AlanaHey

3/16/15
Biology
ResearchProposal

MymainessentialquestiongeneratedfrommyresearchisWhatcausesSchizophrenia?
Basedonmyresearchquestion,Iwillbefocusingoncertainareasofthebrainsuchasthe
prefrontalcortexandthebasalgangliaofthebrain.IhaveresearchedthebasicsofSchizophrenia
focusingontheeffectsandwhathappensinthisstateofmind.
Peoplewiththisdisordermayhearvoicesotherpeopledonothear.Theymaybelieve
otherpeoplearereadingtheirminds,controllingtheirthoughts,orplottingtoharmthem.These
effectsgenerallyterrifythepersonwiththisillnessandcausethemalotofagitations.People
withSchizophreniamightnotmakesensewhentheytalk.Theymaysitforhourswithout
movingortalkingtoothers.Familiesandsocietyareaffectedbyschizophreniatoo.
Manypeoplewithschizophreniahavedifficultyholdingajoborcaringforthemselves,
sotheyrelyonothersforhelp.AsdiscussedinDevelopmentofAnimalModelfor
Schizophrenia,therehavebeenmanystudiesoverthelast60yearswithinfamiliesthathave
clearlyshownthatgeneticshaveabigparttoplaywithschizophrenia.However,themodeof
inheritanceofthediseaseiscomplexand,inalllikelihood,involvescontributionfrommultiple
genesinconjunctionwithenvironmentalfactors.(Arguello,2010)Therefore,thereisno
provencauseforschizophreniabutresearchersdobelievethatthecombinationofcertain
neurotransmittersaswellasaperson'senvironmentandothergeneticfactorscanleadto

Schizophrenia.FrommyexperienceknowingsomeonewithSchizophrenia,Ilearnedthat
psychedelicdrugssuchasLSDcancauseabnormalitiesinthebrainwhichcancontributeto
Schizophrenia.
FormymodelorganismIwillbetestingonamousemodel.BasedonsomeresearchI
havedone,Ilearnedthatmiceareveryreliabletotestonwhenitcomestomentaldisorders.
Thesemicehaveaspecificchromosome,chromosome16,whichcontains22q11.2locus.The
significanceofthe22q11.2locusisthatscientistshaveobservedthatsometimesasmallpieceof
chromosome22inhumansgetsdeletedwhichcancauseSchizophrenia.(GeneticsHome
Reference,2013)Thefactthatthislocusiscontainedinchromosome16inmiceallowsustodo
thesetypeoftestsonthemtofurtherexplorethecausesofschizophrenia.Eventhoughitistough
toseecertainpartsofthediseasesuchasauditoryhallucinations,wecanstillwitnessother
aspectsofthediseasetoseeifthemousehascontractedit.Forexampleattention,memory,
perceptionandhyperactivityarepresentinmiceandcanbemeasuredthroughbehavioraltests.
FormyparticularquestionIamfocusingonthecauseofSchizophreniaandthereforeamableto
usemicetotestwhichofthemwillcontractSchizophrenia.Thereforeitisnotnecessaryforme
totestonotherthingssuchashumans.
Mytestingideaistouseelectrophysiologytorecordactivityinthetheprefrontalcortex
andthebasalganglia,fromamouse'spointofview.Thesetwoareasaresuspectedtobe
involvedinpeoplewithschizophrenia.Researchershavefoundthatpatientswithschizophrenia
experiencedecreasedactivityintheprefrontalcortexandexcessactivityinthebasalganglia
andoftensuspectthatthecircuitbetweenthesetwopartsofthebrainisresponsibleforcognitive

deficitsandperiodspsychosisforpeoplewiththisdisorder.(Yoon,2013)Shownherearethe
prefrontalcortex(inblue)andbasalganglia(inred):

Theprefrontalcortexisanareaofthebrainbehindtheforeheadthatnormallysupports
higherordercapabilitiessuchasprioritizing,categorizing,andstrategizing.Damagetothisarea
causesnotonlydisorderedthinkingbutalsoleadstopsychosisfromtheexcessreleaseofthe
neurotransmitterdopamineintoregionsdeepinsidethebrain.(Yoon,2013)Oftentimes,those
withschizophreniaexperiencethesesymptomsincludingproblemswithhigherorderthinking
skillsordisorderedthinking,whichledresearcherstosuspectthattheprefrontalcortexcouldbe
involvedwiththedisorder.Theconnectionbetweentheprefrontalcortexandbasalgangliais
significantbecause,thebasalgangliaisasubcorticalcollectionofneuronclusters,includingthe
ventraltegmentalareaandsubstantianigra,whichproducethemajorityofthebrainsdopamine,
andthestriatum,animportantsiteofactionofdopamine.(Yoon,2013)Asexplainedearlier,
damageordecreasedactivityintheprefrontalcortexcanleadtoanexcessreleaseofdopamine,

whichwouldnegativelyaffectthebasalgangliabecauseofthisbrainareasimportant
connectionwiththeproductionandactionofdopamine.
TherearemanydifferentmodelsyoucanusetotestSchizophrenia,Idecidedtochoose
theElevatedplusmazeandtheNovelobjectrecognitiontotestonmymice.Theelevatedmaze
hassomeareaswithwallsandsomethatareopenonthesides.Thisallowsscientiststoexamine
theanxietylevelofthemice,whichwouldincreasewithschizophrenia.Thenovelobject
recognitiontestslearningandmemory.Micewillbeexposedtocertainobjectsinsideofan
enclosureandarethenrecordedtoseehowmuchtimetheyspendexamininganewobjectwhen
itreplacesoneoftheolderones.(UniversityofWisconsinMadison)Ifoundagreatexampleof
abatteryofteststhatresearchersmightusetotestlaboratoryanimalsfromtheILARJournal
(InstituteforLaboratoryAnimalResearch.)Iwouldstartwithchartingthephysical
characteristicssuchasbodyweight,age,andsizeofthemicetobeabletohavebackground
informationonmytestsubjectsandbeabletocategorizethemandnoticeanychanges.ThenI
wouldbegintotestthebehaviorofthemicewithdifferenttestssuchastheElevatedPlusMaze
andNovelObjectRecognitionaswellastestingthereflexesandmotorskillsofthemice.This
willgivemeanideaofthecognitivelevelandfunctioningofthemiceandallowmetocompare
thebrainskillsofmicewithandwithoutschizophrenia.Dependingontheresultsofthetestsand
theelectrophysiologyoutcomes,Icanalsorelatethisbacktothetwobrainareastoevaluateif
themiceareexperiencingearlystagesofschizophreniaifdecreasedorexcessbrainactivityis
noticed.
Therearemanyreasonswhyitisimportanttocontinueresearchingthecausesand
treatmentoptionsforschizophrenia.AccordingtotheSchizophreniaInternationalResearch

Society,Schizophreniaisadevastatingillnesswithanearlyonsetandsubstantialdisability
fromitsoutset.Schizophreniashortensthelifespanofpeopleaffectedbytheillnessbyatleast
20years.(Harvey,2015)Thisdemonstratesthattheeffectsofschizophreniaarecatastrophic
andcangreatlyimpactsomeoneslifeaswellasthosearoundthem.Also,thecausesof
schizophreniaarenotfullyknown,socontinuedresearchintothesecausescanhopefullyprovide
amorecompletepictureofthedisease.Ifweareabletofindthecausesofthedisease,wecan
thenhelptopreventcasesfromworseningandbegintodevelopbettertreatmentoptions.
Researchintothecausesandultimatelythetreatmentsofschizophreniawillimpactsociety
becausecurrently,thosewiththedisorderaresubstantiallydisabledandtheirqualityoflifeis
greatlyaffected.Thisresearchwillhelpthosewithschizophreniatoleadabetterlifeandbeable
toexperiencewhatlifehastooffer.Itwillalsoopenthedoorforthemtobecomepartofsociety
bybeingabletoonedayjointheworkplaceandthecommunityaroundthem.

References:
https://schizophreniaresearchsociety.org/publicresources/statementsofresearch/
Harvey,Phillip,Ph.D.,SchizophreniaInternationalResearchSociety,2015.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806899/
Arguello,P.,Markx,S.,Gogos,J.,&Karayiorgou,M.(2010).DevelopmentofAnimal
ModelsforSchizophrenia.DiseaseModels&Mechanisms,3(12),2226.RetrievedMarch5,
2015,fromhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806899/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188305/
http://ghr.nlm.nih.gov/condition/22q112deletionsyndrome
GeneticsHomeReference.22q11.2deletionsyndrome.(2013,July1).RetrievedMarch
15,2015,fromhttp://ghr.nlm.nih.gov/condition/22q112deletionsyndrome
http://www.waisman.wisc.edu/rmcbtstests.htm
UniversityofWisconsinMadison.MouseBehavioralTests.(n.d.).RetrievedMarch5,
2015,fromhttp://www.waisman.wisc.edu/rmcbtstests.htm
http://ilarjournal.oxfordjournals.org/content/41/3/163/T7.expansion.html
Brown,R.(2000).DevelopingStandardizedBehavioralTestsforKnockoutandMutant
Mice.ILARJournal,41(3),163174.RetrievedMarch5,2015,from
http://ilarjournal.oxfordjournals.org/content/41/3/163.full
http://www.nimh.nih.gov/news/sciencenews/2013/mappingbraincircuitsprovidesclues
toschizophreniaearlierdetectionofpsychosis.shtml

YoonJH,MinzenbergMJ,RaoufS,DEspositoM,CarterCS.ImpairedPrefrontalBasal
GangliaFunctionalConnectivityandSubstantiaNigraHyperactivityinSchizophrenia.
BiologicalPsychiatry,publishedonlineJanuary14,2013.