenasystemwheretheflywantstorotateitsbody tokeepaLEDbarwithinitsvisualsystem Becausewasabletoindividuallylabeleachofthe12celltypesinthevisual lamina,wasabletoknockoutindividualcelltypesandascribespecificbehavioral deficitstoeachline Similarly,targetedall58cellsinthemushroombody,whichisresponsibleforlearnign associations(solearningodorcueswithshocksorsugarstimuli) Tracingtheseneurons,findthattheyareverysparselytargettedsothateachcell hasoneinputandoneoutputneurononaverage.Fromtheconnections,there seemtobe13differentunits Gouaux P2XreceptorsandASIC(acidsensingionchannels)sharenosequencehomologybut havesimilarmemranetopology

 ASICisrelatedtoENacandothermechanosensitivechannels Theextracllulardomainsarecompletelydifferent,butthetransmembraneportionsare verysimilar TM2segmentoccludestheporeineachclosedtrimer FortheP2Xchannel TheATPbindsintheextracellulardomain,onepersubunit,inacleft Theextracellulardomainoccludesthepore,soitslikelythattheionsenter throughlateralfenestrations ATPbindingflexesthbodydomain,whichisconnectedtothetransmembrane segments.Thetransmembranedomainsopeninanirislikemannertopullopen pore Forasic Again,nopathwaythroughtheextracellulardomain,soionsenterthroughthe side TheMitTxtoxinstabilizesasicchannelsintheopenstate,whichisimportant becausethechannelrapidlyinactivates Again,onetoxinheterodimerbindstoeachsubunit,anditpriesthechannelopen likeabottleopener Again,thescaffoldportionoftheextrecellulardomaindoesnotmoveandtheres noionpathwaythere,butthelowerportionofthedomainisconnectedtothe tranemembranedomaintoopenit Thereisnosingleresiduethatbindsprotons.Itsdistributedacrossthechannel withaHillslopeof69 Notethattheclosedstatecapturedhereistheinactivestate.Nostructureofthe closedrestinghighpHstateofasic Corey Thestereociliaofearcellsmustmaintaintheirshapeforalifetime Tipsareregeneratedin510hours ManorandKacharfoundTurnoveroftheactincorecanbeveryrapid,in23days Ifthestereociliaarecut,itcanremodelinhours Andhypothesizedthiswasthroughactintreadmilling Coreysgroupthoughtthiswastoofastandusedradioactivenitrogen Usingamultiisotopemassspec,aCs+beamisscannedonthesampleand negativeionsarereflectedbackalongthebeamlinewhilepositiveionsaremoved forward Foundthatthestereociliahadverylowproteinturnovercomparedtothecell bodies.Theverytipsofstereociliahavehigherturnovercomparedtorestof stereocillia Isitpossiblethattheactinistreadmilling,butwitholdprotein,notnewprotein(and thereforewouldnotbelabeled)? whentheybleachgfplabeledactin,theyfindthatthebleachedactindoesnot move,soitdoesntseemtobetreadmilling

Usinganinducibleactinline,findthatonlythtipofthestereocilialosestheold actinwhentheinducibleactinisturnedoff

Brunger Synapticvesicleshavememraneproteinsthatareinvolvedintargetingandtrafficking, andotherproteinsthatarepartofcalciumtriggeringandfusion CreatedanassayusingPEGcoatedsurfacewithreconstitutedproteoliposomeswith synaptobrvin/synaptotagminasaninvitrosystem.Therearevesiclesonthesurfaceto acceptthesyntheticvesicles Labelsthmembranelipidsseparatelyfromthevesiclecontent,socan discriminatebetweendocking,hemifusion,andfullfusion whatisthepathwayforfastcatriggeredfusion? Withsnare/synaptotagminI,seestwotypesoffusionevents allimmediateeventsstartfromahemifusionfreestateandhappensveryfast Ifthereishemifusion,thevesiclesfuseslowly(thisistheclassicalpathway) Addcomplexinanditsynchronizesfusionevents Reduceshemifusiondeadends Thatis,addingcomplexinshiftsthefusiontowardtheimmediatepathway. Sudhof membranefusioninvolvestwomajorconformationaltransitions: First,thesyntaxinhastogofromclosedtoopenstate Second,SNAREcomplexesmustassemble Oncethesetwoeventsoccur,calciumcomesintogetfusion Synatxinisveryimportant intheclosedconformation,bindstomunc18,andwhenitopens,itformsSnarE complex munc18alsobindstotheNterminusintheopenmode DeletionoftheNterminusofsyntaxinblocksmembranefusionandIPSC,soits thsecondmodeofbindingthatisimportantforfusion So,ifthisisallright,openingsyntaxinshouldspeedupprimingbutnotchangeanythign else Openingsyntaxinproduceslethalepilepsyandtheresalossofmunc18complex Wantstotestthespeedofcalciumrelease Findsthatyougethigherreleaseintheopensyntaxineventhoughthecalcium staysthesame Findsthattheopensyntaxinhasa3foldinreaseincalciumsensitivity Inaddition,thespeedoffusionisfasterwhenthesyntaxinisopen Thissuggeststhatthestandardmodelisnotcorrectsincethatwouldpredictthat opensyntaxindoesntchnagethespeedofcalciumactivity Rather,thecalciummustactearlierinthepathway,whensyntaxinisstilclosed. Dulac H2beisanolfactoryspecifichistonevariant

Expressionisreplicationindependentandonlyhas5residuedifferenceswith canonicalH2b H2belevelsarestereotypedaccordingtotheexpressedodorantreceptor Andlossofh2bemakestheanimallessgoodatdiscriminatingodors ThismaybebecauseORexpressionchanges.TheORsthatusuallycolocalize withH2begodownwhileORsthatusuallydontcolocalizegoesdown. H2bedoesnotchooseORsinceitisexpressedafterORexpression H2bealsoisnotpartofstabilityofORexpressionbecausecotransfectionwitha givenORshowsthattheORisstabilyexpressed Instead,H2beaffectsneuronallongevity Atlowlevels,neuronslivelongerthantheydoathighH2belevels AndexpressionofH2beisactivitydependent,sothatneuronthatarenotactive(if youcloseanostril),H2begoesup ThemodelisthatH2beisresponsibleforallowingtheanimaltopromotesurvivalof neuronsthatarerelevanttotehanimal. H2beisboundattranscriptionalstartsitesthroughoutthegenomeandregulatesgene expressionbyreplacingH2B H2Beismissingacetylation/methylationsitesthatindicateactivegene transcription,soitsilencesgenesandcausethecelltodie.

Capecchi Hoxb8genesspendmoretimegroomingthanwildtypemice Hoxb8areexpressedinmicrogliaandareexpressedattwodifferenttimepoints Bonemarrowtreatmentfromwildtypemiceintomutantmicerescuesthegrooming phenotypetransplantfrommutanttowildtypemiceinducesphenotype Hoxb8micehavenociceptivephenotypeaswell Andthebonemarrowtransplantdoesnotrescuethepainphenotype CanrestricttheHoxb8mutanttobonemarrowcellswithTie2creandthisalsocauses groomingphenotypebutnotpain AndrestrictionofHoxb8knockouttospinalcordinducespainphenotypebutnot grooming Possiblyduetosecretionofcytokinesbymicroglainthebasalganglia? themicrogliahavelongprocessesthatcanreachoutlongdistances Crabtree SubunitsofnpBAFareessentialforneuralprogenitorproliferationandthoseofnBAFare essentialforpostmitoticneuraldevelopment Instemcells,mir9*andmir124areinhibited,allowingBaF52atoactivatestem cellgenes.Inneurons,themicroRNAsareexpressedandblockBAF53a,turning onBAF53btomakeneurons Infibroblasts,additionofthesemicroRNAscreateneuronphenotype Themir9*andmir124bindthe3UTRforBAF53aandrepressitandleadtomitoticexit. removalofBAF53aleadstoreducedSphaseentry

extendingBAF53aexpressionbydeletingBAF53bleadstoanincreasein neuronalnumber CangrowthfactorsignalignovercomeBAF53adeletion? TheswitchfromnpBAFtonBAFchangesoccupancyof31000sitesinthegenome

Horwich ManyALScasesiscausedbydominantgainoffunctionsuperoxidedismutaseSOD1 MousemodelswithG85Rismisfolded,notmythelated,doesnotformdimer,etc. Mutantlinehas200orsocopiesofthemutantG85Rgeneandhasashorthalflife TheHsc70chaperonecopurifieswiththemutantprotein.Hsp110isanucleotide exchangerforHsc70andactstodissociateaggregates ManyG85RanimalsarenotparalyzedbuthavebulbarALS,whichiswhenmuscleinthe esophogusareatrophiedandcannotgetfooddowntheirthroatintostomach UsinggiantsquidaxoplasmandpurifiedmutantSOD,observedaxonaltranportand foundthatthemutantSODslowsdownanterogradetransport(retrogradeunaffected) InhibitionofMAPKKKrescuesthis Inaddition,Hsc70andHsp110alsorescuesthis p38isphosphorylated(whichistargetofMAPKK) SosomehowG85rSODactivatestheMAPKKKcascade...whichsomehowdecreases anterogradetransport Axel

Olfactoryneuronssynapseontoglomerulus,whichisthenprojectedbyasingleneuron tohigherbrainareasinflies thisinformationmustconvergeontwoareaslateralhornforinnatebehaviorsand mushroombody Therepresentationofodorsinthemushroombodyisdistributedandthe representationisuniqueandcodesforodor Isthisrepresentationstereotyped?Orisitexperiencedependent? Thekenyoncellsareinnervatedbyasingleprojectionneuronandformsclaws Individuallyinjecteddyeintosingleclawsandtracedeachconnectionbackto createaconnectome Thedataisconsistentwitharandomdistributionofinputs So,thestructuredinputfromtheattenallobe(allsensoryneuronsofthesame ORconvergeonthesameglomerulus)isdiscardedinthemushroombodyand theinputstherearerandom.Sothesameodorwillactivateadifferentrepertoire ofkenyoncellsindifferentorganisms.

Liberger Howdoesthebraininformationacrosstime?(theaccumulator) Trainsmonkeystofollowadotwiththeireyes.Thedotmovesfromlefttorightandstays there. Thisbehaviorrequriesanintegraterbecausethecerebellumfiresonlyatonsetof

movement,butthemusclekeepsfiringaslongasthedotisthere. Downstreamofcerebellum,thFTN(flocculartargtneurons)onlyhasonset,the vestibularneuronhasalittlebitofsustainedfiring,andtheabducenkeepsfiring aslongasmuscleisactivated TheFTNandtheabducensalwaysfireinthesameway.ButtheFTNfiringis diverse Proposesamodelwitharecurrentmotornetworkwithstrongfeedforwardsignalanda weekfeedbacksignal.Thenetworkislinearandisnotfullyinterconnected. themodelintegratesandwasabletoreproducethediversityofthefTN responses Isthereanybiologicalevidenceforthesenetworks? inthezebrafish,Mirietalusedcalciumimagingtorecordneuralactivitywhen zebrafishdothesamebehavior. Sincetheywereabletorecordneuronpairs,wereabletoseethatthesenetworks exist. Newsome Isstudyingintegrationincontext.Sothemonkeyisexposedtogreenorreddotsmoving. Dependingonthecue,heeitherhastoanswera2choicetaskbasedonthemovement orthecolorofthedotsusingasaccade Traditionally,itwasthoughtthattheaccumulatorisinthePFCandthatonlyonesensory inputreachesthePFCdependingontask.Showsthatitsnottruebothsensory pathwayhitsthePFCbuthastobeignoredsomehow RecordingsingleneuronsfromPFC,findmanyneuronswithmixedchoice/motion/color modalities Isabletosimulatethepopulationofcellsseeninthecortexbyweightingthree differentchoice/motion/colormaps Thereasonwhythedatalookslikeamessisbecauseitssomanydifferent modalitiesrepresentedin2dimensions,eachonewithitsownaxesandmaps. Looger GCaMPisaGFPbrokenupintotwopartsthatfoldsupwhencalciumbindstoCaM (whichislinkedtotheGFPhalves) HavecreatedGCaMP6whichcomesinafast,medium,andslowsensitivityflavors. GiveshighersensitivitythanOGB,themostsensitivecalciumsensorpreviously available Givesyieldsasgoodaselectrophysiology.Temporalresolutionisntasfastas eletrophysiologyyet IsmakingaGCaMPforglutamate.Thesensorusesa4uMaffinityglutamatesensorfrom bacteriaandisanchoredinthemembrane Hassubmillisecondrisetimeandisabletodetecteventsfromsingleaction potentials IsnamediGluSnFR

Sabatini Thegenerationofmotorsequencesandtheappreciationofrewarddependonthebasal ganglia Dopamineanbethoughtofasarewardexpectationerrorsignal.Sodopamineis usuallyreleasedatthereward,butastheanimalistrained,dopaminemovesto thecue,sothecueisassociatedwiththereward.Whentherewardiswithdrawn, dopamineisalsoresponsibleforapauseinfiringintheexpectationofreward FoundthatdopaminergicneuronsreleasedGABA KnockoutofVGATdoesnotknockoutGABAcurrentbutknockoutofVMAT2 (whichisthetransporterfordopamine)does.SoGABAispackagedintovesicles byVMAT2 ThismeansthatindividualvesiclesarepackagingbothGABAandDopamine FoundthatdopaminergicneuronsdonotexpressGAD65,whichisenzymetomake GABAfromglutamate Instead,theseneuronsfromplasmamembraneGATwhichtransportGABAfrom theextracellularspace TheGABAreleasebydopaminergicneuronsinhibitstriatalactivity AndtheseneuronsdonotexpressanyclassicalGABAneuronmarkers Lee

Placecellsinthehippocampusspikesinthesamelocationinagivenmazeeverytime. Presumably,theyspikebecausethesummationofofinputscrossesathreshold.And thesilentcellsdonothaveinputsthatsumatthatpoint Butitsalsopossibletahtsilentcellshavelowerrestingmembrane anditsalsopossiblethattheresoscillationinthecellsandthesilentcellsspread outtheiroscillationssothatitdoesntcrossthreshold DoeswholecellrecordingofhippocampalCA1placecell Findthattheresnooscillationsincurrent Findthatsilentcellshaveveryflatmembranepotentials.Soitsnotevenbeing depolarizedbyinputs Andsilentcellsalsohavehigherthresholds Evenbeforeexplaration,findthatsilentcellsburstlessoftenthanonesthatwilleventually becomeplacecellswhencurrentisinjected Thissuggeststhatthesilentcellsarejustlessexcitable Sohowdoyouincreasecellularexcitabiity? Depolarizedthesilentcelltobringitclosertothreshold.Andnowthesilentcell becomesaplacecellandwillspikeatthesameplaceeverytime Andseesthattheinputsalsodepolarizethecellmore Viceversa,canalsoconvertaplacecelltoasilentcell Foundthatdependingonthedistancebetweenrestingandthreshold,theresasudden appearnceofinputdepolarization.Thatis,theremustbesomenonlinear voltagedependentmechanismthatconvertsasilentcelltoaplacecellwhentheresting

membraneispushedabovesomelevel Thiscomesfromthedendritebecauseactionpotentialsarenotrequired Thereissomeinputgatethatisresponsibleforlettingtheinputsin Dan

Duringwakefulness,EEGisnonsynchronizedandtheEMG(muscle)showstone.The EEGbecomessynchronizedintowavesduringslowwavesleepandmusclesare relaxed.Andfinally,duringREMsleep,theEEGagainbecomesdesynchronized,but muscletoneisnonexistnent. Sowhatcontrolssleepandwakefulness? LesionsoftheBFcauseinsomniaandincreaseslowEEGactivity OptogeneticactivationofcholinergicneuronsinBFcausewakefulness Usedoptroderecording,findthatthesecholinergicneuronsareactiveduringawakeand REM,butnotduringREMsleep OptroderecordingofPV+GABAergicneuronsdonotchangemuchduringsleep ActivingPV+neuronincreaseswakefulness ButactivationSOM+GABAergicneuronsshowoppositeresult.theyhaveincreasedfiring rateduringSWSandactivationincreasessleep PatchingontoacholinergicandPV+cell,findthatactivationofcholinergicneuroncauses EPSPinPV+cellsthatisblockedbynAChRblockers forSOM+cells,foundthatcholinergiccellscaneitheractivateorinhibitSOMcells

Jan

Weightgainisknowntobefunctionofageandthisevolutionaryconserved BodyweightisregulatedbyPOMCneuronsinthebrai foundthatPOMCneuronshaveincreasedmTORactivityandkATPchannels LossoffunctionofKATPcauseshypoglycemiaandgainoffunctioncauses neonataldiabetes FoundthatPOMCneuronareexcitableinyoungmicebutnotinoldmice thePOMCneuronsaresilencedbyKATPchannels

Jin studyingaxonregenerationinc.eleganswithfemtolaseraxotomy Axotomytriggerscalciumtransientsthatcorrelatewithregrowthandthisdependson VGCC,cAMP,andPKA Screenedforgenesinvolvedinaxonregenerationandfoundaround750genesthatare requiredforregenerativeresponse Focusedonthekinases,andfoundthatPKAslowsaxonregeneration.DLK kinaseacceleratesregeneration(andlosingitslowsitdown) DLKisaMAPKKKsubstrateandisaleucinezipper TheDLKlocusproducestwoisoformsthatinteract Asitturnsout,theshortisoformisanendogenousinhibitorofthelongisoform. Removingtheshortisoformenhancesregeneration

Duringaxotomy,thelongformofDLKaccumulatespreferentiallyatcutsites Itisactivatedbyphosphorylationattwosites

Krasnow Alveolartype1cellsarethethinnest,flattestcellsinthebodyinordertofaciliategas exchangewithredbloodcellsinthecapillary Type2cellsareresponsibleforsecretingasubstancethatpreventstheaveolar stacksfromcollapsing Bothtypesofcellscomefromthesameprogenitor,thatcantrnoneithera surfactantgeneprogramtoformtype2cellsorasquamousprogramfortype 1cells Lineagelabelingthetype2cellsshowthatmanyoftheat2cellsconverttoAT1 cellswithtimeandbecomethinwalled Inaddition,thesetype2cellsmultiplyandtherearemoreandmoreoflabeled AT1cellswithtime HighoxygenistoxictoAT1cells.ThedyingAT1cellsactivateAT2cellstodivideand replenishAT1cells ThemajorformoflungcanceriscausedbyAT2 Krasisknowntobeamajorcauseoflungcancer.ActivatingKrasinjustAT2 cellsreplicatelungcancer Zoghbi Math1expressingcellsintherhombiclipduringdevelopmentdifereniateto proprioception,hearing,interoception,arousal,andbreathingsystems Math1nullmicedieatbirthbecausetheycannotbreathe Buck

Eachodoractivatesacodeofreceptors.Eachneuronexpressesonereceptorand projecttoaglomerulusthatreceivesinputsfromneuronwiththesamereceptor.Butthis isthemainlfactorybulb.howdoestheVNOwork? UserabiesvirustoretrogradetracecircuitandusedCretomakesureTKisonly expressedinvirus(andthusmakeitviable)inVTAdopamineneurons Findtargetsinmanypartsofbrain(atleast57brainareas) Siegelbaum ThehippocampushasabuiltindelaylinebecauseinputfromDG/CA3toCa1take20ms longerthandirectinputtoCA1fromtheentorhinalcortex TheCA1cellhasatuningcurvetunedto20msdifferentialbetweenperforantpath andschaffercollateralstimulation Blockinginhibitionbroadensthetuningcurve Therearemanyinhibitoryneuronthatmaysharpenthetuningcurveofca1neurons FeedforwardonesfromthePV,feedbackonestargetedfromCA1pyrmidal neuron,interneuronstargettinginterneurons,andEntorinalcortexGABAneurons Hypothesis:WhenyoustimulatetheSCneurons,youalsoactivtethefeedforward

inhibition.Similarly,whenyoustimulatePPneurons,youalsoactivateinterneuron inhibitiontohyperpolarizefeedforwardinhibition.Thisisadisinhibitionmodel Recordedfeedforwardinterneurons.AndstimulationofPPhasamaximal inhibitionoffeedforwardat20ms.Whichfitsmodel BlockinginhibitoryneuronsfromtheEC(whichwouldinhibitthefeedforward inhibioryneurons)blocksthiseffect. Bear

Ifamouseisgivenvisualstimulusofamovingvisualgratingforalongtime,the responseinV1increasesovertime(V1neuronsaretunedtodirection,whichhas preferentialgratingdirection).Andthisplasticityisspecifictothestimulus,because changingthestimulusdoesntgoesbacktobaseline. TheSRP(stimulusresponsepotentiation)isNMDAdependent ShowedthatthisisthesamephenomenonasLTPbecauseitisoccludedbyand occludesLTP Trainedabehavioralresponsewherethemousefidgetsinresponsetostiulus FindsthatthebehaviorgoesdownasSRPemerges.AndthisisblockedbyAP5 Ifamouseistrainedonavisualstimuluswherethegratingchangesdirectioninacertain order,developsaSLIC(squencelearningincortex)sothatresponesincortexgoesup withtime.Thepotentiationisinputspecific,timingspecific,andorderspecific. Ifoneofthestimulusdirectionisdropped(phantom),thecortexstillgivesthe responseatthatsyllable,inanticipationofofthemissingsyllable.Thecortical signalisnotasbigaswhenthestimulusisactuallyadministered

Kandel MicedonotshowspontaneousAlzheimersdisease,buttheydoshw hippocampusdependent,agerelatedlossofspatialmemory.Thisbeginsatmidlifeat 18mo. So,agedependentmemorylossisdifferentfromalzheimers BothyoungandoldmicehaveearlyLTPbutinelderlymice,thelatephaseofLTP isimpaired Rolipram(phosphodiesteraseinbhitiro)canpartiallyrestorethememoryloss, presumablythroughthelateLTPpathway ThereisthoughttobeananatomicaldistinctionbetweenAlzheimersdisease(entorhinal cortex)andagedependentmemoryloss(dentategyrus) Found19genesthatreducedtranscriptionwithage RbAp48,inparticular,decreasedinhumanbrainsinbothtranscriptandprotein Rbap48interactswithCrebCBPcomplex InhibitionofRbAp48inyoungmicecausesimpairmentsinbloodflowtothe dentategyrus,similartohumanpatients.Italsoimpairsyoungmiceonthenovel objectrecognitiontask