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CognitionandHistamine:

H1ReceptorModulationofPrefrontalCortex

FromFungiintheAmazonto

WorkingMemoryFunctionintheRatBrain

JohnEdwardSolderIII

YaleUniversity

SeniorEssayAdvisor:AmyArnsten,Ph.D.

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TABLEOFCONTENTS:

ACKNOWLEDGMENTS............................................................................................................3

GLOSSARY………………………………………………………………………………………………4

ABSTRACT....................................................................................................................................5

INTRODUCTION.........................................................................................................................7

METHODS.....................................................................................................................................20

RESULTS........................................................................................................................................26

DISCUSSION.................................................................................................................................29

REFERENCES...............................................................................................................................38

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ACKNOWLEDGEMENTS:

IwouldliketothankDr.AmyArnstenforsharingherscientificexpertiseandforher

unwaveringencouragementandsupportasIexploredwhatitmeanstoperform,firsthand,

behavioralneurobiologyresearchinanimalmodels.IwouldalsoliketothankMrs.Tracy

SadlonforherpatientandattentiveguidanceasIworkedtobecomecomfortableand

proficientintakingcareofratanimalmodels.IwouldliketothankMrs.Michelle

Beneventoforherhelpinteachingmeproperanimalhealthprotocols.IthankDr.Joshua

KnobeandthefacultyandstaffoftheCognitiveScienceprogramforthetremendous

experienceIhadlearningaboutcognitivescienceatYaleandfortheirguidanceonthis

thesis,specificallyfromDr.MarkSheskin.Lastly,IwouldliketothankProfessorScott

Strobelforbringingmeonthetransformativeresearchexpeditionthatledmetothis

project,Dr.BryanRothwhogenerouslyperformedthereceptorassaysthroughhis

NationalInstituteofMentalHealthPsychoactiveDrugScreeningProgram,andDr.Ronald

Dumanwhoadvisedmeonthereceptorresearch.

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GLOSSARY:

Belowcontainsalistofimportantterminologyandabbreviationsusedinthisthesis,aswellastheirrespectivedefinitions.Assay --AtesttodeterminethecharacteristicsofacompoundCannula

--(pluralcannulae)Atubeinsertedintoanorganismfordeliveringorremovingfluid

dlPFC --DorsolateralPrefrontalCortexEndophyte --AfungusthatlivessymbioticallywithinaplantEthnobotany --ThestudyoftherelationshipsbetweenpeopleandplantsH1R

--Histamine1Receptor.Histamineisaneurotransmitterarisingfromneuronsinthehypothalamusatthebaseofthebrain.

Histaminergic --InteractingwiththehistaminesystemNMDAReceptor --AnN-methyl-D-aspartate,glutamate-activatedproteinionchannelReceptorAgonist/Antagonist --Achemicalthatbindstoareceptortoactivate/inactivateitSpines --Asmallprotrusion,fromthedendriteofaneuron,capableofformingasynapseStereotaxic --Usingathreedimensionalcoordinatesystemtofindlocationsinorgans,e.g.brainVehicle --Thesolutioncarryingthedrugofinterest,e.g.salinevehicleisacontrol2-PyridylethylamineDihydrochloride

--PDEA,anH1receptoragonist

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ABSTRACT:

Background

Thisthesisinvestigatedtherelationshipbetweenspatialworkingmemoryand

histamineactionsattheH1Rhistaminereceptorintheprefrontalcortex(PFC)ofrats.

Neuropsychiatricdisorders,suchasschizophrenia,areassociatedwithdetrimental

cognitiveimpairmentsinvolvingdysfunctionofthePFC.Manymedicationsadministeredto

patients,suchasantipsychoticstopatientswithschizophrenia,blockH1R.Yetitisnot

knownwhetherblockingH1Rwouldhelporfurtherhindercognitiveoperationsdependent

uponthePFC.ThecurrentstudyexaminedhowadministeringH1RagonistsintothePFC

caninfluencespatialworkingmemoryperformanceinarodentmodel.

Methods

SpatialworkingmemoryfunctionwithinthePFCwasassessedinelevenratstrained

onaspatialdelayedalternationT-mazetest.Afterbaselineperformancestabilized,they

wereadministeredadoseoftheH1receptoragonist2-Pyridylethylamine(PDEA)

dihydrochloride(0.001,0.01,0.1,1.0μg/0.5μl)orsalinevehiclebycannula(placedby

stereotaxicsurgery)intoeachsideofthemedialPFC.Theexperimentertestingtheratwas

blindtothedrugtreatmentcondition.Thepercentageofcorrectlyexecutedmazetrials

followingdrugtreatmentwascomparedtothosefollowingsalinecontrol.

Results

Preliminaryresultstodate,from9rats,indicatethatthe0.01μgdoseofPDEA

significantlyimprovedperformancecomparedtosalinecontrol:averageperformance

followingsalineinfusion:73.1+2.6%correct;averageperformancefollowing0.01μg

PDEAinfusion:85.0+3.1%correct,p<0.05.Allratswereimprovedbyeitherthe0.01μgor

0.1μgdosesofPDEA,comparedtotheirperformanceonsalinecontrol(p<0.05).

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Conclusions

TheresultsprovidepreliminarysupportfortheabilityofH1Ragoniststoimprove

spatialworkingmemory.Furthertestinginlargersamplesandofadditionaldosesare

warrantedinordertoconfirmeffectsandestablishdose-responserelationships.

Confirmationofeffectswouldprovidenovelneurobiologicalinformationabouttheroleof

thehistaminergicsystemincognitivefunctionandsuggestthatblockadeofthesereceptors

bymedications,suchasantipsychotictreatments,mayworsencognitiveabilitiesin

patients.Italsosuggeststhathistamineagonists,potentiallyonesderivedfromnatural

sourcessuchasplantsoftherainforest,mayenhancecognitivehealth.

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INTRODUCTION:

TheHistaminergicandCentralNervousSystems

Thehistaminergicsystemiscommonlyknownthroughthewidespreaduseof

antihistaminestotreatallergicreactions.However,thegreatestpotentialoftreatments

thataffecthistaminemightnotbeinmodulatingtheimmunesystem,butratherthecentral

nervoussystem,specificallythebrain.Aregularandofteninseparablesideeffectoftaking

antihistaminicallergymedicationsisdrowsiness,whichservedasthefirstindicationthat

thehistaminergicsystemcanmodulatetheactivityofthecentralnervoussystem(Tsujii,

Yamamoto,Ohira,Takahashi,&Watanabe,2010;Yanaietal.,2011).Itwasthisdrowsiness

thatstimulatedresearchintohowchangesinthehistaminergicsystemcouldmodulate

brainfunctioning(Yanaietal.,2011).In1951,chlorpromazinewassynthesizedand

althoughitwasinitiallyutilizedforitsantihistaminicanestheticeffects,itbecamethefirst

antipsychoticmedicationusedcommonlytotreatthemajorpsychoticsdisorderssuchas

schizophrenia(Ban,2007).

AntipsychoticMedicationsandHistamine

Chlorpromazine,afirst-generationantipsychoticmedication,wasalandmarkdrug

inthetreatmentofpsychoticdisorders.Thiscompoundledtothedevelopmentofthefirst-

generationofantipsychoticmedications,whichallblockeddopamineD2receptorswith

highaffinity.D2receptorblockadehasbeenrelatedtoantipsychoticefficacy,butalsoto

seriousmotorsideeffects,sedation,andcognitiveimpairment.Second-generation

antipsychotics(SGAs),alsoknownasatypicalantipsychotics,weredevelopedtotreat

psychosis,aswellasproblemsinmoodandcognition,whileminimizingunwantedside

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effects(Gaebel&Zielasek,2015;Wuetal.,2005).TheseagentsallblockdopamineD2

receptorswithloweraffinitythanthefirst-generationcompounds,thuslesseningtheir

motorsideeffects.Incontrasttotheirpredecessormedications,SGAstargetdifferentbrain

neurotransmittersystemssimultaneously,andthisisthoughttounderlietheirmore

benigninfluencesoncognition(Roth,Sheffler,&Kroeze,2004).

ThebreakthroughSGA,clozapine,andthecommonlyusedSGA,risperidone,both

havediversereceptoraffinities,butinparticulartheyshareahighaffinityforH1histamine

receptors(Shahid,Walker,Zorn,&Wong,2009).Anothercurrentfrequently-prescribed

SGAisaripiprazole,whichcantreatpsychosisbuthasmixedeffectsoncognition.Tobetter

elicitpatientbenefits,aripiprazolehasbeentailoredtoeffectdopamineandserotonergic

receptors.However,aripiprazolealsohasaffinityforthehistamineH1receptor(Girgiset

al.,2011;Sumiyoshi,Higuchi,&Uehara,2013).ThebalanceofH1receptoreffectscouldbe

animportant,althoughlargelyoverlooked,componentforoptimizingtreatments.

However,itisnotknownwhethertheseactionsshouldbeamplifiedordiminishedtohelp

patients,asthereislittleknownabouttheroleofH1Rinthebraincircuitsthatmediate

highercognition.BlockadeoftheH1Risthoughttounderlietherapidweightgaincaused

bytheseagents(He,Deng,&Huang,2013),butcliniciansmustconsiderwhether

diminishingH1Ractionswouldbehelpfultopatientssuchasinitseffectsoncognition.

Thestudyofcomplexmedicationstotreatcomplexpsychiatricdisorders,suchas

schizophrenia,maylimitunderstandingofotherapplicationsoftreatmentsandthe

potentialimpacttheycouldhaveonthepopulation(Wuetal.,2005).Althoughmental

illnessesarecomplex,thiscomplexitydoesnotcompletelyexplaintheslowprogressof

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psychopharmacology;rather,itrevealsafoundationallackofunderstandingforthe

biologicalintricaciesofthebrain,withoutwhich,thepotentialfortreatingbrain

dysfunctionremainsfartheroutofreach.Untilthehealthybrain’sneurobiologyisbetter

understood,medicalpsychiatrywillcontinuetoberelativelybehinditstruetreatment

potentialincomparisontoothermedicalfields.Researchfocusneedstocontinueto

broadentoelucidatetheimpactofunderstudiedsystems,suchasthehistaminergicsystem.

Thebrainiscomplicatedandinorderforresearchtofocusuponthoseaspectsthatwill

yieldthegreatestmedicalpotential,neurobiologistsmustbecomedetectives.

Chlropromazine’sBackstory

Itistheconsistentreappearanceofsomethingfirstignoredthatoftenconstitutes

thegroundsofagenuineclue.Inthecaseoftryingtotreatpsychosis,therelevanceofthe

histaminergicsystemhasbeenrelativelyoverlooked.First,medicationsthattargetthe

histaminergicsystemweremedicallypursuedasameanstocontrolimmuneresponses.

Then,notingthesedativepropertiesofthesemedications,attentionwasshiftedtowards

thehistaminergicsystem’spotentialtoaidinanesthesiabyaffectingthenervoussystem.

Finally,theseanestheticeffectspointedinvestigationintothecentralnervoussystemand

eventually,whenthesemedicationswereturnedtowardspsychiatricdisorders,theresult

wasthefirstantipsychoticdrug,chlorpromazine.Theissueatthatmomentof

psychopharmacology,wasthatthereseemedtobeonlyacoincidentalconnectionbetween

chlorpromazine’shistaminergicmodulationandthetreatmentofpsychosis.

Whenattemptsweremadetoexplainthetherapeuticeffectsofchlorpromazine,our

scientificunderstandingoftherelationshipbetweenthehistaminergicsystemand

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psychosiswasbasedprimarilyonconjecture(Miyamoto,Miyake,Jarskog,Fleischhacker,&

Lieberman,2012).Whilethediscoveryoffirst-andsecond-generationantipsychoticswill

foreverbeaturningpointinthetreatmentofpsychiatricillness,itshouldnotbethe

conclusion.Neuroreceptorinteractionsarecluestoimportantnewquestions:Howdoes

modulatingthebrain’shistaminergicsystemaffectthewaywethink,ourcognition,andin

itsdysfunction,mentalillness?

CognitiveDeficitsfromSchizophrenia

Thesymptomsofschizophreniacanbedividedintotothreetypes:positive,negative

andcognitive.Allthreearedetrimentaltothepatient,butitistheseverityofcognitive

symptomsthatplaceapatientwithschizophreniaatamorefundamentaldisadvantagein

everydaylife(Strassnigetal.,2015).Psychosisisthoughttoberelatedtoexcessive

dopamineD2receptorstimulationinthecaudatenucleusofthebasalganglia,aswellasto

possibleabnormalitiesinthePFC.Giventhecomplexitiesandrelativelypoor

understandingoftheneurobiologyofpsychosis,thisthesiswillfocusonthecognitive

deficitsofschizophrenia,whicharesoimpairing.Inparticular,itistheimpairmentof

workingmemorythatcanmakefunctioningineverydaylifemoredifficult(Lesh,Niendam,

Minzenberg,&Carter,2011).

Workingmemorycanbethoughtofasthebrain’smentalsketchpad,inthatitholds

newly-acquiredinformationsothatitcanbereadilyaccessedinproblem-solving

situations.Thistypeofmemoryimpairmentcouldbeexemplifiedbyimaginingsomeone

comingtoaforkintheroadand,afterpickingadirection,subsequentlynotbeingableto

rememberwhichdirectionwaspickedbecausethespatialinformationwasnotbeing

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effectivelyheldinthebrain’sworkingmemory(Arnsten,2013).Astudyfocusedon

workingmemoryisessentiallyameansoftakingaverycomplicatedmedicaldisorder,

schizophrenia,andprioritizingaspecificbehavioralaspect,thatisworkingmemory

impairment,soastofocusonimprovingthepatient’swell-being(Sumiyoshietal.,2013).

AmazonianEndophytes

Myinterestintheroleofhistamineinworkingmemorywasoriginallyinspiredby

myexperienceinaremarkableYalecourseinethnobotanythatincludedatriptothe

AmazonianrainforestinEcuadortocollectspecimens.OurYaleresearchteam,ledby

ProfessorStrobel,designedexperimentstobiochemicallyassaypurifiedendophyte

secretions.Endophytesarefungithatlivesymbioticallywithinplanttissues.Before

traveling,eachofmypeersandIhadtodecidewhatparticularsubsetofplantstochoose

outofthestaggeringdiversityoftheAmazon.Eachofuswentindifferentdirections;I

decidedtousetheethnobotanicalremedieshistoricallydevelopedbyAmazoniantribesto

createaconnectionbetweenplantspeciesandtheirpotentialtoaffectthecentralnervous

system.Theoverarchinggoalwastofindbotanicalmedicinesthatmightalleviatebrain

dysfunctiononapsychiatriclevel.

PsychoactiveDrug-ScreeningProgram

However,thisideawasnotnew,andIfoundtheresearchofDr.BryanRothwhohad

traveledtoPeruwithateamtocollectbotanicalsamples.Subsequentlyhedistilledthe

samplestoextractsthatcouldberunthroughthePsychoactiveDrugScreeningProgram

(PDSP),whichhenowoperatesthroughtheNationalInstituteofMentalHealthandisa

supportedprogramattheUniversityofNorthCarolina(McKenna,Ruiz,Hoye,Roth,&

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Shoemaker,2011).ThePDSPisthemeanswithwhichDr.Rothassaystheabilityofa

compoundtointeractwithamyriadofneurotransmitterreceptors(Catapano&Manji,

2007).Hisworkedshowedmetwothings:itallowedmetonotonlystudythe

ethnobotanicalrationalebehindhisplantcollectionlist,butitalsohelpedmetorefinemy

listbydiscountingspeciesandevenwholegenusofplantswhichDr.Rothalreadyshowed

tohaveminimalpsychoactivepotential.Byhavingalistofplantsthatwerebothusedfor

ethnobotanicalremedies,andthatindeedcontainedcompoundswithneuroreceptor

activity,IcouldmakethecollectiontriptotheAmazoninEcuadornottostudytheplants,

butinsteadtostudythepsychoactivepotentialoftheirendophytes(illustratedinFigure1).

Thebenefitofstudyingthesecretionsoftheplantspecies-specificsymbiotic

endophytesisthatthefungi’spastevolutionaryspecializationtoacertainplantspecies

allowedthetwospeciestocoevolveovertime.Thisincreasesthelikelihoodthatthetwo

speciesproducesimilarcompounds,orthatthecompoundoncethoughttobeproducedby

theplantwasactuallyproducedbytheendophytewithinit.Eitherway,byassayingthe

secretionsfromtheculturedendophytes,throughthePDSP,itwaspossibletogatherdata

ontheirneuroreceptoractivity.

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Figure1.ProgressionofResearchfromTargetPlanttoFoundPlanttoCulturedFungiThisfigureillustratestheselec/onofplantspeciestosearchforintheAmazon.Plantscouldthenbefoundbyrecognizingthecorrectphenotype.Plant/ssueisthencollectedandusedtocultureendophy/cfungi.Eachfungi’sextractsarethenassayedthroughthePDSP.

PlantinIllustra:onàPlantintheAmazonàPlant’sEndophytesà

FABACEAEErythrina

megitophyllaAPOCYNACEAE

Tabernaemontanasananho

VERBENACEAELantanatrifolia

E15723ALasiodiplidiasp.

PDSPH1R%

50

E15707AEutypellasp.

PDSPH1R%

50

E15723BTetracladiumsp.

PDSPH1R%

50

E15723DClonostachyssp.

PDSPH1R%

40.4

E15702D

PDSPH1R%40.3

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PDSPResults

ThePDSPdatacollectedcuriouslyshowedthattheneuroreceptorsmostheavily

responsivetotheendophytecompounds,thatIhadextracted,weretheH1histaminergic

neuroreceptors(illustratedinFigure2).This,inconjunctionwiththehistoryof

chlorpromazinebroughtmetoDr.Arnsten,Yale’sleadingneurobiologicalresearcherin

neuroreceptorspertainingtoworkingmemory(Arnsten,2009;Arnsten,Paspalas,Gamo,

Yang,&Wang,2010),whoinspiredmetofocusstudyoneffectsofH1Ractivityonworking

memory.WithDr.Arnsten’sguidance,itwaspossibletoadoptapreexistingexperimental

modelusedtoreliablyevaluateworkingmemoryinrats.Usingthisparadigmin

conjunctionwithdrug-basedmodulationoftheH1Rhistaminergicsystemintherat’sbrain,

throughdirectPFCinfusion,allowsfortherelationshipbetweenworkingmemoryandthe

histaminergicsystemtobeexplored(Robbins,2000).Thedrugbeingadministeredisnot

identicaltothecompoundsfoundintheendophytes,buttheexperimentaldrugdoes

possessthesameH1Ragonisticcapabilities.TherationalebehindtargetingthePFCis

thankstoYale’sDr.Goldman-Rakicwhosehistoricworkdeterminedthatitisthe

dorsolateralPFC(dlPFC)thatcontrolsspatialworkingmemorywithintheprimatebrain

(Goldman-Rakic,1988,1996).

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Figure2.TheCapabilityofDifferentFungalExtractstoBindtoNeuroreceptorsThisfigure illustrates thedata received from thePDSP.ThePDSP’sassay records theabilityofeachsample todisplaceasignalcompoundoccupyingdifferentneuroreceptor types.Thisdisplacement isrecordedasapercentage.Thelargerthepercentage,themorecapableasampleisatbindingtothatspecificneuroreceptor.Percentagesatorbelow50%arenotconsideredsignificantbythePDSP,buttheyaresCllvaliddata.ThisdatatablespecificallyshowstheH1Rbindingcapabilityforfiveextracts.

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SpeciesDifferencesinPFCandWorkingMemory

Nonhumanprimateshavehighlydevelopedbrains,includinganextensivedlPFC

thatconferspowerfulworkingmemoryabilities.However,infusionexperimentsin

nonhumanprimatesareextremelyexpensive,andthusarerarelytheappropriatestarting

placeforneuropsychopharmacologicalresearch.RodentshaveamuchsmallerPFC,anddo

nothavethenewlyevolveddlPFC,buttheydohaveamedialPFCregionthathasbeen

showntobenecessaryforperformanceofspatialworkingmemorytasks(Kolb&Robbins,

2003).Asrodentsarenocturnal,theirsensorysystemsarenotwell-equippedtoprocess

visualfeatures.Inparticular,albinoratshaveexceptionallyweakvisionanddonoteven

possessaventralstreamforvisualfeatureanalysis;onlyprimateshavethat.Instead,the

nocturnalrodentbrainisproficientatprocessingvisualspatialinformation.Duetothis

species-specificspecialization,theidealmethodofobservingworkingmemoryinrodents

istouseaparadigmthatreliesontheirspatialworkingmemoryspecifically,especiallyas

theneurobiologyofspatialworkingmemoryhasbeenextensivelystudiedinprimates,

therebyallowingforcross-speciesresearchcomparisons.

SpatialWorkingMemory

Onthecellularlevel,pyramidalneuronswithinlayerIIIofthemonkeydlPFCare

crucialforspatialworkingmemory.Whenananimalattemptstoremembertherecently

learnedlocationofsomethinginordertosolveapuzzle,layerIIIpyramidalneuronsexcite

eachotherthroughNMDAreceptorsynapsesondendriticspinestokeepthespatial

position“inmind”.Thesepyramidalcellmicrocircuitshaveapreferredorientation,i.e.they

preferentiallyfiretothememoryofaneventinaparticularareaofvisualspace,butnotto

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otherareas.Theseneuronsarecalled“Delaycells”becausetheyareabletomaintainfiring

acrossthedelayperiodinaspatialworkingmemorytask.

Forexample,oneclusterofDelaycellsmaintainsfiringforthememoryofstimuliat

90degrees,whileadifferentclusterofpyramidalneuronsfiresforthememoryofstimuli

at45degrees.Itisthispersistentneuralactivitythatallowsforthespatialinformationto

beavailableforimmediaterecallasaworkingmemory(Goldman-Rakic,1995).Toassess

thespatialworkingmemoryofananimalistoassesshowtheirpyramidalneurons,inthe

PFC,arebehaving.ParallelphysiologicalstudiesintheratPFChaveshownthatthereare

alsoneuronsthatareabletofireduringthedelayperiod(Yang,Shi,Wang,Peng,&Li,

2014).However,rodentPFCneuronscannotmaintainfiringforaslongatimeasthosein

monkeys,andthusmustcreateachainofresponsiveneuronstoholdmemoriesaslongas

required.ThePFCneuronsalsointerconnectwiththehippocampustoallowcorrect

performanceatlongerdelays.

H1ReceptorsandthePFC

Thebrain’shistaminepathwayoriginatesfromthetuberomammillarynucleus

(TMN)oftheposteriorhypothalamusandfromthislocationitmakesconnectionstomany

otherbrainregionsincludingthePFC(Blandina,Munari,Provensi,&Passani,2012;Brown,

Stevens,&Haas,2001;Haas&Panula,2003).Inreactiontothehistaminesignal,thereare

fourknownhistamineneuroreceptorsubtypes,H1,H2,H3andH4,whicharedistributed

throughoutthebrain(Funkeetal.,2013;Martinez-Miretal.,1990).

Interestingly,thePFCdoeshaveapopulationofH1receptor-containingneurons

andfurtherintriguingisevidencethatindividualswithschizophreniahaveareducedH1

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neuroreceptorbindingprofilewithintheirPFC(Iwabuchietal.,2005).Thissuggeststhat,

shouldsomeoneingestacompoundthathasH1Ragonistactivity,perhapsfroman

ethnobotanicalremedy,thatthiscompoundcouldaffectthebrain’sH1histaminergic

system,includingtheH1neuroreceptorswithinthePFC(Panula&Nuutinen,2013).Ifthat

personhasschizophrenia,perhapsitcouldtreattheH1activityreductionsinthePFC.

Withinaratmodel,ithasbeenshownthatupontheadministrationofSGAs,theratmedial

PFCshowsagreaterhistamineefflux.

Specifically,whensystemicadministrationoftheSGAclozapineiscomparedtothat

oftheH1antagonistpyrilamineinratmodels,bothinducesimilarhistamineeffluxinthe

PFC.ThisimplicatesantipsychoticssuchasclozapineasinfluentialontheH1

neuroreceptorsysteminitsrelevancetomemory(Felletal.,2012;Roegge,Perraut,Hao,&

Levin,2007).Inaddition,ithasbeenshownthattheSGAolanzapinehasasignificant

occupancyeffectonthesubpopulationofH1neuroreceptorsinhumans(Satoetal.,2015).

Thus,ifcompoundsthatmodulatetheH1neuroreceptor’sactivityareadministered

directlytothePFC,theneffectsofdirectlymodulatingPFCH1receptorscanbeassessed

(Schwartz,Arrang,Garbarg,Pollard,&Ruat,1991).

Therehasbeenoneintriguingstudydemonstratingthatmicewithaknockoutfor

theH1receptorshowedimpairedspatialworkingmemoryperformance(Zlomuzica,

Ruocco,Sadile,Huston,&Dere,2009).However,therehavebeennostudiesofeffectsof

histamineagonistsontheworkingmemoryfunctionsofthePFC,despitetheclinical

relevanceofthisissue.ThecurrentstudyprovidesthefirstexaminationofhistamineH1R

actionsontheworkingmemoryfunctionsoftherodentPFC.ByinfusinganH1receptor

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agonistdirectlyintotheratPFC,inconjunctionwiththeanimaltryingtosolveaspatial

workingmemorypuzzle,itispossibletoobservethepotentialeffectofmodulatingtheH1

histaminergicneuronsofthePFConspatialworkingmemoryfunctioning.

TMazeParadigm

TheexperimentperformedutilizesH1neuroreceptoragonistsbeinginfusedinto

theratPFC,suchthattheanimal’ssubsequentabilitytosolveaTmazespatialworking

memorypuzzlecanbeobserved.ThefundamentalprincipleofaTmazeisthatitpositions

theanimalatthebaseofaT-shapedmazeandthen,astheanimaltravelstheverticallength

oftheT,itapproachestheopportunitytoturnrightorleftatthetopbranchpoint.Afterit

hasmadeadecision,theratisgivenarewardandplacedatthebaseoftheTagain,thus

completingtrial0of10.Whentheratreachesthejuncturepointfortrials1-10,itisonly

rewardedifitchoosesthepathoppositethepathpreviouslyrewardedinpriortrial.

Throughtraining,theratlearnstoalternatewithproficiencywhicharmofthemazeit

chooses,tothepointatwhichastablemodelofspatialworkingmemoryiscreated.Then,

byinfusingtheH1histaminereceptoragonist,PDEAintotheratPFC,itispossibleto

observesubsequentchangesinworkingmemorydependentmazesolvingbehavior.

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METHODS:

AnimalModel

MaleSpragueDawleyrats(n=11),weighing300-550g,wereindividuallyhousedin

filterframecages.Theseratswerekeptona12hrlight/darkcycle,andtheexperimentwas

conductedduringthelightphase.Theanimalswerefedadietofauto-clavedPurinarat

chow(14-16g/ratperday)immediatelyafterbehavioraltesting.Waterwasavailablead

libitum.Ratswereweighedweekly,andmaintainedat~300-400gforyoungrats(age4-12

months)and400-550gforagedrats(age24-36months).Foodrewardsduringcognitive

testingwerehighlypalatableminiaturechocolatechips;thisminimizedtheneedfor

dietaryregulationtoaccountforcaloricintakethroughfoodrewards.Ratswereassigneda

singleexperimenterwhohandledthemextensivelybeforebehavioraltesting.The

experimentertestingtheanimalwasblindtothedrugtreatmentconditions.Allanimal

procedureswereperformedinaccordancewiththeprotocolapprovedbytheYale

InstitutionalAnimalCareandUseCommittee.

Delayed–AlternationTask

Thedelayed-alternationtaskwasselectedastheparadigmtoassessPFCfunction,as

itiswidely-usedintestingofPFCfunctioninratsandisconsideredtobeavalidtaskfor

sensitivelyassessingalterationsinPFCfunction.Useofthistaskprovidedtheopportunity

forcomparisonwithpreviousstudiesinDr.Arnsten’slaboratoryof(1)PFCdopamine

depletionand(2)stress,forwhichthisparadigmwasalsoused.Optimalperformanceof

thedelayed-alternationtaskrequiresprocessessubservedbythePFCthatincludespatial

workingmemory(Goldman-Rakic,1987),egocentricspatialprocessing(Kesner,

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Farnsworth,&DiMattia,1989)andinhibitionofproactiveinterferenceandinappropriate

motorresponses(Mishkin,1964).Cognitivetestingmethodsweresimilartothose

developedpreviouslyinthislaboratorybyMurphyandArnstentoexaminetheeffectsof

stressonspatialworkingmemoryinrats(Murphey&DavisGw,1994).

RatswereinitiallyhabituatedtoaT-maze(dimensions,90by65cm)(illustratedin

Figure3)for5daysuntiltheywerereadilyeatingchocolatechipsplacedinthefoodwells

attheendofeachmazearm.Afterhabituation,ratsweretrainedtoperformthedelayed-

alternationtask.Onthefirsttrial,animalswererewardedforenteringeitherarm.In

subsequenttrials,foratotalof10trialspersession,ratswererewardedonlyifthey

enteredthemazearmthatwasnotchosenforrewardintheprevioustrial.Betweentrials

themazewaswipedwithalcoholtoremoveanyolfactoryclues.

Thedelaybetweentrialswas“0”secduringtheinitialtraining.Afterapproximately

2-4weeksoftrainingsessions,animalsunderwentsurgerytoimplantindwellingguide

cannulaedirectedtothePFClocation.Testingonthedelayed-alternationtaskwas

reinstatedonlyaftertheimplanthadhealedcompletely,~1weekaftersurgery.Foreach

animal,delayswereadjustedtoproduceperformancelevelsstabilizedatbetween60-80%

correct.Delaysaveragedanywherefrom0-20secforagedrats,to60+secondsforyoung

rats.Thisbaselinelevelofperformanceallowedforthedetectionofeithermazesolving

improvementorimpairmentwithdrugadministration.

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Figure3.TMazeforDelayed-Alterna8onTaskforPrefrontalCortexTes8ngThefigureillustratestheT-mazefortes3ngratsonaspa3aldelayedalterna3ontask.Toperformatrialcorrectly,ratsmustrecallthearmofthemazeitwenttoonthepreviouslyrewardedtrialsotheratcanthengototheothersideforachocolatechipreward.Baselineperformanceisstabilizedat~80%trialscorrectbeforeeachdrugorsalinecontrol.Theintertrialdelayis5-30seconds.

T-Maze:Trial0of10

HoldGate

START

0:00

ChoicePoint E

ND

END

?

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CannulaImplantation

Aftertrainingonthedelayed-alternationtask,ratsunderwentstereotaxic

implantationofchronicguidecannulae.Surgerywasperformedunderinjectable

(IP)ketamine+xylazine,withinhalationofisofluraneifneededasasupplementanesthesia,

usingasepticmethods.Guidecannulaeconsistedof9.0mmof23gastainlesssteeldirected

immediatelydorsaltothemedialPFC[prelimbic(PL)PFC;stereotaxiccoordinates:

anteroposterior,+3.2mm;mediolateral,+/-0.75mm;dorsoventral,-4.2mm](illustratedin

Figure4).Cannulae(PlasticsProducts)wereaffixedtotheskullusingdentalcement

securedwithsterilestainlesssteelscrews.Asterilestylettewasscrewedintoplaceineach

guidecannulaetopreventocclusion.Styletteswerechangedonaregularbasistomaintain

patency.Greatcarewastakentominimizepainandinfectionaftertheoperationto

decreasestresstotheanimal.Ratsweremonitoredonadailybasisforsignsofdistressor

infection,andwereinitiallytreatedwithsubcutaneousinjectablemetacam(1.0mg/kg)to

decreasepain.Ratswerehousedsinglyduringtheperiodaftertheoperation.

InfusionProcedure

Animalswereinitiallyadaptedwithamockinfusionprotocoltominimizeanystress

associatedwiththeprocedure.Ratsweregentlyrestrainedwhilestyletteswereremoved

andreplacedwith30gasterileinfusionneedlesthatextended1mmbelowtheguide

cannulae.Theratsreceivedbilateralinfusionsof2-Pyridylethylaminedihydrochlorideat

concentrationsofeither0(salinevehicle),0.01,0.1or1μg/0.5μlThedoseswerechosento

providearangeforpilottesting.InfusionsweredrivenbyaHarvardApparatussyringe

pumpsetatflowrateof.225μl/minusing25μlHamiltonsyringesforaninfusiontimeof2

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min.Needlesremainedinplacefor2minafterthecompletionoftheinfusion.Stylettes

wereinsertedbackintothecannulaeandbehavioraltestingbeganimmediatelyafterthe

infusionprocedure.Itisalsoworthnotingthattheadministereddrugislikelymetabolized

outoftherat’ssystembythenextday,buttobesureanadditionalweekisgivenbetween

infusions,duringwhichitisverifiedthattheperformancereturnedtonormalizedbaseline.

Theexperimentertestingtheratwasblindtodrugtreatmentconditions.

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DataAnalysis

Thepercentofcorrecttrialswascalculatedforeachratforeachdrugconcentration

tested.Performanceforeachdrugconcentrationwascomparedtoperformancewith

vehicle,includingdatafromallratsthatreceivedthatdrugconcentration,with

independenttwo-tailedt-tests.Thepeakperformanceondrugforeachratwasalso

comparedtoperformanceonvehicle.Resultswereconsideredsignificantatp<0.05.Means

andstandarderrorswerecalculatedforperformanceatvehicleandeachdrugdoseand

graphedtointerpretrelationshipsbetweenconditions.

RESULTS:

Statistics

Thestudyisstillinprogress.Todate,9ofthe11animalsweretestedwiththesaline

vehicletoestablishcontrolvalues.Nineanimalsweretestedat0.01μg,8at0.1μgand6at

1.0μgofPDEA.Tenratsweretestedat0.01μgand/or0.1μg.Sevenratsweretestedat

bothdoses;tworatsweretestedonlyat0.01μgandoneat1.0μgonly.50%ofrats

exhibitedpeakperformanceat.01μgandtheremaining50%exhibitedpeakperformance

at.1μg.Asthiswasapilotstudy,peakperformancewasalsocalculatedforeachratat

eitherthe0.01μgor0.1μgconcentrationandalsocomparedtovehicle.Thegraphbelow

(Figure5)demonstratesthesignificantimprovementofperformanceintherats

administereddrug,incomparisontopeakperformancetovehicle:[vehiclemeanpercent

trials-correct73.1±2.6(standarderror),PDEA0.01-0.1μgtrials-correct83.5±3.15

(standarderror),p=0.037](Figure5).

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Resultstodatefrom9ratsindicatethatthe0.01μgdoseofPDEAsignificantly

improvedperformancecomparedtosalinecontrol:averageperformancefollowingsaline

infusion:73.1+2.6%correct;averageperformancefollowing0.01PDEAinfusion:85.0+

3.1%correct,p<0.05.Allratswereimprovedbyeitherthe0.01μgor0.1μgdosesofPDEA

comparedtotheirperformanceonsalinecontrol(p<0.05).

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FIGURES

50

55

60

65

70

75

80

85

90

95

100

Vehicle(n=9) .001(n=3) 0.01(n=9) 0.1(n=7) 1(n=6) 0.01-0.1

MeanProviciency(%TrialsN

avigatedCorrectly)

InfusedDrug(2-Pyridylethylaminedihydrochloride)Concentration(μg/0.5μl)

RatProNiciencyNavigating10TrialT-Maze(PostDrugInfusion)

p<0.05

*

Figure 5. Effects of Histamine H1 Receptor Agonist 2-PyridylethylamineDihydrochlorideonDelayed-AlternationTaskPerformance This graph displays the performance (% correct out of 10 trials) on the spatialworking memory task in rats administered 2-Pyridylethylamine Dihydrochloride atdosesof0.001,0.01,0.1and1.0μg/0.5μlcomparedtothoseadministeredthecontrolvehicle.Means and standard errors are graphed. A cohort of 11 individual ratswastested. The varying N values indicate the number of rats thatwere testedwith thespecificdose.Themeanfortheright-mostbarwascalculatedbyincludingtheoptimalperformanceateither0.01or0.1:16datapointswerecollectedfrom10ratsforthisrange;7ratsweretestedatbothdoses;50%ofratshadoptimalperformanceat0.01andtheother50%hadoptimalperformanceat0.1.*Denotessignificancelevelp<0.05inthedrugcondition,comparedtothecontrolvehicle.

p<0.05

*

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DISCUSSION:

ThepreliminaryfindingsofthisstudysuggestthatstimulationofH1RintheratPFC

withalowdoseofPDEAsignificantlyimprovesspatialworkingmemoryperformanceon

thedelayedalternationtask.Thisprovidessomeofthefirstevidencesupportingbeneficial

cognitiveeffectsforH1RagonistsinthePFC.

MovingForward

Thefoundationoftheexperimentconsistsofacohortof11rats,allofwhichhave

beensuccessfullytrainedtonavigatethedelayed-alternationT-mazeworkingmemory

assessmentparadigm,andhavereceivedthepropersurgerytoallowfordruginfusionsto

bemadedirectlyintotheirPFC.Effectively,theanimalsarenowinastatewheretheycan

performfurtherexperimentaltrialsandmoredatacanbeconsistentlygathered.Atthis

point33datapointshavebeencollectedbetweenthreedrugdosagesandacontrolvehicle.

ThefirstdrugbeingtestedisPDEAatconcentrationsofeither0(vehicle),0.001,0.01,0.1,

or1μg.ThisdrugisaknownH1Ragonistbutithasneverbeenadministereddirectlytothe

ratPFCtoassessitseffectsoncognition.

Ideally,futureexperimentationwouldprioritize:theacquisitionofmoredatapoints

toperformredundanttesting,replicationofalready-collecteddata,increaseinthesizeof

theanimalcohorttocollectdataacrossmoreindividuals,andlastly,expansionintherange

ofdosagesadministeredtobettersmoothdatatrendsandassessdose-response

relationshipswithmoreincrementaldosevariation.Pursuingthisincreaseindata

collectionwillnotonlyservetostrengthenthevalidityandsignificanceofconclusions,but

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willalsoopentheexperimenttodrawingnewconclusionsespeciallyaspreviously

unstudieddosageswillbetested.

ExpandingDosages

Ofthefourdosagestested,thetwolowerdosages,0.01and0.1ug,together

exhibitedastatisticallysignificantability(p<0.05,atp=0.016,comparedtoperformance

withsalinecontroladministration)topositivelyaltermazesolvingproficiency.Forthe

determinationofadditionaldosestobetested,severaloptionspresentthemselves.

Dosagescanbeaddedeitherbetween,aboveorbelowalreadytesteddosages.Ofthese

threeoptions,thetrendofthecollecteddataservestoindicatethattheoptionwiththe

mostpromiseistoadddosagesbelowthealreadytestedlowerdosagesof0.01and0.1.The

justificationresultsfromthedatacollectedatthe1μgdosage.Thisdosage,thehighest

dosagetested,wasunique.Itcontainednodatapointswherethemazeproficiencyscore

wasanygreaterthanthatofascorereceived,bythesameanimal,atalowerdosage,i.e.

.001,.01or.1μg.Bynotexceedinganyoftheresultsproducedfromthelowerdosages,the

findingsatthehighestdosageof1μgbecomesarationalefornotpursuingfurtherdosage

increases.Thetrendofthefourdosagessuggeststhatthegreatestpromiseforcognitive

enhancementiswithlowerratherthanhigherdosages.

InvertedU-ShapedCurve

Thespeculationregardingthepotentialoptimaldoseisgroundedintheprincipleof

theinvertedU-shapeddosageresponsecurve,whichremainsasafoundationofadvisorDr.

Arnsten’sresearch.TheinvertedU-shapeddosageresponsecurve,forbehavioral

neurobiology,fundamentallyassertsthatmoreisnotnecessarilybetterandlessisalsonot

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necessarilybetter,butratherthatthereisaninherent“sweetspot”atwhichadosagecan

bemaximallybeneficial.Dr.Arnstenandcolleaguesperformedpioneeringresearch

showingthatthePFChasawindowofneurotransmitterreceptoractivitywithinwhichits

performanceisoptimal.Forexample,theyhaveshownforreceptors,forthe

neurotransmittersdopamineandnorepinephrine,thateithertoolittleortoomuchimpairs

PFCfunction(Arnsten,2009;Vijayraghavan,Wang,Birnbaum,Williams,&Arnsten,

2007)(illustratedinFigure6).Whenitcomestoconsideringcognitiveenhancingpotential

ofamedication,thisprinciplehelpsexplainwhycontinuallyincreasingdosagesdoesnot

increasebenefitbecauseafterthe“sweetspot”issurpassed,theexcessivedosagecan

becomenotonlylessbeneficialbutalsopotentiallydetrimentaltocognitiveperformance.If

theH1Ragonistisindeedacognitiveenhancer,thenitisanticipatedthatuponincreasing

thebreadthoftesteddosages,aninvertedU-shapedpatternwillarise.

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Figure6.TheInverseU-ShapedRela8onshipBetweenReceptorAc8vityandPFCPerformanceThefigureillustratestheobservedrela2onshipforreceptorac2vity,ofneurotransmi:ersystemssuchasdopamineandnorepinephrine,comparedtoPFCfunc2oning. Whenac2vityislow,thereisimpairedPFCfunc2oninganddeficitsinPFC-mediatedfunc2onssuchasworkingmemory.ImpairmentsinPFCarealsoobservedwhenPFCneuronsfireexcessively, causingdysfunc2on. Forop2malPFC-mediatedcogni2on,receptorac2vityneedstobewithinanop2malrange.

NeurotransmiEerReceptorAc8vityVs.

PFCPerformance

HIGHReceptorAc8vity

LOWReceptorAc8vity

DYSFUNCTIONSignalNoiseOverexcitabilitySubstanceAbuse

DEFICITSAgingStress

Fa8gue

OPTIMALFUNCTION

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Forthedoserangeof0.01-0.1μgthereisapvalueoflessthan.05,atp=0.016,

whichsupportsthatthisdoserange’sabilitytoimprovemaze-solvingproficiencyisnotan

artifactofexperimentalerror.Whilethedataisonlypreliminary,itdoessuggestthatan

H1Ragonisthasthecapabilitytoimprovearat’sPFCfunctioningandabilitytosolvea

workingmemorydependentmazetask.Asthiswasobservedinhealthyrats,itsuggests

thatthenatureofthisbehavioralmodificationisindicativeofcognitiveenhancement.That

beingsaid,itisnotpossibletoknowwherethe“sweetspot”dosageis.Itispossiblethatit

existswithinthemostbeneficiallytesteddosagerangeof0.01-0.1μg,butitismorelikely

thatitexistssomewherebelowthe0.01μgdosage.Regardlessofwherethe“sweetspot”is,

itwillnotbediscernableunlessmoredosagesaretestedbelowthecurrentbestminimum

doseof0.01ug.Ifthosedosagesyieldcompellingdata,thenthenextareatofocusonwould

bedosageswithintherangeof0.01-0.1μg.Ultimatelythedatadoesindicatethattheleast

promisingdosagestotestfurtherwouldbethoseexceeding1.0μg.

Nic-α7RandH1RAgonists

Theplantostudylowerdosagesisalsosupportedbythesimilaritybetweenthis

preliminarydataandapaststudyconductedbyDr.Arnstenassheinvestigatedhow

administeringanicotinicnic-α7RagonistintotheprimatedlPFCalteredDelaycellfiringas

themonkeyperformedaspatialworkingmemorytask(Yangetal.,2014).Thesedata

showedthatitwasthelowerdosagesofnic-α7RagonistthatimprovedDelaycellfiringfor

theneurons’preferredspatialdirection,whilethehigherdosagesproducednonspecific

increasesinexcitabilitythatimpairedtheneuralrepresentationofvisualspace.

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Theseconclusionsarefromtheprimateinvivoelectrophysiologicalrecordingof

dlPFCDelayneuronsspecifictodifferentorientationsofvisualstimuli.Atthe“sweetspot”

lowdosageitwaspossibletoincreasethepersistentfiringofonlytheDelayneurons

associatedwiththecorrectstimuliorientation,butatthehigherdosagesitgeneratedlarge

amountsofneuronalnoise.Thisnoisewasgeneratedathigherdosagebypersistentfiring

ofDelayneuronsspecifictoothervisualstimuliorientations,otherthanthetestedone.The

resultisamuddyornoisyworkingmemoryrepresentationoftheorientationofthevisual

stimulus,thusleadingtheprimatetobecomeincreasinglyinaccuratewiththeirattemptsto

exercisetheirspatialworkingmemoryintheexperimentaltask.Thispriorexperiment

providedfurtherhighlycompellingsupportfortheinvertedU-shapeddosageresponse

curveforcognitiveenhancersandtheideathatlowerdosagesmay,counterintuitively,be

themostbeneficial.

ItispossiblethattheH1RalsoinfluencesneuronalexcitabilitywithaninvertedU-

shapeddose-responsepattern.TheH1RiscoupledtoGqproteins,whichincreaseinternal

calciumreleaseandactivateproteinkinaseC.Futurestudiescouldexaminethese,and

otherpotentialspecificmechanisms,throughwhichH1RstimulationaltersDelaycellfiring,

andwhethertherepresentationofvisualspaceisenhancedbylowbutnothigherdoses.

ImplicationsofResearch

IntheeventthatfutureresearchcansignificantlyconfirmthatH1Ragonistsare

indeedcognitiveenhancersforspatialworkingmemoryintheratPFC,thentheimmediate

implicationsfortheresearchcommunitywillbeanovelcontribution.Itwillserveto

identifyanewmechanismthatmodulatesPFCfunctioning.Duetothehistoryofourlimited

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understandingofthehistaminergicsystemasitpertainstocognition,thehistaminergic

systemhasgenerallynotreadilybeenassociatedwithcognitivefunction.Ifconclusive

futuredatadoesbringthespotlightontothehistaminergicsystemforcognition,thenitwill

encouragefurtherexplorationintotherelationshipbetweencognitionandtheH1receptor

system,andpotentiallyotherneurotransmittersystemsthatwere

overlooked/deprioritizedinthepast.Furtherdiscoverieswillhelptheresearchcommunity

decipherthebiologicalcomplexitiesunderlyingcognition.

NatureandNeurobiology

FindingsofH1RagonisteffectsonthePFCcouldalsobringattentiontousingnature

asameanstofindcluespertainingtothecognitivecapabilitieswehaveevolved.Itisa

generalbutsignificantshiftinmindsetfortheresearchcommunitytoincreasethe

attentionitpaystothewaysplantsandfungiaffectourbodies,whichwillhopefullydistill

downtodiscoveringnewmolecularmechanisms.Thiscouldhavebroad-ranging

implicationscontributingtosupportforthepreservationofnaturalecosystemsasyet

anotherscientificcommunity,neurobiologists,becomemoreattentivetostudying

naturallyoccurringcompoundsandhowtheycaninteractwithourbrains.

MedicalApplications

Newinformationaboutthehistaminergicsystemcouldleadtonovelhistaminergic

medicationstrategiesandimprovedtailoringofthereceptoraffinityprofilesofcurrently

existingmedicationclasses.Anexampleofaresultofthiscouldbethetweakingofatypical

antipsychoticstoreducetheirH1Rblockingactions,whichappeartohaveharmfuleffects

onweightgain,(Heetal.,2013)andfromthisstudy,itappearsmayalsohaveharmful

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effectsoncognition.Thisalterationinreceptorbindingmayhelptoalleviatetheselife-

impairingsideeffects.Itwouldbeexcitingifthisresearchcouldresultinanewtypeof

psychiatricmedicationderivedfromnaturally-occurringsubstances,butevenifthis

researchonlyservestohelptobettertailortheactivityprofilesofexistingdrugs,thenthat

willbeagreatstepforwardforalleviatingthesufferingofpatientswithapsychotic

disorderandpotentiallyothercausesofcognitivedeficits.

CognitiveEnhancement

Lastly,thebroaderimplicationsofthisresearchpertaintothefutureofcognitive

enhancement.Initially,researchofthisnaturewillservetoimprovethedegreetowhich

neurobiologistsunderstandthemechanismsthatunderliecognition,downtothemolecular

level.Thisknowledgecouldthenimprovetheexistingcapabilitiestomedicallytreat

psychiatricdisorders,andthen,perhapsmightevenbeconsideredtoapplytodeveloping

methodstoimprovethecognitivefunctioningofhealthyindividuals.

Thatbeingsaid,thereisaverybigdifferencebetweencompensatingfora

psychiatricdisorderandraisingthethresholdabovewhatourbrainsarecapableof

functioningatahealthybaseline.Reachingwhatsomeconsidertobetheholygrailofatrue

“smartpill”willlikelybeprecededbysmallerstepsandwillrequirecarefulconsideration

ofethicalissues.Thefirststepforwardwouldbeincreasingtheabilitytotreatthose

individualswhoarenotpsychiatricallyhealthy.Afterbeingabletofixthingswhentheygo

biologicallywrong,thenextstepwillbetocreatetheidealneurologicalconditionsforusto

achieveournaturalpotential.Ratherthanexceedourpotential,animportantaimcouldbe

toachieveourpotential,i.e.insteadofa“smartpill”todesigna“cognitivehealthpill.”

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Arelatedexampleistherolecaffeinehasplayedinourculture.Arguablyan

individualwhoisideallywellrestedshouldn’tneedcaffeinetofunctionatpeakmental

capacity;infact,itmayimpairthembycausingovershootingsideeffects,likejitterinessfor

example.Caffeinehasthusbecomeameanswithwhichwecanadjustforourlivesnot

providingtheidealconditionsneededforcognitivefunction.Itmightbeimpossibleforan

averagecollegestudenttogettheamountofsleeprequiredforoptimalcognitive

performance,butluckilycaffeinecanstepintohelpaccommodateforthehandicapsthat

ourwayoflifeplacesonourhealth,particularlyallowingustofunctiononlesssleepthan

wemayneed.Thisprinciplecouldbeappliedtonextstepstowardsa“cognitivehealthpill.”

Itsuggeststhatbeforeexceedingourbiologicalcapabilitiesunderidealconditions,firstitis

necessarytoaccountingforthelackofidealconditionsaroundus.Bythislogic,the

predecessorforthe“smartpill”maynotbeacognitiveenhancersomuchasamedication

toaddressmoresubtlecognitiveimpairmentstobringthemintooptimalhomeostatic

rangeforanindividual,a“cognitivehealthpill.”

Itishardtoruleoutthefuturepossibilityofa“smartpill”hypotheticallybeingable

topushhumanintelligenceandcognitivefunctionbeyondwheretheyhaveeverbeen

before.However,morerealisticallytheinterimstepwillbelevelingtheplayingfield

betweenourneurobiologyandourwayoflifesuchthatourcognitivefunctionisashealthy

asitcanbeevenifourlifestyledirectlyinterfereswiththatcapacity.Whoknows,maybea

naturally-derivedcompoundthatmodulatestheH1Ractivityinsomeone’sPFCtooptimal

levelscouldbringcognitivescienceonestepclosertoa“cognitivehealthpill”.

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ImageComponentReferences:http://plantgenera.org/illustration.php?id_illustration=98791&mobile=broad&code_category_taxon=0http://plantillustrations.org/illustration.php?id_illustration=8458http://tropical.theferns.info/image.php?id=Tabernaemontana+sananho