CindyChauLong-termGlialResponseTo56FeRadiationInAPP/PS1TransgenicMice,the.ResearchDirector:Dr.CindyLemereWeseektodeterminecognitiveimpairment,CNSchanges,andrisksforAlzheimer'sdiseasefollowingexposureto56Feirradiation(IRR)inpreparationforfutureinterplanetarymissionstodeepspace.Previously,wedemonstratedthatasingledose56FeIRR(1000MeVlu;10CGyor50CGy)inyoungadultmiceincreasedsusceptibilitytocognitivedeclineandenhancedAlzheimer'sDisease(AD)amyloid-β(Aβ)pathogenesisinmale,butnotfemale,APP/PS10E9transgenic(Tg)mice8monthslater.FemaleTgmicewereresistanttolong-term56FeIRReffectsinneurobehavioralmeasurementsinadditiontochangesininsolubleAβlevelsandplaqueload,despitehavinggreateroverallAβplaqueburdenthanmaleTgmice.Thus,weundertookafollow-upstudytofurtherelucidatethesex-anddose-specificeffectsof56FeIRRonplaque-specificglialpathologiesinordertounderstandwhethergliamediateAβplaqueclearanceinirradiatedTgmice.Weusedimmunofluorescence(IF)stainingandconfocalmicroscopyinadditionto3,3diaminobenzidine(DAB)stainingtoquantifymorphologicalchangesandco-localizationbetweengliaandAβplaques.WefoundthatfemaleTgmicehadmoreplaque-associatedgliosis(IF)thanmaleTgmice(4plaquespermouse).Afterincreasinganalysisto30-40plaquespermouse(DAβ),wealsofoundmodestradiation-specificeffectsinfemale,butnotmaleTgmice.Weconcludethatwhile56FeIRRmayincreaseoverallgliosisinbothfemaleandmaleAPP/PS1mice,theremaybesexspecificandradiation-specificeffectsintherecruitmentofmicrogliaandmacrophagestoAβplaques.
SarahChunFrontalgammaactivityisassociatedwithlanguageabilityin18-month-oldswithhighfamilialriskforautism.ResearchDirector:Dr.ChuckNelsonThegoalofthisresearchwastoinvestigatewhetherinducedgammapowerduringapassivelanguage-basedtaskisassociatedwithlanguageabilityin18-month-oldsathighfamilialriskforautism.Thisstudyanalyzed18-monthEEGdataandlanguagemeasurescollectedaspartofthelongitudinalInfantSiblingProject,comparinginfantsbytheirrisklevelforASDdevelopment.InfantswithasiblingwithASDwereassignedtohigh-riskgroup(HRA)andthosewithoutsiblingsorfirstdegreerelativeswithASDwereassignedtolow-riskgroup(LRC).LanguageabilitiesweremeasuredusingtheMullenScalesofEarlyLearning(MSEL).TwotypesofauditorystimuliwerepresentedwhileEEGwascontinuouslyrecorded;wordswereidentifiedaseither“familiar”or“unfamiliar”basedontypicallanguagedevelopmentstandardsofMacArthur-BatesCommunicativeDevelopmentInventories(MBCDI).Linearregressionmodelswereusedtoexaminegroupdifferencesintherelationshipbetweenlanguage-inducedfrontalgammapowerandreceptivelanguageability.Anegativerelationshipbetweenlanguage-inducedlowgammapower(40-45Hz)inresponsetofamiliarwordswasobservedintheHRA+group(p=0.053).Inaddition,therelationshipbetweengammaandlanguageinHRA+groupwassignificantlydifferentfromHRA-group(p=0.014)andmarginallydifferentfromLRCgroup(p=0.078)inresponsetofamiliarstimulus.Nosignificantrelationshipwasshowninanygroupsbetweenthegammaresponsetounfamiliarwordsandlanguageability.Thisstudydemonstratesearlydifferencesinbrain-languageassociationsbetweenhigh-risk18-months-oldswithandwithoutASD.Futuredirectionscanincludeinvestigationofthelongitudinaltrajectoryoflanguage-inducedEEGpower.
MarkCzeislerCharacterizingtheMorphologyofSuprachiasmaticNucleusNeuronalInteractions:ExploringUltrastructuralFeaturesthatMaySubserveCircadianSynchronizationinMammals.ResearchDirector:Dr.JeffLichtmanCircadianrhythmsarenear-24-houroscillationsofdailycyclesincludingthoseofrestandactivity,feedingandmetabolism,andhormoneproduction.Mammaliancircadianrhythmsarecoordinatedbyahypothalamicpacemakercalledthesuprachiasmaticnucleus(SCN).TheSCNreceiveslight-darksignalsviaaxonalinnervationbyintrinsicallyphotosensitiveretinalganglioncells(iPRGCs).DenseSCNconnectivitycontributestothegenerationofacoherentwave-likeoutputrhythmpropagatedfromtheSCNtootherbrainareasandthebody.UnderstandingtheneuroanatomicalfoundationsofintercellularcouplingcouldhelptoelucidatecommunicativemechanismsoftheSCN.Inthisstudy,Iusedserialelectronmicroscopicaltechniquestogeneratea2.97x10^6-um3super-high-resolutionimagevolumeof180(um)x330(um)-50(nm)sectionsofSCNandopticchiasmtissue.ItracedaclusterofSCNneurons,plusaxonalanddendriticprocessesextendingfromeachneuron,tocreateadigitizedwiringdiagram.Thewiringdiagramrevealsstructuresprovidingpotentialmechanismsforphoticentrainmentandintercellularcommunication.SCNneuronsprojectedintotheopticchiasm,wheretheydisplayedsignificantsynapticconnectivity.Moreover,myelinatedaxonscontactingSCNneuronscouldoriginatefromipRGCs.SCNneuronsdisplayedextensivesomato-somaticcontact,providingapotentialopportunityforephapticcouplingviaionexchangebetweencloselyapposedcells,whichcouldhaveastronginfluenceonsynchronizationandenabletheobservedwave-likepatternsdrivenenmass.SeveralneuronsalsoprojectedtowardtooutershelloftheSCN.HelpingtoelucidatestructuralfeaturesofSCNconnectivitythatmayleadtoanimprovedunderstandingofphoticentrainmentandcircadiansynchronization,whichwillbetterinformsleepandcircadianphysiology.
ShenyeceFergusonExplorationoftheEffectsofAttentiononNeuralProcessingofVisualInformation,an.ResearchDirector:Dr.GeorgeAlvarezAttentionisamajorcognitivefeaturethatconstantlyworkstoidentifysalientinformation.Theprincipalobjectiveofthisexperimentwastodeterminewhetherthewayattentionwasallocatedhasaneffectontheprocessingofvisualinformation.Themainhypothesisstatesthatduringbilateralattention,inwhichthereareobjectsinbothhalvesofthevisualfield,eachbrainhemisphereprocessesinformationfromthecontralateralvisualfield,butduringunilateralattention,inwhichthereareobjectsonlyinonehalfofthevisualfield,bothhemispheresareinvolvedinprocessingtheinformationinthatvisualfield.FunctionalMRIwasusedtogaininformationaboutchangingpatternsofneuralactivity,specificallyintheintraparietalsulcus,whileparticipantscompletedamultipleobjecttrackingtaskthatinvolvedbothbilateralandunilateralattention.Amachinelearningclassifierwasusedtoanalyzethedissimilaritiesinactivityduringthetwoattentionalconditionsandtodetermineiftherewereconsiderabledifferencesbetweenthepatternsofactivityineachcondition.Theclassifierwasresponsibleforextractingpatternsofneuralactivityfromasubsetofthedataandapplyingthatinformationtopredictwhichconditioncorrespondedtowhichpatternofbrainactivityinadifferentsubsetofdata.Theresultsoftheclassifierdidnotshowasignificantdifferencebetweentheclassifier'saccuracyduringunilateralandbilateralattentionineitherhemisphere,howeverthroughtheuseofbrainpreferencemapsandacrossdecoder,thereisevidencethatvisualprocessingdoeschangedependingonthewayattentionisallocated.
HeatherForbesOxytocinandtheInductionofLaborinDeterminingEarlyNeurodevelopmentinPrairieVoleModels.ResearchDirector:Dr.MarcyKingsburyMythesisexamineshowtheadministrationofsyntheticoxytocin(sOT)atbirthaffectsthedevelopmentofbraincircuitryinoffspring.WeknowthatOTsignalingatbirthisneuroprotectiveinthatit1)mediatestheGABAexcitatory/inhibitoryswitchandestablishesnormalpatternsofneuralsynchrony,and2)servesasabufferagainstoxidativestressbyreducingthemetabolicdemandofneurons.Previousstudieshavedemonstratedthatbrainperineuronalnets(PNNs)whichsurroundparvalbumin-expressinginterneurons(PVIs)aresensitivetoearlyhypoxic-likeconditionsandthattheirmalformationmaycontributetothedysregulationofGABAinterneuronsandaberrantneuralactivity.ItisnotcurrentlyknownifdifferentconcentrationsofOTimpactneuralcircuitrydevelopment.Pregnantprairievolesreceivedalow,mediumorhighdoseofsOTpriortolabor.Atpostnatalday20,weexaminedthebrainsofoffspringborntosOT-injectedmomsandcomparedthemtothebrainsofoffspringbornviaanuntreatedvaginalbirth.Specifically,weexaminedPVIs,PNNsandmicroglia,immunecellsthatrespondtoinflammatoryevents.Bytrackingthedensityofthesecellswithintheanteriorcingulatecortex,weexaminedtherelationshipbetweenoxytocinadministrationandthedevelopmentofPVIs,PNNsandmicroglia.WefoundthatthelowandhighdoseofsOTadministrationgivesrisetothedevelopmentofnormalPVI/PNNbraincircuitrywhilethemediumdosedoesnot.WehaveexaminedonlymaleoffspringsoitwillbeimportanttoinvestigateiftherearesexdifferencesinneuralcircuitryfollowingtheadministrationofsOTatbirth.
PollyGabrieliNeuronalandGeneticCorrelatesofProsocialBehaviorinMice.ResearchDirector:Dr.ZivWilliamsProsocialbehavior–volunteeringtohelpothers–playsacentralroleinhumansociety.Understandingthepathwaysthatdriveprosocialbehaviorisakeyquestioninmodernpsychology.Bettermodelsofthisbehaviormayalsoprovideinsightsintothepathologyofsocialdisordersinhumans.However,noassayshavebeendevelopedtoassessprosocialbehaviorinmice,akeymodelanimal.Inthisstudy,wedevelopedanovelbehavioralassayinwhichmicecouldsaveaconspecificfromtheaversiveexperienceofshockbymovingbetweenzones.Ourresultsdemonstratethatthesemiceavoidtheshock-inducingzoneonlyforcagematesbutnotunfamiliaranimals,indicatingprosocialbehaviortowardsfamiliarconspecifics.Wealsorecordedfromtheanteriorcingulatecortex(ACC)inthemedialprefrontalcortexduringtheassay.Usingtheserecordings,weidentifiedasubsetofneuronsinthisregionthatpredictthedecisiontomoveoutoftheshock-inducingzone,aswellasneuronsthatselectivelyrespondtoacagematebeingshocked.Finally,westudiedthebehaviorofmicefromtwomodelsofalteredsocialcognition,includingtheShank3+/fxmodelofautismandGtf2i-2+/-modelofWilliamsSyndrome.Ourpreliminaryresultsindicatethatthesemicebehavedifferentlyintheprosocialassay.Ultimately,studyingthedifferencesbetweenthebehaviorofwild-typeandsociallydisorderedmicemayprovideshedlightinformationonunderstandingtherootcausesofthesedisorders.Moreover,examininghelpingbehaviorinmicemaybeastepforwardstowardsunlockingthecomplexneuralmechanismsbehindhumanprosocialbehavior.
EmmaHeDevelopmentof5-HT3AR-ExpressingInterneuronsinAuditoryCortex,the.ResearchDirector:Dr.AnneTakesianDuringearlylife,thebrainexperiencescriticalperiodsofheightenedplasticitytorepresenttheexternalworld.Ourlabhasidentifiedaclassofinhibitoryinterneuronsintheprimaryauditorycortex(A1)thatgatecriticalperiodplasticity.Thesecellsresideincorticallayer1(L1)andexpressionotropicserotonergicreceptors(5-HT3AR).Themechanismsbywhich5-HT3ARcellsintegrateneuromodulatoryandthalamicinputtocontrolcriticalperiodtimingremainunclear.Here,wecharacterizehowtheactivationof5-HT3ARcellschangeswithinandoutsideofthecriticalperiod.First,weperformedimmunocytochemistryonBrainbow-expressing5-HT3ARinterneuronstorevealdistinctmorphologicalchangesacrossdevelopment.Next,wecharacterizedneuromodulatoryandthalamicinputsonspecificsubtypesof5-HT3ARcells.Weusedvesicularglutamatetransporter2(vGluT2),amarkerofthalamocorticalboutons,torevealapreferentialthalamicinnervationof5-HT3ARcellsthatdidnotexpressvasoactiveintestinalpeptide(non-VIP).Wethenusedinsituhybridizationtofindthatthesenon-VIPcellsalsopreferentiallyexpressednicotinicacetylcholinereceptors(nAChRs)containingtheα4subunit.Finally,sincepaststudieshaveshownthatprenatalexposuretoserotoninreuptakeinhibitors(SRIs)affectscriticalperiodtiminginhumans,weexaminedwhether5-HT3ARcellsmaybeimplicated.Weperformedfunctionalstudiesusingvoltage-sensitivedyeimaging(VSDI)torevealaheightenedsensitivitytoSRIsinA1duringtheauditorycriticalperiod.Takentogether,ourpreliminarydatasuggestthatneuromodulatoryandthalamicinputsstronglyactivate5-HT3ARcellsduringthecriticalperiod,andthatthisactivationchangesacrossdevelopment.
ChrisHinojosaOptimizingIn-VitroMotorNeuronDifferentiationfromPluripotentStemCellsviaEpigeneticAlteration.ResearchDirector:Dr.KevinEgganPluripotentstemcellsdifferentiateintomotorneuronsaccordingtohighlyspecificepigeneticregulationofDNA.However,thisprocessoccursslowly,diminishingthefeasitmotorneuronregenerationandlimitingtherateofresearchonneurodegenerativediseaseinvitro.Weaimedtoaddresstheseissuesinaccordancewithpreviousresearch-byinhibitingtheactivitiesofDNAmethyltransferases(DNMTs)andhistonedeacetylases(HDACs)indifferentiatingcells,withtheintentofelucidatingtheeffectsoftheseparticularepigeneticalterationsontherateofmotorneurondifferentiation.Specifically,wetreatedmultiplelinesofdifferentiatingembryonicstemcellswith5-azacytidine,valproicacid,andvitaminC,eachofwhichmodifytheactivitiesofparticularepigeneticmechanisms.5-azacytidineandvitaminCreduceDNAmethylationlevelsviainhibitingDNMTactivityandinducingdemethylation,respectively,whereasvalproicacidfunctionsasanHDACinhibitor.After7and14days,weusedimmunofluorescencestainingtoquantifythepresenceofknowndifferentiationmarkersintreatedandcontrolcelllines,allowingustodeterminetheextentofmotorneurondifferentiationwithineachline.Quantificationanalysisisstillbeingperformed,thoughweexpecttoobservethatDNMT-inhibitedcellsexperiencedsloweddifferentiation,whereasHDAC-inhibitedcellsexperiencedaccelerateddifferentiation,relativetothatundergoneincontrolcelllinesbytheendoftheexperiment.Theseresultswouldprovidegreaterinsightintotheroleofepigeneticmechanismsinmotorneurondifferentiation,inadditiontohowsuchmechanismsmaybemodifiedtooptimizetherateofdifferentiationforresearchand/ortherapeuticpurposes.
IsabelleIversenFetalAlcoholSpectrumDisorder:Alcohol’seffectonthebrainandtheriskforchronicadultdiseases.ResearchDirector:Dr.WolframGoesslingFetalalcoholspectrumdisorder(FASD)istheleadingpreventablecauseofmentalretardationinAmericaandisestimatedtoaffect2–5%oftheUnitedStatespopulation,including200,000newcaseseachyear.Thedisorderoccurswhenthedevelopingfetusisexposedtoalcoholthroughmaternaldrinkinghabits.Alcoholanditsprimarymetaboliteacetaldehydearetoxicandcanimpairfetaldevelopment.WeaimedtodescribethepathogenesisofFASDinzebrafishandidentifynovelbiochemicaltargetsfordrugtreatment.FASDwasinducedinzebrafishbyexposingfertilizedembryostoethanolatvaryingconcentrationandduration.DevelopmentaldamagewasassessedbymeasuringthesizeofvarioustissueswithImageJ,andstatisticalanalysiswasperformedwithPrism.Wefoundthatgreaterethanolexposurewasassociatedwithsevereedema,facialabnormalities,shorterlength,organdamage(includingtheliver,pancreas,andthebrain),andmortality.WealsofoundthatFASDfishhadsignificantlymorefataccumulationwhengivenahighfatdiet.ThirdlywefoundasignificantrescueeffectofFASDcharacteristicsusingVitaminC,anantioxidant,andN-AcetylCysteine,asupplementformofcysteine.Finally,wefoundthatprenatalalcoholexposurecausesanxiousbehaviorwhichcanberescuedbycurrentanti-anxietymedications.Theseresultssuggestthatprenatalalcoholexposuregreatlyeffectsthedevelopmentofthefish,FASDisariskfactorfordietinducedobesity,andsomedevelopmentalandbehavioraleffectsofFASDmaybeprevented.
AnahitaIyerIdentifyingPhospholipidPathwayProteinsasModifiersofα-SynucleinPhenotypesinCellularModelsofParkinson’sDisease.ResearchDirector:Dr.DennisSelkoeParkinson'sdisease(PD)isaneurodegenerativedisorderthatcausesseveremotordysfunction,Whilecurrenttherapiestreatsymptoms,theydonotsloworreversediseaseprogression.PDischaracterizedbythepresenceofLewybodies,abnormalcytoplasmicinclusionscomposedofinsolubleaggregatesoftheproteinalpha-synuclein(as),withinneuronsinthebrain.Thesevesicle-richinclusionsarebelievedtoresultfromthebindingofastomembranes,contributingtoprogressiveneuronaldegeneration.Understandingas-membraneinteractionsthatcontributetoastoxicitymayleadtotheidentificationofnewtargetsforPDtreatment.Membranepropertiessuchassaturation,fluidity,charge,andcurvaturehavebeenfoundtomediatethelipidbindingabilityofas.Becausethemajormembranephospholipidtypeshavedifferentstructuresthatinfluencesuchmembraneproperties,weinvestigatedwhetheralteringmembranephospholipidcompositionaffectsasinclusionformation.Westrategicallyincreasedordecreasedtheproductionofthesedifferentphospholipidsaccordingtoknownlipidpathwaysusingbothageneticandbiochemicalapproach.WeoverexpressedcandidategenesinvolvedintheselipidpathwaysandtestedpathwayactivatorsorinhibitorsininduciblehumanneuroblastomacelllinesexpressingatoxicformofaSpronetoaggregation,andobservedtheeffectsoninclusionformation.Fromthesescreens,weidentifiedcandidateslikelytorescueinclusionformationforfurtheranalysis,includinglipidprofilingandadditionalparametersoftoxicity.Weperformedinclusionassayswiththemostpromisinglipid-modifyingoverexpressiontargetsinratcorticalneuronstobettermodeldisease.Thisworkcontributestoamechanisticunderstandingofhowas-membraneinteractionsmayparticipateinPD.
AlecJonesExploringtheGlymphaticSystem:AForayintotheFunctionofParavascularSpaces.ResearchDirector:Dr.CharlesCzeislerBackground:Whilesleepisnecessaryforpropercognitivefunction,thephysiologicalneedforsleepisstilluncertain.Recently,itwasdiscoveredthatthecerebralglymphaticsystem,whichisanetworkofperivascularspacescontainingcerebrospinalfluid(CSF),maybemeaningfullyaffectedbysleep-wakestates.Importantly,researchsuggeststhatCSFflowratesaresignificantlyhigherduringthesleepstate,enablingmoreefficientclearanceofsmall-moleculewasteproductslikeamyloid-betafromthebrain.Althoughthesefindingshavebeenshowninanimalmodels,thereisnotyetdirectevidencethattheglymphaticsystemworksthesamewayinthehumanbrain.|¶|Methods:Westudiedhealthyadultsbetweentheagesof18-25usingmagneticresonanceimaging(MRI)andelectroencephalogramtechnologythroughoutafour-daysleepstudy.Individualsunderwenta36-hourconstantroutineprotocolduringwhichtheyparticipatedinneurobehavioraltestsincludingthepsychomotorvigilancetest,Karolinskasleepinessscale,addition-calculationtask,andvisualanaloguescale.Followingthis,anatomicalchangesinparticipants’brainsweremonitoredintheMRIwhiletheysleptandlateranalyzedusingbiostatisticalanalyses.|¶|Results:Statistically-significantnumericaldifferencesinperivascularspacesbetweensleepandwakestateswerefoundinthemidbrain,butnotinthecentrumsemiovale,basalganglia,orhippocampusregionsofthebrain.|¶|Conclusions:Participantswithnumericalincreasesinperivascularspacesthattrendedtowardsstatisticalsignificanceperformedbetterthanthoseindividualswithoutvisibledifferences.FurtherexperimentsinvolvinghigherresolutionMRIscanners,largersamplesizes,andlongerdurationrapideyemovementsleepdatamightshowsignificantdifferencesinmoreregionsofthebrain.
EJKimElectrodermalReactivityandDistressToleranceinAdultswithaHistoryofNon-suicidalSelf-Injury(NSSI).ResearchDirector:Dr.MatthewNockGreateremotionalreactivityandlowereddistresstolerancehavebeensuggestedasexplanatoryfactorsinthedevelopmentandmaintenanceofnon-suicidalself-injury(NSSI).ThisthesisinvestigatedwhetherheightenedlevelofarousaliscorrelatedwithNSSI.AdultswithahistoryofNSSIandhealthycontrolsperformedadistressingcardtask,andelectrodermalactivity(EDA)levelsweremeasuredatbaselineandduringthetask.Physiologicalarousalwascalculatedusingtonicskinconductancelevel(SCL)andnon-specificskinconductanceresponses(NS-SCRs).Individualswithrecent,butnotlifetimehistoryofNSSI,showedlargerSCLincreaseandhigherfrequencyofNS-SCRsduringthedistresstaskcomparedtocontrols.ThesefindingssuggestthatgreateremotionalreactivitycontributesmoretothedevelopmentandmaintenanceofNSSIbehavior.TheneurobiologicalimplicationsoftheEDAfindingsarefurtherexploredgiventhatEDAactivationisdirectlydownstreamoftheautonomicnervoussystemarousal.
DeepikaKurupInvestigationofEndosomalandLysosomalBiologyinAlzheimer’sDiseaseUsingPatient-DerivedInducedPluripotentStemCells.ResearchDirector:Dr.TracyYoung-PearseAlzheimer’sdisease(AD)istheleadingcauseofdementia,whichaffects40millionpeopleworldwide.Inthisstudy,inducedpluripotentstemcells(iPSCs)coupledwithcomprehensiveclinicalstudiesareusedtomodelthespectrumofpathologicalandclinicalphenotypesseeninAD,andtoinvestigatetheroleofendosomalandlysosomalbiologyincontributingtothesephenotypes.ItwashypothesizedthatinvitrophenotypesfromiPSClinescouldbeusedtounderstandthemolecularbasisoftheheterogeneouspathologicalandclinicalphenotypesofAD.iPSC-derivedneuronallinesweregeneratedfromsubjectsintheReligiousOrderStudy(ROS)andMemoryAgingProject(MAP),twostudiesforwhichpre-andpost-morteminformationhasbeencollected.ImmunostainingwasusedtoidentifyAD-,endosomal-andlysosomal-relevantmarkers.TheseresultswerequalitativelyanalyzedusingconfocalmicroscopyandquantitativelyevaluatedusinganInCellAnalyzercombinedwithoptimizedCellProfilerimage-processingmodules.AD-relevantproteinssynthesizedandsecretedbytheculturedneuronswerequantifiedthroughELISA.SignificantdifferencesinthenumberoflysosomesandendosomespercellandratiosofAβ42toAβ40amongthelinesstudiedshowheterogeneityintheagingpopulation.Theseresultsindicatethatpatient-derivediPSClinesfromtheROS/MAPcohortsserveasavaluabletoolforprobingtheheterogeneityofADandinvestigatinghowdifferencesinendosomalandlysosomalbiologymaycontributetopathologyandcognitivedecline.Ultimately,thisstudyseekstoprovidefurtherinsightintothemechanismsofADprogressionandmayfacilitatethediscoveryofnovelpathwaysinvolvedinAD-relatedcognitivedecline.
TylerLeComerPrefrontalCortexResponsesinInfancyPredictAnxiousBehaviorsinEarlyChildhood.ResearchDirector:Dr.ChuckNelsonAnxietyisthemostprevalentmentaldisorderintheworld,affectingone-thirdofthepopulation.Despitethisprevalence,littleisknownabouttheneuralcorrelatesunderlyingitsonset.Itisgenerallybelievedthattheonsetofanxietyinchildrenresultsfromacombinationofindividual-specificandenvironmentalfactors,buttherespectiveimpactofeithergroupisnotwelldefined.Paststudieshaverevealedacorrelationbetweenanxietyandmetabolicactivityintheprefrontalcortexinadulthumans,suggestingthatindividualbrainactivitymayplayaroleinproducinganxiety.This,however,doesnotprovideinsighttothedisorder'sonset.Thisresearchsetsouttobettercharacterizetheroleofbrainmetabolicactivityintheonsetofanxiousbehaviorsthroughoutearlychildhoodbyinvestigatingthebehaviorofindividualtoddlers,asreportedontheInfant-ToddlerSocialandEmotionalAssessment(ITSEA),andtheirrespectivebrainactivityduringinfancy,asmeasuredusingnear-infraredspectroscopy.WhiletheresultsdonotindicateastatisticallysignificantrelationshipbetweentheInternalizing'scoreoftheITSEAatthreeyearsoldandthemagnitudeofthehemodynamiceffectintheprefrontalcortexduringinfancy,thereisaslighttrendtowardanegativecorrelation.Theresultsadditionallysuggestasignificantpositivecorrelationbetweenthe'Fear'scoreoftheInfantBehaviorQuestionnaireandtheInternalizing'scoreoftheITSEA.Overall,theresultssuggestthecomplexityoftherelationshipbetweenindividualbrainactivityandanxiousbehaviors.Anxiousbehavioratthreeyearsoldcannotbefullyexplainedwithonlyinfantbrainmetabolicactivity.
MelissaLiEffectofageonthepatternofblood-brainbarrierdisruption,matrixmetalloproteinase-9upregulation,anddamageinalargeanimalmodelofseveretraumaticbraininjurywithunilateralhemispherichypodensity,the.ResearchDirector:Dr.BethCostine-BartellHemispherichypodensity(HH)isaninjurypatternassociatedwithsevereabusiveheadtrauma(AHT)inchildren.UnilateralHH,underaunilateralsubduralhematoma,resultsindestructionoftheipsilateralcortexwithrelativesparingofthecontralateralhemisphere.Itiscommonintoddlersbutnotinfants,anditspathophysiologyremainspoorlyunderstood.Wehypothesizedthatblood-brainbarrier(BBB)disruptionregulatedbymatrixmetalloproteinase-9(MMP-9)resultsinunilateralHHinpigletsdevelopmentallysimilartohumantoddlers(1monthold)butnotinpigletsdevelopmentallysimilartohumaninfants(1weekold).|¶|InourmodelofHH,pigletsaged1week(“infant”)or1month(“toddler”)receivedunilateralfocalinjuriesandglobalinsults(N=19)orshamsurgery(N=7).Damage,MMP-9expression,andBBBdisruptionpatternsweredeterminedincoronalsectionsencompassingeachhemisphere.|¶|Albuminextravasation,indicatingBBBdisruption,andMMP-9expressionparalleledthedamagepatternandwasgreaterintheipsilateralvs.contralateralhemispherein“toddlers”butnot“infants”.Theparallelpatternsofalbuminextravasation,MMP-9upregulation,anddamagealongwithsignificantsparingofthecontralateralhemispherein”toddlers”indicatesBBBdisruptioniskeyinthepathophysiologyofHH.“Toddlers”mayhavegreaterspreadingofdamageinonehemisphereduetoagreaterincreaseofMMP-9andBBBdisruption,while“infants”haveabluntedincreaseinMMP-9andlessBBBdisruptionanddamage.Furtherclarifyingtheseage-relatedpathophysiologicaldifferencesmayresultinimprovedtherapiesforAHT.
KarenMalaconEffectsofprenatalexposuretoairpollutionandmaternalstressonsocialbehaviorandunderlyingneuro-immunemediators.ResearchDirector:Dr.StaciBilboAutismSpectrumDisorder(ASD)isaneurodevelopmentaldisordercharacterizedbyimpairedsocialinteractionandcommunication,engagementinrepetitivebehaviors,andasexbiasinprevalence(higherinmales).Severalepidemiologicalstudieshavelinkedprenatalairpollutionexposure,aswellasmaternalstressduringpregnancy,withanincreasedriskofASD.Ourlabhasdevelopedaprenatalexposureparadigminmicewhichcombinesdieselexhaustparticles(DEP)withamaternalstressor(resourcedeprivation;MS)duringpregnancy.Usingthismodel,wefoundthatDEP/MSexposuredecreasessociabilityandsocialnoveltypreferenceinmaleoffspringonly.Microglia,theresidentimmunecellsofthebrain,arekeyregulatorsoftheneuralresponsetoimmuneactivationandappeartobechronicallyactivatedinasubsetofpatientswithASD,makingthemgoodcandidatesfortranslatingsuchenvironmentalexposuresintoneuraloutcomes.Therefore,weassessedmicroglialcellnumber/density,aswellassocial-andmicroglial-relatedgeneexpressionpatternsinthenucleusaccumbens(NAc)andbasolateralamygdala(BLA),regionsimportantforsocialbehaviorandimplicatedinASD.WefoundthatalthoughDEP/MSexposurehadnoeffectonmicroglialcellnumberintheNAc,wedidobservesex-specificeffectsinsocial-andmicroglial-relatedgenesintheNAc,includingdopaminereceptormRNA.TheseeffectsappearedtobebrainregionspecificaswedidnotobservegeneexpressionchangesintheBLA.Together,theseresultsadvanceourknowledgeoftheneuro-immunemechanismsbywhichprenatalimmuneactivationmightleadtoASD-relevantchangesinsocialbehavior.
TheodoraMautzAnatomicalFoldingPredictstheLocationsofFace-SelectiveDomainsinMacaqueInferotemporalCortex.ResearchDirector:Dr.MargeLivingstoneGyrificationinthedevelopingbrainleadstoadrasticincreaseinthetopologicalfeaturesofthecortex.Previousresearchhasdemonstratedastructure-functionrelationshipbetweencorticaltopologyandbrainfunctionintheprimateprimaryvisualcortex.Thepresentstudyexpandsthislineofresearchtotheorganizationofthehigher-ordervisualcortex.Macaquebrainshavefocalregionswithinthesuperiortemporalsulcus(STS)oftheinferotemporalcortexthatareselectivelyactivewhenviewingimagesoffacesascomparedtoothertypesofimages.Usingfunctionalandstructuraldatafromtwelvemacaques,weinvestigatedtherelationshipbetweenanatomicaltopologyintheSTSandthelocationofthemiddlelateral(ML)facepatch.WithintheSTS,weidentifiedthreefocalbumps(convexcurvatures)thatwereinconsistentlocationsalongtheanterior-posterioraxisacrossindividuals.WefoundthattheMLfacepatchwaslocalizedtothemiddleofthesebumpsinallindividuals,demonstratingthatfocalanatomicalfeaturesoftheSTScanserveaslandmarksforthelocalizationoffunction.Inadditiontonormally-rearedmonkeys,thiscorticalfeaturealsoexistedintwogroupsofmacaquesraisedunderconditionsthatpreventedthefunctionaldevelopmentofface-selectiveregions.Thissuggeststhatthestructure-functionrelationshipisnotnecessarilycausal,butcouldinsteadcomeaboutfromearlyorganizingprinciples,suchaslow-leveltuningandretinotopy,thatcorrelatewiththelocalizationofface-selectivedomains.Animprovedunderstandingofthenatureofthisrelationshipholdsinterestingimplicationsforbraindevelopmentandthepressuresthatshapegyrification.
OrgilmaaMunkhbaatarMother’sPain,a:TheEffectsofPostpartumDepressionandChildhoodMaltreatmentonMaternalNeurobiology.ResearchDirector:Dr.MartyTeicherExtensiveresearchhasidentifiedtheenduringeffectsofchildhoodmaltreatmentonbrainstructureandfunctionandhasimplicatedthesechangeswithpsychopathologydevelopment.However,therelationshipandassociatedneuralcorrelatesofearlyadversityandpostpartumdepressionremainpoorlyunderstood.Toaddressthis,thepresentstudyaimstoassesstheinfluenceofchildhoodmaltreatment,quantifiedbytheMaltreatmentandAbuseChronologyofExposurescale,incontributingtopostpartumdepression,measuredbytheEdinburghPostnatalDepressionScale.Wehypothesizedchildhoodmaltreatmentisassociatedwithaberrantresting-statefunctionalconnectivityandcorticalchangesthatmaymediatethedevelopmentofdepression.Functionalactivityin13regionsofinterestcompellinginmothering,postpartumdepression,andchildhoodmaltreatmentwasanalyzedusingtheBrainConnectivityToolboxandcorticalarea,volume,andthicknessanalyseswereconductedwithFreeSurfersoftwarefor65mothers.Weidentifiedchildhoodsexualabuseasthemostimportantpredictorofpostpartumdepressionwitha14.4-foldincreasedriskwithexposure.Assessmentofmaternalneuraldifferencesshowedincreasedconnectivitybetweentheleftamygdalaandleftcerebellummediates14.5%oftherelationshipbetweenexposuretochildhoodsexualabuseandpostpartumdepression.Giventheroleoftheamygdalainthreatdetectionandthecerebelluminemotionprocessing,theobservedalteredconnectivitybetweentheseregionsmaycontributetothedevelopmentofsymptomsasearlyexperiencesmaysensitizevulnerabilitytodepression.Thesefindingsmaycontributetounderstandingthepredictiveneurobiologyofpostpartumdepressionandhighlightstheimportanceofchildhoodsexualabuseasapotentialriskfactor.
ChinazaOchiInvestigatingVisualEvokedPotentialsasaPossibleBiomarkerforAutismSpectrumDisorderinTuberousSclerosisComplex.ResearchDirector:Dr.ChuckNelsonChildrenwithTuberousSclerosisComplex(TSC),araregeneticdisorder,areatanelevatedriskfordevelopingautismspectrumdisorder(ASD),adevelopmentaldisorderthatleadstoimpairmentinsocialinteractionandcommunicationskills.ResearchsuggeststhatearlyinterventionsforASDmaybemosteffectiveinremediatingtheseimpairments,butitisdifficulttopredictwhichinfantswillgoontodevelopASD.TSCcanbediagnosedinuteroandmayprovideuniqueinsightintotheneuralmechanismsthatgiverisetoASDlaterindevelopment.Inthisstudy,wewillusevisualevokedpotentials(VEPs)toevaluatethemechanismsunderlyingelevatedriskforASDininfantswithTSC.VEPsareevent-relatedelectricalpotentialsinducedbyavisualstimulusthatcanbemeasuredwithelectroencephalography(EEG).Thisneuralmarkerreflectsbasiccorticalprocessingandisnotdependentonlanguage,motorcoordination,orauditoryabilitiesmakingitausefulmeasuretoutilizeforinfants.OurhypothesisisthatchildrenthatlaterdevelopASDwillhaveacharacteristicdifferenceintheirVEPtrajectories.Ifourhypothesisissupported,weexpecttofindapotentialmarkerofriskfordevelopingASD.Thisinformation,incombinationwithothermeasures,couldbeusedtohelppredictwhichkidswillgoontodevelopASD,therebyallowingforearlyidentificationofkidswhowouldbenefitmostgreatlyfrominterventionservices.
EdwinOwoloInvestigatingtheroleofthePAGinprocessingpupvocalizationsinmice.ResearchDirector:Dr.CatherineDulacThematernalresponsetoaninfant’scriesisanadaptivelyadvantageousbehaviorthatishighlyconservedamongmammals.InmyundergraduatethesisIaimedtoidentifycellsintheperiaqueductalgray(PAG)thatareinvolvedinprocessingpupvocalizations.ThePAGreceivessynapticinputfromareasofthe“emotionalbrain”includingthecortex,amygdala,andhypothalamusandisinvolvedinfunctionssuchaspain,analgesia,fear,anxiety,andautonomicregulation.MyinvestigationbeganwithmappingthePAG’sauditoryprocessingnetwork.Retroadeno-associatedvirus(AAV)wasinjectedintotherostral,medial,andcaudalPAGinordertovisualizeknownauditorycenterswherethePAGreceivesprojectionsfrom.ImagingoftheseinjectionsrevealedtheconnectivitythePAGshareswiththeauditorycortexaswellastheinferiorcolliculi.ProjectionsiteswereconfirmedtobespecifictothePAGbyinjectingavirusthatlabelscellbodiesandtheirsynapsesfromauditorycortextothePAG.AftermappingthePAG’sauditoryprocessingnetwork,cellsthatwereactivatedbypupvocalizationsinadultvirginfemales,males,andmotherswereidentifiedandquantified,usingtheimmediateearlygenec-fosasamarkerofrecentneuralactivity.TheresultsofmythesishelptoelucidatetheroleofthePAGintheprocessingofpupvocalizations
LeslieRamosRoleofRUNX1intheProgressionofEpithelialtoMesenchymalTransitioninProliferativeVitreoretinopathy,the.ResearchDirector:Dr.LeoKimProliferativeVitreousRetinopathy(PVR),mostcommonlyoccurringaftereyetrauma,isoneofthemostcommoncausesofsurgicalfailureforretinaldetachmentsurgery.PVRischaracterizedbytheformationofscartissue,andpathologicalmembranesoverlyingandunderneaththeretina,andisthemostcommoncauseofrecurrentretinaldetachments.Theformationofthisscartissueiswidelybelievedtobecausedbyepithelialtomesenchymaltransition(EMT),whichaffectstheretinalpigmentedepithelialcellsintheeyeandturnsthemfibrotic.Inthisthesis,weexploredtherolethattranscriptionfactorRUNX1playsintheprogressionofEMT,andthusformationoftheretinalPVRscar.WewereabletocollectPVRretinasamplesfromrealpatients,aswellasculturePVRcellsfromthesescartissues,creatingthemostaccuratein-vitrodiseasemodelforPVR.ThereisanumberofpaperslinkingRUNX1toEMT,however,thisisthefirsttimethatRUNX1hasbeenshowntoplayaroleinthetheprogressionofPVR.ThisnovelinterplaybetweenRUNX1andEMTintheretinacanhelpdecipherthetherapeuticfutureofPVR.Furthermore,wewillexploretheimportanceofresearchingEMTandpotentialtherapeuticspromisesofRUNX1intreatingnumerousdevastatingfibroticandcancerousdiseases.
PabloReimersStochasticIndividualityinDrosophilamelanogaster:AnInvestigationoftheNeuralGenerationofIdiosyncraticBehavior.ResearchDirector:Dr.BendeBivortDeterminingwhatmakesus“us”isattheheartofindividualityresearch.Thoughinvestigationsintothisfieldhaveoftenlookedthroughthelensofgeneticorenvironmentalfactors,anunderappreciatedbranchofindividualityresearchistheeffectofrandomness.Here,westudytheeffectthatneuralmorphologicaldifferences,whichcouldoccurstochastically,haveonbehavioralbiasinthefruitflyDrosophilamelanogaster.Usinghighthroughputtechnologiestotrackfliesastheywalkfreelyinathree-armedchamber,individualidentitiesweremaintainedasbehaviorwasrecordedforeachanimaloverthecourseofmanyhours.Withthehelpofestablishedgeneticdriverswhichcansilenceaspecificgroupofneurons,ascreenwasconductedtoidentifykeyneuronsinvolvedinestablishingafly’sindividualbias.Usingimmunohistochemistryandconfocalimaging,pre-synapticvolumeofthesetargetneuronswasquantified,andleft-rightasymmetrywascorrelatedtotheindividual’sbehavioralbias.Thefinalexperimentinthisprojectaimedtotestthesufficiencyoftheidentifiedtargetneuronsincreatingabiasforthefly,byusingheatshock-FLPrecombinationtostochasticallyinducefunctionalleft-rightasymmetriesinphysiologicalpropertiesofthetargetneuronsandtrackingtheeffectonbehavioralbias.Inthefirstexperiment,agroupofneuronswithpost-synapsesintheProtocerebralBridge(PB)andFan-shapedBody(FB)andpre-synapsesintheLateralAccessoryLobe(LAL)wereidentifiedashighlyinvolvedinestablishingabiasinturningbehavior.Withfurtheranalysis,asymmetryatthebasal-mosttipofthesePF-LALneuronsbetweentheleftandrightsidewassignificantlypredictiveofafly’sbias.Analysisofsufficiencyfortheseneuronsisstillbeingconducted.Here,wehavesuccessfullyidentifiedakeymorphologicalfeature,afewcubicmicronsinvolume,whoseasymmetrieshavemagnifiedeffectsvisibleinthebehaviorofanorganism.Thisfeatureisexplanatoryoftheidiosyncrasieswhichexistbetweengeneticallyidenticalanimalsraisedinthesameenvironment,whosestochasticasymmetriessuggestarootofrandomnessinindividuality.
EmmaStoneConsequencesofearlysightdeprivationinmacaquesandtheroleofmotionfollowingsightrestoration.ResearchDirector:Dr.MargeLivingstoneAshumans,werelyonvisionmorethananyothersense.Weunderstandandnavigateourworldbyseeingit,whichmakesnormalvisualdevelopmentandfunctioncrucial.Whenindividualsaredeprivedofvisualinformationatanearlyage,theysufferfromseverelimitationsinvisualabilityandperceptionduetomissedcriticalperiods.However,studiesshowthatbothnormalandvisiondeprivedindividualscanprocessvisualinputmosteffectivelywhenitcontainsmotion.Thepresentstudyaimstoexplorehowmotionmodulatesandreshapesformrecognitioninboththevisuallynormalanddeprivedbrain.Physiologyfromavisuallynormalmacaquewasexaminedtounderstandhowmotionmodulatesobjectrecognitionininferotemporalcortex.Motivatedbythefindingthatmotionisessentialforprocessingshapeinformationafternormalvisualdevelopment,amotion-basedtrainingtaskwasusedtointroducevisuallydeprivedmacaquestonovelshapes.Monkeysunderinvestigationexperiencedbilateralvisualformdeprivation,meaningtheyonlyhadaccesstodiffusedlightuntilfullsightwasrestoredafter1year.Wetestedwhethermonkeyswouldrecognizeformsmoreeffectivelywhenitwaslearnedinmotion.Oneoftwomonkeyslearnedthecomplexvisualtaskover20days,butstillhaddeficitscomparedtoavisuallynormalmonkey.Findingsshowedthatlearningaforminmotionisnotconduciveforpromotingrecognitionoutsidethetask.Thus,thepresentedmotion-basedtrainingparadigmdoesnotappeartostrengthencircuitryfordiminishedvisualfunctioninthesightdeprivedbrain.Evidencesuggestingthattheonevisiondeprivedmonkeycouldstilllearnimportantmotioninformationandoftensoughtmovingstimulioverstaticequivalentsconfirmsthatmotionisanessentialcueforperception,particularlywhenrecoveringfromformdeprivation.Thisstudyhelpstoinformandadvancealternativetrainingregimesthatmayreducebarriersforattainingfullvisualfunctionduringsightdeprivationrecovery.
EilySullivanStatisticallearningandlanguageoutcomesof5-year-oldurbanBangladeshichildren:AnfNIRSinvestigation.ResearchDirector:Dr.ChuckNelsonWhenachildgrowsupinpoverty,theyaremorelikelytoexperiencevariousformsofadversitythatcannegativelyimpacttheirbraindevelopment.Languageisonedomainthatisparticularlyvulnerabletoadversity.Cognitivestimulation,orthelevelofenvironmentalenrichment,hasbeenlinkedtobetterlanguageoutcomesinchildren.Inthisstudy,weinvestigatedwhethercognitivestimulationisrelatedtolanguageoutcomesof81five-year-oldchildrenfromlow-incomebackgroundslivinginDhaka,Bangladesh.Resultsrevealthatcognitivestimulationwassignificantlyrelatedtoverbalintelligencequotient(IQ)scores(p<0.01),overandabovetheinfluenceofsocioeconomicstatus(SES)andnutritionalstatus.Next,weinvestigatedwhetherstatisticallearning,ortheextractionofpatternsfromthespeechtrain,couldunderliethisassociation.Eachparticipant’sbrainwasimagedusingfunctionalnear-infraredspectroscopy(fNIRS),whichuseslighttomeasurehemodynamicresponsesinthebrain,whilelisteningtoanauditorystatisticallearningparadigmcontainingaseriesoftonepatternswithvaryingtransitionprobabilities(TPs)betweentones.Wehypothesizedthatstatisticallearningresponsesintheinferiorfrontalgyrus(IFG)andsuperiortemporalgyrus(STG)wouldmediatetheassociationbetweencognitivestimulationandverbalIQ.PreliminaryanalysesrevealthatboththeSTGandIFGaresensitivetodifferencesinstatisticalstructureoftonepatterns.Participants’statisticallearningresponsesinthesebrainregionsweresomewhatdistinctbasedoncognitivestimulationlevelandverbalIQ.Futureanalysesareneededtoinvestigatewhetherstatisticallearningresponsesmediatetheassociationbetweencognitivestimulationandlanguageoutcomes.
JoannaTaoTowardUnderstandingtheRoleofPhysicalActivityandFunctionalConnectivityinHealthandPathologyUsingMachineLearning.ResearchDirector:Dr.JustinBakerPsychoticdisorders,arebotheconomicallyandpersonallycostly.Diagnosesofpsychoticdisordersaresubjective,anddonotaccountforunderlyingmechanismsthatproducesymptoms.Identificationofindividualizedbiomarkersinfactorslikebehaviorandfunctionalconnectivitythatcanpredictandtracksymptomlevelscouldmakeitmucheasiertodiagnoseandtreatpatients.Thepresentstudyusedmachinelearningtodevelopmethodsforidentifyingbiomarkersinbehaviorandfunctionalconnectivityandcollectedalongitudinaldatasettowhichthesemethodscouldbeapplied.Actigraphydatacollectedwithactigraphymonitorswerefirstanalyzedinlabtoverifythatdifferenttypesofmovementscouldbeidentifiedandcategorizedusingmachinelearning.Then,aniterativeapproachwasusedtoproduceindividualizedmapsoffunctionalconnectivitynetworksin131patientswithpsychoticdisorders,thenusedtopredicteachindividual’ssymptomlevels.Concurrently,datawerecollectedathighfrequencyonelevenparticipantswithpsychoticdisordersovermorethantwoyears.Participantscompleteddailysurveyswhileobjectivemeasureswerecollectedusingactigraphydevices,acustomsmartphoneapplication,andfMRI.Thoughstillincomplete,thestudyhasbeenabletocollectlargeamountsofdataandcapturechangesintheparticipants’illnesses.Themethodsfromthefirsttwoanalysescouldthusbeappliedtothethirdstudy.Resultsfromthefirsttwopartssuggestthatbiomarkerscanbeidentifiedfromthedatainthethirdpart,andthatthedatacanbeclusteredusingvariousmachinelearningtechniquestopredictthecourseofeachindividual’sillnessduringthestudy.
EllieUnderwoodBehavioralTestofDepthPerception:MeasuringBinocularVisioninMice.ResearchDirector:Dr.TakaoHenschPlasticityinthevisualcortexofthemousebrainhasbeenshowntoriseandfallinsuccessivecriticalperiodsoverthecourseofdevelopment.Onesuchcriticalperiodinvolvesthebinocularmatchingoforientationpreferenceofneuronsreceivinginputsfrombotheyes,allowingforintegrationofthisinputnecessaryfordepthperception.Theprincipalobjectiveofthisthesisistoestablishabehavioraltesttoassessthefunctionaleffectofbinocularmatchingondepthperception.Thevisualclifftestwasusedinthisstudytoassessbinocularvisionoverdevelopment,withnosignificantdifferencesfoundinperformancebetweenjuvenile(agesP21andP30)oradultmice(overP60).AdultmicewithspecificmutationsinmolecularfactorsofinterestincludingNR2A,Icam5,CDKL5,andGAD65werealsotestedwithnosignificantdifferencesobserved.Iftherearefunctionaldifferencesbetweenthesemouselines,thevisualclifftestascurrentlyimplementedisunabletodetectthesedifferences.Futurestudiesmaylookatmiceatayoungeragebeforeotheraspectsofvisualprocessinghavefullydeveloped,aswellasmutantmicepredictedtohavemoreseverephenotypes.
MelonieVaughnFeverEffect,the:InvestigatingBehavioralChangesObservedDuringFebrilePeriodsinAutisticMouseModels.ResearchDirector:Dr.CatherineDulacPastobservationalstudieshavedemonstratedthatchildrenwithAutismSpectrumDisorder(ASD)exhibitdecreasesinbehavioraldeficitswhilefebrile.However,themechanism(s)behindthisfevereffectandtheextenttowhichtheeffectcanbereplicatedinotherASDmodelsremainsunknown.Inanefforttofurtherourunderstandingofthisphenomenon,wehaveconductedseveralbehavioralassayswhichquantifiedchangesinmultipleASDmodelmouselinesaftertheinductionoffever.OurfindingssuggestCNTNAP2--andShank3B-/-linesmayexhibitimprovementsinsocialbehvaviorandsocial-inducedvocalizationwhilefebrile,respectively.TheseresultsallowforfurtherinvestigationusingASDmouselinestounderstandthecircuitryresponsibleforthesechanges.
SoniaWangHowMicrogliaAffectAdultNeurogenesisandLearningintheOlfactoryBulb.ResearchDirector:Dr.VenkiMurthyPlasticityintheadultmammalianbrainplaysacriticalroleinlearningandmemory.Thisphenomenonhasbeenlinkedtoadultneurogenesis,ortheprocessofgeneratingnewneuronsthatintegrateintoexistingbraincircuitrythroughoutadulthood,intheolfactorybulbandthedentategyrus.Bystudyingtheseadult-bornneuronsandtheirregulators,itispossibletobetterunderstandhowthesecellscontributetoplasticity.Possibleregulatorsoftheseadult-borncellsincludemicrogliawhicharetypicallyassociatedwithimmunefunctions,includinginitiatinginflammatoryresponsesandphagocytosisofdyingcellsinvolvedindisease.However,morerecentworkhaslinkedmicrogliafunctiontoadult-bornneuronregulationinthehealthyadultbrain.Byincorporatingmethodologiesthatablatemicroglia,whichdecreasestheireffectsonadult-bornneuronsregulationofadultneurogenesis,weinvestigatedperformanceonodordiscriminationtasksthatrequireadultneurogenesis.Focusingontheolfactorybulbinmousemodels,wehypothesizedthatmicrogliaablatedmicewouldperformsimilarlytocontrol,non-ablatedmiceoneasierolfactiontasks,butwouldexhibitsignificantlydecreasedperformanceonmoredifficultfinediscriminationtasksbecauseofadecreaseinadultneurogenesisregulationandintegrationoftheadult-borncellsintoexistingbraincircuitry.Ourresults,however,demonstratedsimilarperformanceoneasiertrialsandmoredifficulttrialsbetweenablatedandcontrolgroupsinbothhead-fixedandfree-roamingexperimentalsetupssignifyingthatmicrogliaablationmaynotsignificantlyimpairperformanceonolfactorydiscriminationtasksaspreviouslybelieved.
GraceXiaoInterictalSpikeCharacteristicsandSeizureRiskinBECTSEpilepsy.ResearchDirector:Dr.CatherineChuEventhoughepilepsyisacommonneurologicaldisorderaffectingmorethan2millionpeopleintheU.S.(AES),itisfrequentlytreatedaccordingtoprobabilisticdatainsteadofaclearunderstandingofdiseaseprogressionandseizurerisk.Currentclinicaltreatmentofepilepsyrequirestrial-and-failmethodforanti-epilepticmedicationsincetherearecurrentlynoindicatorsavailabletopredictongoingseizurerisk.Thus,thereisneedforabiomarkertodevelopobjectivemeasuresofdiseaseprogresstoavoidtheadverseeffectsofoverorunder-medicationoncognitive,psychosocial,andbehavioralfunction.InterictalEEGepileptiformdischarges(IEDs)areawell-recognizedhallmarkofepilepsy,definedasabrief(<250ms)electricaldischargethatcreatesasuddenpeakonaEEGrecording(StaleyandDudek,2006).Sincebenignepilepsywithcentrotemporalspikes(BECIS)hasatransientperiodofepilepsyanduniquepatternofEEGspikes,weidentifieditasanaturalmodeltodevelopobjectivemeasurestoevaluateseizureriskandpredicttheonsetofremission.Weinvestigatedwhetherepileptiformspikecharacteristicslikefrequency,amplitude,sharpnessandwidthevolveoverthecourseofBECTSdiseaseprogression.Wefoundthatspikeratedecreasesastimesincelastseizureincreases,suggestingthattheremaybearelationshipbetweenspikerateanddiseasestage.Wefoundthatspikemorphologylikeamplitude,durationandfrequencydonotchangesignificantlyasBECTSepilepsyprogresses.Theseresultssuggestedthatonlyspikerateandnotspikemorphologymattersforpredictingseizurerisk,butfurtherresearchisneeded.
MeganYertonPharmacologicalDisruptionofPrepulseInhibitionofAcousticStartleinIntervendorSpragueDawleyRats.ResearchDirector:Dr.BarakCainePrepulseinhibition(PPI)referstotheneurologically-basedprocessofsensorimotorgatingwhereaweakstimuli(prepulse)precedesastrongerstimuli(pulse)andinhibitsthereactiontothepulse.DeficitsinsensorimotorgatingasmeasuredbyPPIareseeninhumanswithschizophreniaandotherdisorders.DrugsthatactonneurotransmittersinvolvedinthesensorimotorgatingpathwaycanbeusedtoinducePPIdisruptioninanimalmodelssuchasrats.Apomorphine(adopamineagonist),scopolamine(amuscarinicantagonist),dizocilpine(aNMDAantagonist),andDOI(aserotonergicagonist)haveallbeenshowntodisruptPPI.ThoughresearchhasshownthattherearedifferencesinPPIdisruptionamongdifferentstrainsofrats,nonehavestudieddifferencesbetweendifferentvendorssupplyingthesamestrains.ThisstudyusedthepharmaceuticalinterventionslistedabovetomeasurepotentialdifferencesindisruptionofPPIinSpragueDawleyratsfromeitherCharlesRiver(n=7male;n=8female)orEnvigo(n=7male;n=7female)vendors.PPIwasmeasuredusingstartleresponsefollowingthesubcutaneousinjectionofvehicle,apomorphine(0.5mg/kg,1.5mg/kg,and3.0mg/kg),scopolamine(0.1mg/kg,0.5mg/kg,and1.0mg/kg),dizocilpine(0.5mg/kgand1.5mg/kg),andDOI(0.25mg/kg,0.5mg/kg,and1.0mg/kg).ResultsshowedthatpercentPPIdisruptionwasrelatedtovendorinallcasesexceptvehicleandDOI,suggestingthatvendorchoiceisasignificantfactorinstudiesinvolvingselectivedisruptionofPPIviaapomorphine,scopolamine,anddizocilpine.
SofiaZoullasBrainactivityasamediatorofinstitutionalrearingonsocialcommunicationinadolescence.ResearchDirector:Dr.ChuckNelsonInstitutionalrearinghasbeendemonstratedtohavedetrimentaleffectsonseveraldevelopmentaldomains.Notably,theseverepsychosocialdeprivationexperiencedbychildrenininstitutionssignificantlyaffectstheircognitiveandsocioemotionalcapabilities.Thecurrentstudyexaminedtherelationbetweenbrainactivityandsocialcommunicationamongchildrenraisedininstitutionsbydrawingfromaprospectivelongitudinalstudy.Specifically,theBucharestEarlyInterventionProject(BEIP),arandomizedcontroloffostercareasanalternativetoinstitutionalcare.ChildrenlivingininstitutionsaroundBucharest,Romaniawererandomizedintoafostercaregrouporremainedintheinstitutionscomparedwithanever-institutionalizedcontrolgroup.Brainelectricalactivitywasacquiredatage12usingrestingelectroencephalogram(EEG)data.Socialcommunicationskillswereassessedatage16usingtheSocialCommunicationQuestionnaire(SCQ).WetestedalongitudinalmediationmodelwithrestingEEGalphapoweratage12asamediatorbetweeninstitutionalizationandSCQscoresatage16.Pathanalysiswasusedtotesttheproposedmediationmodel.EEGalphapoweratage12didnotsignificantlymediatetherelationshipbetweeninstitutionalizationandSCQscoresat16.However,institutionalizationwaspredictiveofSCQatage16.Furthermore,EEGatage12ispredictiveofcertainSCQsubscoresatage16.Thesefindingselucidatealongitudinalrelationbetweenbraindevelopmentandsubsequentsocialability.
