Temperament and arousal systems

21 Pages·2016·2.74 MB·English

by  Irina Trofimova

NeuroscienceandBiobehavioralReviews64(2016)382–402

ContentslistsavailableatScienceDirect
Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev
Reviewarticle

Temperament and arousal systems: A new synthesis of differential

psychology and functional neurochemistry

IrinaTrofimovaa,∗,TrevorW.Robbinsb,1

aCILab,DepartmentofPsychiatryandBehavioralNeurosciences,McMasterUniversity,92BowmanSt.,HamiltonL8S2T6,Canada
bDepar tmentofPsyc ho logyandth eBe haviourala ndClinicalNeu roscience Institute,Do wn ingSt.,C amb ridgeCB2 3EB,UK

a r t i c l e i n f o a b s t r a c t

Articlehistory: ThispapercriticallyreviewstheunidimensionalconstructofGeneralArousalasutilisedbymodelsof
Receiv ed3May2015 temp erame ntindiff erential psyc hologyforexam ple,toun der lie‘Extr aversion ’.E vidence sug geststh at
1R5ecNeoivveedm inb errev2i0 s1e5d form specialization wi thin monoa mine neurot ran smitter sy ste ms cont rasts with the a ttribution of a “gen eral
arousal”oftheAscendingReticularActivatingSystem.Experimentalfindingsshowspecializedroles
Accepted5March2016
ofnoradrenaline,dopamine,andserotoninsystemsinhypotheticallymediatingthreecomplementary
Availableonline8March2016
formsofarousalthataresimilartothreefunctionalblocksdescribedinclassicalmodelsofbehaviour

withinkinesiology,clinicalneuropsychology,psychophysiologyandtemperamentresearch.Inspiteof
Keywords:
functionaldiversityofmonoaminereceptors,wesuggestthattheirfunctionalitycanbeclassifiedusing
Generalarousal
Neurotr ansmitters three universal aspects of actions related to expansion, to selection-integration and to maintenance of
Temperamenttraits chosen behavioural alternatives. Monoamine systems also differentially regulate analytic vs. routine
Specialization ofmonoaminesystems aspects ofactivities atcorticalan dstriatalne uralleve ls.A convergence between mainte mpe rament

Functionalensembleoftemperament modelsintermsoftraitsrelatedtodescribedfunctionalaspectsofbehaviouralarousalalsosupportsthe
model ideaofd if ferenti at ionbe tweent he seaspects analysedh ereina fu nctionalper spective .

©2016ElsevierLtd.Allrightsreserved.

Contents
1. Theconceptofgeneralarousalinpsychophysiologyandtemperamentresearch...................................................................383

1.1. Theconceptoftemperamentindifferentialpsychology......................................................................................383

1.2. Whatthisarticleisnotabout..................................................................................................................383

1.3. Adoptionofaconceptof“generalarousal”bydifferentialpsychology.......................................................................384

2. Problemswiththeconceptofgeneralarousal........................................................................................................384

2.1. Problemsinempiricaltemperamentresearch................................................................................................384

2.2. Problemsinstudiesofarousalandperformanceefficiency...................................................................................385

2.3. Neurochemicalperspective....................................................................................................................385

2.3.1. Theorexinsystem:evidenceoffunctionalheterogeneity..........................................................................385

2.3.2. MonoaminenetworksinARAS:theirdiversityspeaksagainstuni-functionalconceptsofarousal................................387

3. Ifthereisnoonearousalsystem,howmanypartitionsofarousaldoexist?........................................................................387

3.1. Specificregulatoryarousalsystemsrelatedtobasicneeds...................................................................................387

3.2. Facetsofextraversioninfactor-analyticmodelsbasedonverbaldescriptors(lexicalapproach)...........................................387

3.3. Proposedfocusonfunctionalfeaturesofbehaviorwhichareuniversalacrosssituations...................................................387

4. ThreepointsofconsensusinregardtothefunctionalspecializationofMAarousalsystems.......................................................389

4.1. MutualregulationanddiversitywithinMAsystemscreatechallengesforassessingtheirfunctionality...................................389

4.2. Theroleofthecoeruleo-corticalNAsystemsinorientingtonoveltyandalertingbehaviour...............................................389

4.3. Theroleofdopaminereleaseinprioritizingstimulussalienceandactionproduction......................................................390

∗
Correspondingauthor.

E-mailaddresses:iratrofi[email protected](I.Trofimova),[email protected](T.W.Robbins).
1 Fax:[phone].

http://dx.doi.org/10.1016/j.neubiorev.2016.03.008
0149-7634/©2016ElsevierLtd.Allrightsreserved.
I.Trofimova,T.W.Robbins/NeuroscienceandBiobehavioralReviews64(2016)382–402 383

4.4. Neurotransmittersystemsformaintenanceofbehaviouralarousal..........................................................................391

4.5. Functionalinteractionsbetweenneurotransmittersystems.................................................................................391

4.6. Summarisingfunctionaldifferencesandco-operationamongstthemainneurotransmittersystems......................................392

5. PossiblefunctionaldifferentiationbetweencorticalandbasalgangliaMAsystems................................................................393

5.1. Betweendifferentlevelsofprocessing(analyticandautomatic).............................................................................393

5.2. SpecializationoftheMAsystemsforlevelsofprocessinge.g.corticalvs.basalgangliafunctions..........................................394

5.2.1. Functionaldifferencesbetweencorticalvs.subcorticalNAnetworks..............................................................394

5.2.2. Functionaldifferencesbetweencorticalvs.striatalDAnetworks..................................................................394

5.2.3. TheroleofACh-NAnetworksinmentalformsofendurance(sustainedattention)................................................394

5.2.4. Functionaldifferencesbetweencorticalvs.subcortical5-HTsystems.............................................................395

5.3. Convergencewithtemperamentmodelsondifferentiationbetweentraits..................................................................395

6. Generalizedeffectofarousalrelatedtobasicneedslikelyreflectstheirprioritiesforbehavioralregulation.......................................397

7. Concludingsummary..................................................................................................................................397

References.............................................................................................................................................398

1. Theconceptofgeneralarousalinpsychophysiologyand them“second-orderpersonalitytraits”.Despitethesedifferencesin

temperamentresearch terminologytherehasbeenconsensusconcerningthemainprop-

erties characterizing temperamental traits (Kagan and Snidman,

1.1. Theconceptoftemperamentindifferentialpsychology 2009; Derryberry and Rothbart, 1988; Rusalov and Trofimova,

2007; Strelau, 1998; Zentner and Shiner, 2012). These proper-

This paper reviews the convergence of findings in behavioral ties relate to independence from the content of activities (i.e.

neurochemistryandintemperamentresearchonhowarousalcan from values, motivation and attitudes which comprise personal-

bepartitioned,andfurthermoretherelevanceofthisconvergence ity):temperamentmanifestsindynamicaspectsofbehavior(e.g.

fordifferentialpsychology. thedurationforwhichapersoncansustainbehavior,orthespeed

Inthispapertheconceptoftemperamentreferstoneurochem- withwhichanewactioncanbegeneratedorshiftedfromaprevious

ically based individual differences in behavioral regulation. The action).Thesepropertiesarerelativelystableduringthelifetime

originalconceptofHippocratesandlater,ofGalen,wasoffourtypes ofanindividual;theyemergewithouttheawarenessoftheindi-

of“temperamentums”,ormixturesofbodilychemicalcomponents. vidualconcerningtheseformsofbehavior,andtheyhaveanearly

In their theories a balanced mixture creates normality, whereas behavioralexpressioninchildhood.

imbalancecausesidentifiablepatternsofbehavior.Thecharacter-
isticsdescr ibedin theorigina l“tempe ram entums” −im pulsivity, 1.2. Whatthisarticleisnotabout

aggressivetendencies,depressivetendencies,socialdetachmentor
sociability −appeared toexhibita peculiarco nsiste ncyonceide n- Thisarticleanalysesconvergentpointsbetweentwolargebut
tified in so m eone’s be ha vior, su gg estive o f underlying biolo gical distant discipl ines − be havioral ne uroche mistry an d di fferen tial
factor s. psycho logy(namel y −temperam entresearch)an dth erefore,for

Twodifferentapproacheshavebeentakentothemethodology the sake of space, it must be very selective as to the topics cov-

andtheconceptualframeworkinstudyingtemperament.TheEuro- eredinthecitedreferences.Herearethemainaspectsofwhatthis

pean tradition in theory and studies of temperament (following articleisnotabout.

upontheworkofHippocratesandGalen)wasdevelopedfurther Theliteratureonthefunctionalrolesofneurotransmittersand

byWundt(seeRobinsonandRieber2001),Stern(1900,citedfrom theirreceptorsisvast,andeachofthesesystemsdeservesaspe-

Lamiell2003),Lazursky(1921),Jung(1923),Pavlov(1928,1941), cialreviewarticle.Thisinter-disciplinaryreview,however,focuses

Heymans(1929),Adler(1925,citedfromLundin1989),Kretschmer on evidence not from one science, but on points of convergence

(1925), Spränger (1914), Teplov and Nebylitsyn (1963), Eysenck betweenseveralsciencesinregardstothefunctionaldifferentia-

(1967), Thayer (1978), Gray (1991), Tellegen (1985), Rusalov tionofbehavioralactivation,eventhoughspecialattentionisgiven

(1989),WatsonandTellegen(1985),StrelauandZawadski(1993), tofindingsinneurochemistry.Thereviewsandreferencestoexper-

Strelau(1998),Trofimova(RusalovandTrofimova2007;Trofimova imentalstudiesaregivenherethereforeonlyasanillustrationof

2010a,b,2016a).ThisEuropeantraditionstarted,asnoted,within objectionstothegeneralarousalconcept,withanofferofanew

medicineandprimarilyusedexperimentalmethodswithinneu- frameworkfortheanalysisofneurotransmitters’functionality.

ropsychology,neurophysiologyandpsychiatricresearchinvolving This article limits its scope only to neurochemically based

bothadulthumansubjectsandexperimentalanimals. individualdifferences,i.e.temperamentanddoesnotincluderefer-

The North American tradition of temperament research was encestostudiesinpersonalitytheory.Personalityreferstoawide

scattered within three different disciplines: developmental psy- rangeofindividualdifferencesinteractingwithsocio-culturalfac-

chology(BussandPlomin,1984;KaganandSnidman,2009,1966; tors, including attitudes, systems of values, personal experience,

Rothbartetal.,2000;ThomasandChess,1977;WindleandLerner, etc.Sex,ageandmentalillness,however,arebasedonbiochemi-

1986), clinical psychology/psychiatry (Akiskal, 1998; Cloninger, calfactors(forexample,hormones,neurotransmitterimbalances)

2000;Mehrabian,1996;Pankseppetal.,1987;Zuckerman,1994) andarenotconsideredaspersonality,eventhoughtheyinteract

and the lexical/psychometric approach in personality theory withsocio-culturalfactors.Similarlytosex,ageandmentalillness,

(Borgatta, 1964; Digman and Takemoto-Chock, 1981; Goldberg, temperament (based on neurotransmitter imbalances) is viewed

1993;McCraeandCosta,1997;Norman,1963;Thurstone,1951). hereasaconceptcontributingtopersonalitybuthavingitsown

Historically,therefore,therehavebeendifferencesinterminol- nature.Allfourofthesebiochemically-basedcharacteristics(sex,

ogy and methodology in studies of these consistent, biologically age,mentalillnessandtemperament)shouldnotbeconflatedwith

based individual differences. The European tradition and devel- theconceptofpersonality,eventhoughtheyinteractwithsocio-

opmental psychology in North America called these differences culturalfactors.

“temperament”,whilemostNorth-Americanpsychologistscalled Topicsincludingtheunfoldingtemperamenttraitsinchildhood,

theirinteractionswithsocialandgeneticfactors,theepigenetics
384 I.Trofimova,T.W.Robbins/NeuroscienceandBiobehavioralReviews64(2016)382–402

of such interactions, their contribution to personality or to psy- Strelau,1998),“extraversion”,“arousal”(DerryberryandRothbart,

chopathology.andevolutionaryperspectivesontemperamentwill 1988),“activity”(BussandPlomin,1984;WindleandLerner,1986),

not be covered here. This paper focuses on the dimensions (and the Behavioral Activation (Approach) System (BAS; Gray, 1991),

functionalroles)oftemperament,primarilyonfindingsrelatedto “drivepersistence”(CarverandWhite,1994;Cloninger,2000)or

differentialstructure,i.e.theseparationbetweensystemsoftem- simply“arousal”(Mehrabian,1996).Followingtheappearanceof

perament. theBigFivemodel,Eysenck(1992)notedthatthetwobasictem-

Thispaperconcernsadulttemperament,andreferencestotem- peramentdimensionsweresimilartotwoofitslargestfactors(i.e.

peramentmodelswithindevelopmentalpsychologyareonlyused ExtraversionandNeuroticism).

forcomparingdimensions.

Itwillalsonotdiscusstemperamentmodelsandfindingsusing

mainly the emotionality-related traits of temperament, and the 2. Problemswiththeconceptofgeneralarousal

role of neurotransmittersand the HPA axis in emotionality. This

paperfocusesprimarilyonthetraitsandneurochemicalsystems 2.1. Problemsinempiricaltemperamentresearch

underlyingtheenergeticaspectsofbehavioralactivation.

Intemperamentresearchearlyclaimsfromthe1960’slinking

1.3. Adoptionofaconceptof“generalarousal”bydifferential extraversiontophysiologicalparametersofgeneralarousalwere

psychology contradicted by subsequent reports that failed to find such cor-

relations.Inearlyexperimentsadministrationtointrovertsofthe

TheoriginalideaofHippocratesandGalenthatchemicalimbal- classicalarousingagentcaffeineledtoaworseningoftheirperfor-

ances can form the bases of behavioral differences is echoed by mancewhereasforextravertsitimprovedperformance(Eysenck,

severalmoderndisciplinesofscience.Formanydecadesanumber 1983;Revelleetal.,1980).However,theimpactofcaffeineonthe
ofrelat ivelyind ependentd isc iplines− dif ferent ialpsych o logy,i.e. perfor manceo fi ntr overts andextrav erts reverse s througho ut the

thepsychologyofindividualdifferences,neurochemistry,aswellas day(Revelleetal.,1980),ormighthaveonlyaweakeffectonmood,

psychopharmacologyandpsychiatry,wereattractedtoeachother’s slightlyincreasinghappinessandvigor,moresoamongextraverts

research in this regard. Early on, psychologists and psychiatrists thanintroverts(Liguorietal.,1999).Kerkhof(1985)pointedoutin

developed theories linking single monoamine neurotransmitters hisreviewthatamong12studiesofrelationshipsbetweenthetime

tospecifictemperamenttraits,andviceversa,neuroscientistswere ofwakingandextraversion-introversion,the4earlierstudieshad

extendingtheirviewsonbehavioralregulatorysystemstopsychol- foundsuchrelationshipswhilethelater8studieshadnot.Body

ogy,offeringtheirmodelsofsuchtemperamenttraitsas“arousal”, temperaturewasfoundtobeconsistentlyhigherforpeoplewho

mobility,impulsivity,compulsivity,sociability,andsensationseek- awakenearlier,buttherewerenoconsistentdifferencesbetween

ing. extravertsandintrovertsonthisvariableof“morningness”:5ear-

One of the main concepts unifying these theories is that of lierstudieswerefor,3laterstudiesagainst.Asimilarinconsistency

arousal. The idea of the existence of a general arousal system wasfoundfordifferencesbetweenextravertsandintrovertsinper-

emergedinthemid-20thcenturywiththediscoveryoftheAscend- formingvarioustasks(3studiesfor,3against)(Kerkhof1985).

ingReticularActivatingSystem(ARAS)intheso-calledisodendritic The idea of a “general arousal trait” was challenged in tem-

core of the brain. At first it was thought that the ARAS provides perament research by suggestions that too many distinct traits

global,non-specificarousalandwakefulnessthatfuelsallaspects were being assigned to the unidimensional concept of general

ofbehavioralactivation,subjectiveconsciousness(Lindsley,1951; arousal(or“extraversion”,or“approach”)(Corr,1999;Fahrenberg,

MoruzziandMagoun,1949),andlearning(Hebb,1961;Anderson, 1991;Hough,1992;Guilford,1975;Kerkhof1985;Matthewsand

1990;Grossberg,1987). Gilliland, 1999; Rusalov and Trofimova, 2007; Trofimova, 2009,

AttributionoftheactivatingpropertiestotheARASandthedis- 2010a,2014).Forexample,ithasbeenshownthatthiscategory

coveryofemotionalregulationbythelimbicsystemtogethergave conflatedthehighsociabilityofextravertswithtraitsofimpulsivity

astrongboosttotwo-dimensionaltheoriesoftemperament.Even and/orpsychopathy,andthelowsociabilityofintrovertswiththeir

beforethen,severalresearchershadsuggestedthatthefourclas- highperceptualsensitivity.Sociability,impulsivityandperceptual

sicHippocrates-Galentemperamenttypescouldbeexplainedby sensitivityallrequirebehavioralarousal,howeverthearousalsys-

twodimensions:“energetic”and“emotional”.Thisideawasfirst temsunderlyingthesetraitsappearedtobedifferent.

proposed by Kant (1798) and then developed in empirical stud- Thus,Eysenck(1967)explainedJung’sobservationsofsociabil-

ies by 20th century psychologists – Wundt (1893), as described ityinextravertsbyaninsufficiencyoftheirARAS-corticalarousal

by Robinson and Rieber, 2001), Stern (1900), cited from Lamiell, thathypotheticallyleadsthemtoorienttheirbehaviortoexternal

2003),Heymans(1929),Pavlov(1928)–presentedas“strength” (socially provided) stimuli expressed as distractibility, sensation

and“balance”),Kretschmer(asconstitutionalenergeticcapacities seeking, social dependency and learning difficulties. Participants

characterizing schizothymic and cyclothymic types and “gay vs. classifiedas“extraverts”inexperimentalstudieshaddifficultyfol-

sad”subtypes).Cholericsweredescribedasemotionalandener- lowingtheinstructiontoliequietlyonacouch(Eysenck,1967),or

getic;Phlegmatics–asbalancedandweak;Sanguines–asbalanced inhibitingtheirbehaviorwheneitherrewardorpunishmentwere

andenergetic,andMelancholicsasemotionalandweak. possibleoutcomes,andinsituationsofapproach-avoidancecon-

The idea of general arousal was immediately adopted in dif- flictweremorelikelytoapproach(Dienstbier,1984;Newmanetal.,

ferential psychology by Eysenck (1967) and Nebylitsyn (1972), 1985;Pattersonetal.,1987;Zuckerman,1994).Atthesametime,

whosuggestedthatthereticular-corticalprojectionsprovidedthe criticalassessmentofEysenck’sstudiespointedoutthathisinven-

energeticcomponent(“Extraversion”,inEysenck’sterms),andthe tory measured impulsivity (premature responding in the social

limbic-corticalprojectionsprovidedtheemotionalitycomponent context)ratherthansociability(Gray,1991;Eysenck,1995;Rocklin

of temperament (or “Neuroticism”). This idea was echoed in the andRevelle,1981;Raine,1989;Smillieetal.,2006).O’Gormanand

workofThayer(1978),WatsonandTellegen(1985)followedby Lloyd(1987),whorecordedEEGsinextravertsandintroverts,found

CarverandWhite(1994).Intheothertemperamentmodels(that lowcorticalarousalinindividualswithhighpsychoticismbutnot

movedawayfromthefourHippocrates-Galen“temperamentums”) inextraverts.MatthewsandAmelang(1993)usedEEGmeasures

ageneral“energetic”traitwasdescribedbypsychologistsas“vig- duringperformancetaskssuchastracking,visualprobeRTduring

ilance”(Cattell,1965),“strengthofexcitation”(Nebylitsyn,1972; short-termmemorytasks,concentrationandverbalcomprehen-
I.Trofimova,T.W.Robbins/NeuroscienceandBiobehavioralReviews64(2016)382–402 385

siontasks.Theyconcludedthat“thepresentstudyprovideslittle thisideafromcognitivepsychologicalstudiesabouttwocompo-

supportfortheusefulnessoftraditionalarousaltheoryasaunifying nentsofarousal–sustainingandrelatedtotransfer/shiftsprocesses

principle...”(p.361) –echoeswithmodelsindifferentialpsychologyandneurophysiol-

Reportsshowingthatimpulsivity,sociability,perceptualsensi- ogydistinguishingtwocomponents.

tivityandlearningabilitiesareregulatedbydifferentphysiological

systems raised concerns about the validity of the concept of 2.3. Neurochemicalperspective

Extraversion based on general arousal. After all, high sociability,

i.e.theabilitytosustainprolongedcommunicationsinextraverts, 2.3.1. Theorexinsystem:evidenceoffunctionalheterogeneity

alsorequiredattentionandbehavioralarousal,andthereforeboth Recentdiscoverieshaverevealedasubstantialroleofhypotha-

introvertsandextravertsrelyonarousal,thoughindifferentways. lamicneuropeptidessuchasorexins(alsoknownashypocretins)

Thismeantthatarousalsystemshavemultiplecomponents,which inbehavioralarousal.Orexinsappearedtobemediatorsofenergy

sometimesregulatebehaviorinoppositedirections,butshouldnot metabolismandregulatorsofendurance,adenosine-basedarousal

be aligned into one dimension. For example, Pivik et al. (1988) andappetite(Taheri,2005).Theeffectsofbehavioralarousallinked

showedthatextravertsdifferfromintrovertsinmotorexcitability, toARASfunctioncouldbemediatedbyprojectionstomonoaminer-

but not in sensory sensitivity—contradicting the opposite place- gicARASneuronsfromorexin-containingcellslocatedexclusively

mentofextravertsandintrovertsonasensitivityscale. inthelateralhypothalamus,withwidespreadprojectionstoavari-

Inthe1980’sGray(1982)proposedaReinforcementSensitivity ety of other brain structures (de Lecea et al., 1998; Sutcliffe and

Theory(RST)thatdescribedtworegulatorysystems,theBehavioral De Lecea, 2002; Sakurai et al., 1998; Tsujino and Sakurai, 2009).

ActivationSystem(BAS)andtheBehavioralInhibitionSystem(BIS), In other words, if there is a “general arousal” system, it should

underlyingtemperamenttypes.Accordingtothismodel,impulsiv- includethesehypothalamicneuropeptides,andnotsimplyARAS

ityoccurswheneverthereisanexcessofBASactivationoverBIS, monoamine(MA)networks(Fig.1A).

whilehighsensitivity(includinganxiety)occurswheneverthere However,complexityandfunctionaldifferentiationwithinthe

isanexcessofBISoverBAS.Inexperimentsusingnegativerein- orexinsystemdampenstheideaofattributinggeneralarousalto

forcement(asastrongarousingcondition)introverts,accordingto theorexinsystemandthereforequestionsthenotionofwhethera

Eysenck’s theory, should learn worse because of excessive corti- neuralsysteminducingnon-specificgeneralarousalevenexists:

calarousal,whereasinGray’smodelintrovertsshouldlearnbetter

(Gray,1991).Severalstudieshaveshownthatparticipantslabeled 1) Orexins apparently have at least two types of receptors with

asintrovertsreproduce(recall)learnedmaterialbetterunderthis a differential distribution and specialization within the brain

strong arousing condition, and that they are more resistant to (Marcus et al., 2001) and different functionality (Harris and

habituationoftheorientingresponse(Corr,1999,2002;Eysenck, Aston-Jones, 2006; Gozzi et al., 2011; Gotter et al., 2012). For

1983; Stelmack and Michaud-Achorn, 1985; Wigglesworth and example,thenoradrenergiclocuscoeruleusisdenselypacked

Smith, 1976). Gray’s idea that behavioral arousal is a product of with orexin-1 (Hpct1) receptors but does not contain orexin-

twosystems,andnotonegeneralarousalsystem,appearedthere- 2 (Hpct2) while the histaminergic tuberomammillary nucleus

fore to be supported. However, recent studies have suggested containsHpct2butnotHpct1receptors(Mignot,2001).More-

that the RST is insufficient to explain the complexity of arousal over, the orexin system is not the only system in the lateral

systems.HighimpulsivitywasreportedinpatientswithGeneral- hypothalamusthatregulateswakefulnessstate.Burdakovetal.

izedAnxietyDisoder(GAD)(TrofimovaandSulis,2010;Trofimova (2013) reviewed the role of three systems regulating basic-

andChristiansen,2016),especiallycomorbidGADanddepression needsarousalinthisbrainregion(neuronsthatproduceorexin,

(TrofimovaandSulis,2016a)contradictingGray’smodel,sincein melanin-concentratinghormoneandleptinreceptors)andtheir

this model impulsivity cannot be a symptom of anxiety because contrastingfunctionality.

anxietyandimpulsivityariseinmutuallyexclusivestatesofBAS- 2) Orexin regulation of ARAS monoamines appeared not to be a

BISbalance(Gray,1982,1991). unidimensional, linear, “fuelling behavior” system, but rather

Theseresultsofearlyempiricalstudiesintemperamentresearch a complex, contingent and nonlinear system (Phillips and

showedevidencethatvarioustraitsunifiedundertheumbrellaof Robinson,2008;Saperetal.,2001;Tamakawaetal.,2006).Even

Extraversion are regulated by different psychophysiological sys- whenappliedtotransitionsbetweensleepandawakestates,the

tems,andnotbyone,“generalarousal”system. veryarousalsystemsthatareinhibitedbysleep-promotingneu-

ronsalsoservetodisruptthesesamesleepprocessesinorder

2.2. Problemsinstudiesofarousalandperformanceefficiency toreturnthebodytoawakefulstate(Saperetal.,2005).This

dynamicsuggestsahighlyspecificandcoordinatedarousalsys-

Sincethebeginningofthe20thcenturystudiesondiscrimina- tem.Inthissense“generalarousal”mediatedbyorexinsappears

tionlearninghaddiscoveredthatarousalhadaninvertedU-shaped to be calibrated according to the amount of arousal needed

functionlaterknownastheYerkes-Dodsoneffect.Thiscurvilinear withinthecontextofthesituation,ratherthantothegeneral

relationbetweenarousalandefficiencyofperformancesuggested requirementsofthetask.

an underlying complexity in arousal systems emphasized in the 3) TheorexinregulationofMAneuronsappearedtobeselective

writingsofBroadbent(1971)andothers(e.g.Robbins,1984)on“the andspecialized.Tsujinoetal.(2013)reported,forexample,high

twoarousalsystems”.HumphreysandRevelle(1984)intheirstud- responsivenessofnoradrenalin(NA)-containingneuronsinthe

iesofmemorizationalsoproposedthattheinvertedU-shapeofthis locuscoeruleus(LC)butlowresponsivenessofserotonin(5-HT)

functionisnotduetotheactionofonearousalsystembutislikely cellsinthedorsalraphéduringorexinrelease.Incontrasttothe

aproductofcombinationoftwoarousalcomponents:arousalasan othermonoamines,theregulationof5-HTneuronsinthedorsal

abilitytosustaininformationtransfer(SIT)overextendedperiods raphénucleusbyorexinswasstate-dependent(Takahashietal.,

andarousalthatfacilitatesthespeedofinformationtransferfrom 2005)andactedinoppositedirections,intheformofadirect

inputstooutputsandthereforehinderstheimmediateavailability excitatoryactionandanindirectinhibitoryone(Liuetal.,2002).

ofinformationheldinworkingmemory.Lowarousalledtoalack 4) Theactivity5-HT,NAandhistaminergicneuronswasreportedto

of SIT resources and suboptimal performance whereas excessive respondtoadecreaseinorexinreleaseduringtheNREMstageof

arousalledtoaslowerspeedofinformationtransferwithinwork- sleep,whereasdopamine(DA)neuronalactivitydidnotchange

ingmemoryduetomemoryinterference.Wewillseebelowthat significantly across the sleep cycle (McCarley and Massaquoi,
386 I.Trofimova,T.W.Robbins/NeuroscienceandBiobehavioralReviews64(2016)382–402

Fig.1. Comparisonof“generalarousal”conceptwithspecificityfoundwithinorexin-MAarousalsystems.Twotypesoforexinreceptorswerefoundtobespecializedin

innervatingdifferentbrainstructuresandalsodifferentialandmutualregulationofMAsystems.Note:1)onlyorexin-MAprojections,andnotallMAprojectionsareshown;

2)grey-blueshadowsindicatedifferentialimpactoforexin-MAinteractionduringthesleepcycle;3)MA:monoamines,LHT:lateralhypothalamus,BF:basalforebrain.

1992).Suchdifferentialcontributionsbymonoamines,includ- valence, even in such arousing conditions as foot-shocks or

inglowDAactivityinsleepregulationissurprising,considering expectationoffootshocksinducesignificantlylessorexinactiv-

thatperiodiclegmovements(regulatedbyDAsystemofmotor ity in comparison to situations that elicit positive emotions,

control),decreasedprolactinandGrowthHormonerelease(also suchastheexpectationofpalatablefoodordrugreward(see

regulated by DA system) are symptoms of narcolepsy (Hungs Alexandreetal.,2013forreview).Fromageneralarousalper-

and Mignot, 2001). At the same time, classically “arousing” spective it is hard to explain why negative emotional arousal

functionofNAappearedtobenotalwaysthecaseintheNA- (commonly considered as a behavioural mobilization needed

ergic regulation of the orexin system and melatonin in sleep forsurvival)haslessofaresponsefromtheorexinsystemthan

disorders: an increase of NA release under certain condition positiveemotionalarousal.

could facilitate sleep and not a waking state (Mitchell and 7) Orexinsdonotmerelyregulateotherneurotransmittersinauni-

Weinshenker,2010). directionalmanner.Dopaminehasbeenfoundtobeamodulator

5) Orexin neuron activity in the LH is not the same for all types oforexinaction,suggestiveofmutualDA-orexinregulationin

of behaviour: it is high in heightened attentional states, in suchbehaviorasorexin-inducedhyperlocomotion,stereotypy

explorationandhastightinteractionswithcholinergicnetworks and grooming (Alberto et al., 2006 Nakamura et al., 2000). A

involved in sustained attention, but it is lower in grooming similarregulationoforexineffectswasreportedthroughthe5-

and eating (Alexandre et al., 2013; Mileykovskiy et al., 2005). HT receptorbyserotonin(Murakietal.,2004),suggestiveofa
1A

Moreover, orexin neurons in another section (posterior) of two-wayregulationbetween5-HTandorexinsystems.

hypothalamus were linked to arousal related rather to main-

tenance,andnotinitiationofactivities,incontrasttotheorexin
The contrast between theories attributing general arousal to
neurons in the LH that show maximum activity in situations
orexinsystemsandrecentreportsonthespecificityandcomplexity
requiring attention and processing novely (Alexandre et al.,
withinorexin-MAinteractionsissummarizedinFig.1B.Behavior
2013).
requiresarousalthatismorethanjustanawakestate,andfunc-
6) A degree of orexin acitivity is different for arousal related to
tionalspecificitywithinorexin-MAsystemslikelyrelatestomore
adifferentemotionalvalence.Situationsofnegativeemotional
thansimpleregulationofthesleep-wakecycle.Functionaldiffer-
I.Trofimova,T.W.Robbins/NeuroscienceandBiobehavioralReviews64(2016)382–402 387

entiationwithinorexinsystemssuggeststhateventhesesystems 2008). Pfaff (2006) further argued that a primitive core of mas-

cannotbeviewedasthebasisofgeneralarousal,andwiththisthe tercellsinthebrainstemrepresentsthesubstrateofgeneralized

conceptofgeneralarousalisnotsupportedbyfindingsinneuro- arousal since a relatively small number of long-axoned connec-

chemistry. tionsofthesemonoaminergicneuronscanfine-tunelocalmodules

ofneurons(p.50–51).Thesebasicneedssystems,however,likely

2.3.2. MonoaminenetworksinARAS:theirdiversityspeaks co-existwithaverydifferentarchitectureofarousalmechanisms

againstuni-functionalconceptsofarousal regulatingthecomplexitiesofmosthumanbehavior.

OurviewsonthefunctionalityoftheARASchangedconsiderably

withthediscoveryofspecificchemicalneurotransmittersystems, 3.2. Facetsofextraversioninfactor-analyticmodelsbasedon

withacetylcholine(ACh)andthemonoamines(i.e.NA,DAand5- verbaldescriptors(lexicalapproach)

hydroxytryptamine, 5-HT) systems originating in the brainstem,

mesencephalon and basal forebrain regions (2003). Moreover, Another(lexical)approachindifferentialpsychologyderivesthe

monoaminergic networks projecting to and from the ARAS have structureofbiologically-basedtraitsrelatedtoarousalbyapply-

adiversityofneurotransmittersandreceptorsthatimplymultiple ingfactoranalysistoestimationsofverbaldescriptorsrelatedto

functionalitywithinthesenetworks.Eachoftheseneurotransmit- individualdifferences.UniversallyallmodelshavealargeExtraver-

tershasseveraltypesofreceptors:thereare(sofardiscovered)5 sionfactor,asamaintraitenergizingthebehavior(Digmanand

typesofdopaminereceptor,9typesofadrenergicreceptor,17types Takemoto-Chock,1981;Eysenck,1995;Goldberg,1993;Guilford

ofserotoninreceptor,andmorethan100neuropeptidesmanyof andZimmerman,1956;McCraeandCosta,1997;Norman,1963;

whichco-existwiththemonoaminesasco-transmitters(Cooper Thurstone,1951).Trofimova(2014)pointedoutthattheconcept

etal.,2003;Siegeletal.,2006).Asimilardiversityofreceptorshas ofExtraversionmightbeanartifactofthesociabilitybiasoflexical

been found for acetylcholine, histamine, Gamma-Amino-Butyric materialusedtoderiveBigFiveandotherpersonalitymodelsthat

Acid(GABA),glutamate(GLU)andtheendogenousopioids.Inaddi- includethescaleofExtraversion.Herexperimentsdemonstrated

tiontothisdiversity,brainstructureswithneuronscontainingthe thattheuseoflexicalmaterialskewstheresultingdimensional-

sametypeofneurotransmittersdifferintermsoftypesofreceptors, ityofmodelsbasedonafactoranalysisofsuchmaterialduetoa

andapparentlytherearedifferencesbetweenmammalianspecies sociabilitybiasoflanguageandanegativitybiasofemotionality.

(forexample,seeAzmitia,2010). Attemptshadbeenmade,however,topartitiontheExtraversion

Concerns about the validity of the general arousal concept intomorespecificfacets,andtheresultsshowhighinconsistency

emerged several decades ago (Venables, 1984; Matthews and betweenmodelsandconceptualoverlapsbetweenthesefacets.For

Amelang,1993),howevertheseconcernsdidnotpreventaflood example, the Extraversion factor in the Eysenck Personality Pro-

ofstudiesoverthepast30yearsusingExtraversionasatemper- filer(1995)separatesthefacetsofSociabilityandExpressiveness,

ament/personality trait. In their analysis of the functionality of Aggression and Assertiveness, and Ambition and Dogmatism, in

the main monoaminergic and cholinergic neurotransmitter sys- spite of the overlap between these facets within each pair. The

tems, Robbins and Everitt (1996) noted: “The arousal construct structure of the Extraversion factor within the Big Five model

issubjecttoenormousembarrassmentfromanumberofempir- has components termed Warmth, Gregariousness, Assertiveness,

icalsources.Variousindicesofarousaldonotintercorrelatetoa Activity,Excitement-Seeking,whicharedifficulttooperationalize

highdegree,aswouldbeexpectedofaunitaryconstruct(Eysenck, forinvestigationoftheirneurophysiologicalcorrelates.Noneofthe

1992),andputativemanipulationsofarousal,whetherpharmaco- modelsincludedthefacetofPlasticity,which,aswediscussbelow,

logicalorpsychological,donotinteractinamannersuggestiveof isbasedonadistinctneurophysiologicalsystem.

anunderlyingunidimensionalcontinuum”(p.703).

3.3. Proposedfocusonfunctionalfeaturesofbehaviorwhichare

3. Ifthereisnoonearousalsystem,howmanypartitionsof universalacrosssituations

arousaldoexist?

Herewesuggestadifferentapproachtotaxonomyandtothe

Thediversityandcomplexityofneurochemicalsystemsrelated functionalpartitioningofarousalsystems.Ourapproachsuggests

tobehavioralarousalclearlyshouldbereinforcedinevolutionby a need to relate this partitioning to the functional architecture

their importance in behavioral regulation. It is unlikely that we of human activities. When we examine the differentiation of

possessthisdiversitymerelytoprovideredundancyfortheprotec- neurochemicalsystemsregulatingbehavior(whichtemperament

tionofgeneralarousallevels.Moreprobably,humanspossessthis researchdescribesas“traits”)itisusefultobearinmindthatthis

neurochemicaldiversityandcomplexitytomanageunpredictable, differentiationhasbeenreinforcedthroughouthumanevolutionby

novelandcomplexsituationswhichentailseveraldifferentpsycho- thepressuresofeverydayfunctioning(Trofimova,2016b).Humans

logicalprocessesthatarerecruitedaccordingtoprevailingcontexts andotheranimalsregularlyrespondtodiversesituationsofvari-

orstates.Aquestionarises:howtoclassifyandpartitionthisdiver- able complexity, unpredictability and instability. Therefore, it is

sity,orvariousaspectsofarousal? impossible to have special arousal systems that have evolved to

copewitheverysinglesituationorneed,likethesystemsassoci-

3.1. Specificregulatoryarousalsystemsrelatedtobasicneeds atedwiththirst,hunger,sexorfear.Neitherwoulditbeeconomical

intermsofresourcessincemostsituationsareencounteredonly

Thelatestversionsofthe“generalarousal”theorysuggestdis- onceortwiceinlife.Inthissenseitisunlikelythatthebiological

tinctions between two major classes of arousal: general versus systemsunderlyinghumanbehavioralregulationarosefromthe

localized,whichco-existandinteract.Actionsoflocalizedarousal developmentofmultiple“specificarousal”systemscorresponding

elements are described as being limited to basic needs behav- toparticularneeds.

ior(food,sex,danger-related),whereasgeneralarousalelements, Morelikelyisthatregulatorysystemsdevelopedintunewith

accordingtothisview,influencemultipleclassesofbehavior,and thosefunctionalpropertiesofbehaviorthataregeneralacrosstasks

mediatebothspecificandnonspecificeffectsofarousal(Jingetal., andsituationsratherthanforspecifictaskssuchaseating,drinking

2009;Pfaff,2006;Pfaffetal.,2008).Ithasbeenproposedthatbasic andsex.Adescriptionofsuchuniversalproperties,orcomponents

needssystemsaremaintainedrelativelyindependentlyfromeach involved in the construction of behavioral actions and routines

otherandhavespecificarousalsystems(Jingetal.,2009;Pfaffetal., wasofferedinearly(Anokhin,1964,1975;Bernstein,1947,1996;
388 I.Trofimova,T.W.Robbins/NeuroscienceandBiobehavioralReviews64(2016)382–402

Table1

MappingofneurochemicalsystemsandtemperamentfactorswithinneurophysiologyanddevelopmentalpsychologymodelsintheframeworkoftheFunctionalEnsemble

ofTemperament(FET).Emotionalitydimensionsoftemperamentandmodelswithprimarilyemotionalitytraitsareexcluded.Traitsrelatedtosocial-verbalandphysical

typesofenduranceandtempoarenotseparatedinthisTable(andgroupedunderdeterministicaspectsofbehavior),howevertheyaredifferentiatedintheFETmodel(Fig.4,

Table2).Note:*-anoppositepoleofthetraitiscomparedheretoasimilarFETtrait;5-HT:serotonin;DA:dopamine;NA:noradrenalin;ACh:acetylcholine;OX:orexins;

OXY:oxytocin,PRL:prolactin;AdrR:adrenergicreceptors.

Functionalaspects Maintenance Speedofintegration Orientation

Corticalvsbasalgangliaregulation analytic determined analytic determined analytic determined

TraitsinFETmodel Attention/mental Endurance Plasticity, Tempo Sensitivityto Sensation

endurance re-programming Probabilities Seeking
Main neuro-transmitter systems Ach, NA5-HT 5-HT, GH, OX DAGABA, 5-HT DA, PRL NA, DA NA, AdrR1
Neuropsychology, psychophysiology models:

Pavlov,1928,1941 Balance CNSstrength Mobility Mobility

Anokhin,1975 Executive block Programof action Afferent Synthesis

Luria,1948-70 Energetic block Programming block Information- sensory

Teplov,1947-61 Stren.ofinhibition Stren.ofexcitat-n Mobilityof varioustypes

TeplovandNebylitsyn,1963 Strengthofinhibition Strengthofexcitation Mobility Lability,

Dynamism
Gray,1982 BAS BIS BAS

Rusalov,1989;RusalovandTrofimova, Intellectual Motorandsocial Plasticityin3areas Motorandsocial

2007 ergonicity ergonicity tempo
NA,DA NA,DA DA,GABA DA,5HT,ACh

PosnerandPeterson,1990 Executive network Orienting network Alerting Network

HalgrenandMarinkovic,1995 Sustained behavioursystem Eventintegration Responsechoice Orienting Complex

sys
RobbinsandEveritt,1996 NA-Ach 5-HTandACh DA DA NA,DA NA

JacobsandAzmitia,1992 5-HT 5-HT NA NA

Developmental psychology models:

KaganandSnidman2009 Repression Sexuality

Thomas&Chess,1977 Persistence/Att Activitylevel Adaptability Rhythmicity Distractibility

BussandPlomin,1984 Activity,Sociability

Rothbartetal.,2000 Effortfulcontrol Activity,arousal Orienting Sensitivity

Differential psychology models:

Stern,1900 Attention Psychicenergy Combinatorial Reaction,psychic Association Sensereceptivity

ability tempo
Wundt,1902(seeRobinsonandRieber Excitability

2001)
Heymans,1929 Activity/drive Reasoning

Spränger,1914 Economic Theoretical

Lazursky,1921 Combinator.abil Sensitivity

Jung,1923 Thinking Introversion Sensing

Kretschmer,1925 Cyclothymia Psychomotility Psychictempo Schizothymic

Adler,1925 Energy CreativeSelf Func.finalism

Cattell,1965 Perfectionism* VigilanceLiveliness Opennessto Apprehension

Change
Eysenck,1967 Extraversion Extraversion

Thayer,1978 Energeticarousal

Strelau,1998 Stren.ofinhib Stren.ofexcit-n Mobility

Eysencketal.,1985 Drive Venturesoms

Tellegen,1985

BigFive,1949-93 Extraversion ConscientiousnessOpennessto

Experience
Hough,1992 Locusofcontrol Potency Intellectance Dependability*

TaylorandMorrison,1992 Depression*Social Objectivity

activity
StrelauandZawadzki,1993 EnduranceActivity Perseve-rance* Briskness Sensory

sensitivity
Carveretal.,94 Drive Funseeking

Cloninger,2000 Self-Directedness Noveltyseeking

Eysenck,1995 Obsessiveness Activity, Dogmatism*, Irresponsibility* Risk-taking

(EPP) Hypochondria* Non-conformity* Practicality
Manipulativeness
Mehrabian,1996 Arousal

Akiskal,1998 Depression*

Cyclothymia
Zuckerman,02 ActivitySociability Sensastion

Seeking
*-anoppositepoleofthetraitiscomparedheretoasimilarFETtrait;5-HT:serotonin;DA:dopamine;NA:noradrenaline;ACh:acetylcholine;PRL:prolactin;AdrR:adrenergic

receptors.
Luria,1966;PribramandLuria,1973)andmoremodern(Joeland ologybetweenthesesciences,theyconvergeduponatleastthree

Weiner,2000;HalgrenandMarinkovic,1995;PosnerandPetersen, generalcomponentsofanyaction(SeeTable1)

1990;Schall,2001)studiesandmodelsofbehaviouralregulation

withinkinesiology,neurophysiologyandclinicalneuroscience.In
• componentsvariouslynamed“afferentsynthesis”,“orientation”,
spiteofthediversityofthesemodelsanddifferencesinmethod-
“orienting”,“sensory-informationblock”,or“exploration”;
I.Trofimova,T.W.Robbins/NeuroscienceandBiobehavioralReviews64(2016)382–402 389

• componentsvariouslynamed“programming”,“decisionblock” Eiseneggeretal.,2014;SeamansandRobbins2009).Increased(for

or“eventintegration”; D1 and D5 receptors) vs. decreased synaptic excitability (for D2,
• co mpone ntsvariouslynamed“execution”,“exploitation”,“sus- D3 and D4) asdifferen tfu nctionsoft hesedop aminergicr ecep tors

tainedbehavior”,“energeticblock”. suggests that common functionalities of DA receptors cannot be

understoodintermsofarousal(excitation)vs.inhibitionfunctions,

andalternativefunctionalperspectivesmustbeadvanced.
Regulationoftheorienting,plasticityandenergeticaspectsof
Taking into account this functional diversity, the multi-stage
behavior has been linked to specific brain structures or systems
natureofreleaseandcontingencyofthisreleaseonthestateofmul-
butsincethelate1980sithasbeenrecognizedthatfunctionaldif-
tiplechemicalsystems,thetaskofunderstandingneurotransmitter
ferentiation between three particular MA systems might have a
functionalityappearstobeenormousandcannotbeaccomplished
similarspecificity(Bloom,1985;Jacobs,1987,1992;Robbins,1997;
justatonelevelofanalysis.However,attemptstothequestionof
RobbinsandArnsten,2009;RobbinsandEveritt,1996).
classificationofthefunctionalityofMAsystemsshouldbemade,

and we are sure that other researchers will offer different per-

4. Threepointsofconsensusinregardtothefunctional spectives. The next sections compare most commonly reported

specializationofMAarousalsystems functionalityofMAsystemstothethreeformalaspectsofbehavior

asnotedintheprevioussection.

4.1. MutualregulationanddiversitywithinMAsystemscreate

challengesforassessingtheirfunctionality 4.2. Theroleofthecoeruleo-corticalNAsystemsinorientingto

noveltyandalertingbehaviour

The diversity of MA receptors and their specificity in various

brain structures should not be underestimated, and we do not Asnotedabove,NAsystems,aswellasotherneurotransmitter

suggestthatitcanbereducedtojustthreefunctions.Moreover, systemsdonotmodulateonehomogenouspsychologicalprocess.

behaviouralneurochemistryisarelativelyyoungsciencetryingto Insteadallthesesystemsmayactdifferentlydependingonthelevel

investigatethefunctionalityofthesediverseneurochemicalsys- ofarousal,typeofreceptorsandtheirpreciselocationwithinthose

temsandisstillattheearlystagesofgatheringacompletepicture neural systems controlling behavior (Berridge and Waterhouse,

ofthisfunctionality.Yet,attemptsshouldbemadetooffersolutions 2003;RobbinsandArnsten,2009).Justtoillustratethatanattri-

tothepuzzleofthediversityandcomplexityofthesesystems,and bution of general arousal to NA systems (indeed implicated in

webelievethatabehavioralconstructivismperspectiveprovides attention processes) is not appropriate, it has been shown that

a first important approximation into the classification of arousal under conditions of hyperarousal, NA release in the prefrontal

systems. cortex (PFC) impairs working memory but enhances long term
Thefollowingsectionsbrieflyreviewtheexperimentalevidence memo rycon solidatio nintheam ygdala− the reforethe same level

inregardtothefunctionalrolesoftheclassicalmonoamineneu- of NA arousal has differential effects on different psychological

rotransmittersystems,butletusfirstcommentonthechallenges functions(RobbinsandArnsten,2009).

encounteredinstudiesofneurotransmitterfunctionality. Of the diversity of roles attributed to the noradrener-

First, there is likely no single neurotransmitter the release of gic coeruleo-cortical projections, their functioning in regulating

which is independent of the action of other neurochemical sys- attention to novelty and orientation is prominent. Other neuro-

tems,includingotherneurotransmitters.MAsystemsregulateone transmitters,especiallyacetylcholine,havealsobeenimplicatedin

another’sreleaseinacontingentmannerviaseveralmechanisms a spectrum of attentional processes (Everitt and Robbins, 1997),

withdifferentreleasepatternsdependingontheintensityofstim- however NA appeared to be a key neurotransmitter specifically

ulationandthelocationanddensityofreceptors(seeSection4.5.) in attention dealing with novelty and/or uncertainty, whereas

Inthiscomplexity,asFinkandGöthert(2008)noted,noneofthe5- the ACh system was linked mostly to sustained forms of atten-

HTreceptortypesmodulatingthereleaseofDAandNAshowedan tion(ChamberlainandRobbins,2013;EverittandRobbins,1997;

exclusivecontroloverthereleaseofjustoneoftheseneurotrans- HasselmoandSarter,2011;Robbins,1984;RobbinsandRoberts,

mitters.Whenweexamineevidencerelatedtothefunctionalityof 2007).AbodyofevidenceshowsthattheresponseofNAneurons

MAsystems,therefore,weoftenseechangesinallthreeMAsys- rapidlyhabituatestorepetitivesensorystimuli(Aston-Jonesetal.,

temsinresponsetoexperimentalmanipulations.Forthisreason 2000;ChamberlainandRobbins,2013;Gibbsetal.,1997;Jacobs,

the model presented at the end of this article is called a neuro- 1987,1992).Thebrain’sNAsystemismostactiveinanawakestate,

chemical Ensemble, and it criticizes the dimensionality approach instress,indarkness(forrodents),andintasksrequiringfocused

employingtheconceptofindependentdimensions. attentionandorientation,especiallyupontheoccurrenceofunex-

Second,wheneverthefunctionalityofMAsystemsisdiscussed pectedsensoryevents.Jacobs(1987,1992)describedtheactivation

we have to keep in mind that MA release does not happen in ofNAreleasewithsympatheticresponsetonoveltyordangerin

onecontinuousstage.Thereareseveralstagesinthisprocessthat cats(heatedenvironment,drug-inducedincreasesordecreasesin

involves a cascade of GABA/GLU, enzymes and metabolites, G- bloodpressure,insulin-inducedhypoglycemia,painfulstimuli,sys-

proteincoupledreceptors,BDNF,CREB,calciumandotherchemical temic injections of morphine, loud noise, physical restraint, or a

systems,includingpartnermonoamines(HolzandFisher,2006).In dog). These conditions invariably led to a doubling or tripling of

this sense the outcomes of pharmacological studies of the func- NAactivityintheLCaboveanactivewakingbaseline(Jacobs1987,

tionalityofneurotransmittersthatuseagonistsorantagonistsof 1992;JacobsandAzmitia,1992,p.214).TheNAresponsetonovelty

specificneurotransmittersoftenhavelimitedvalueforconclusions issospecificthatevennovelstimuli,whicharepresentedrepeat-

ontheirfunctionality,asitisveryhardtomatchand/orcontrolallof edly,graduallyevokelessandlessNAneuronalfiring(Aston-Jones

thecomplexityofnaturallower-levelneurochemicalmediations. etal.,2000;Everittetal.,1983;Jacobs1987,1992).

Moreover,chronicexposuretoagonistsoftenresultsindiminished Moreover,forthepast3decadesithasbeenwellestablished

responsivenessandchronicexposuretoantagonistsoftenresults (sinceLevittetal.,1984)thatNAprojectionswereespeciallydense

inincreasedresponsivenessofMAreceptors(Kuharetal.,2006). inthesomatosensory,parietalandvisualcortex.Thisisinlinewith

Third,asnotedabove,thediversityofMAreceptorsandtheir the “orientation” function defined as an expansion of behavioral

differentactionsindifferentbrainstructurescreateanotherserious alternatives,especiallynotedunderconditionsofnovelorunpre-

challengeforunderstandingthefunctionalityofMAsystems(e.g. dictableevents.AdeficitofNAhasbeenlinkedtocompromised
390 I.Trofimova,T.W.Robbins/NeuroscienceandBiobehavioralReviews64(2016)382–402

attentional functioning (Robbins and Arnsten, 2009) and to new (Siegeletal.,2006;SeamansandRobbins,2009;SeamansandYang,

learningwhichbothimplyamodulationoforientingresponsesto 2004;YinandKnowlton,2006).

novelty(BeaneandMarrocco,2004;Gibbsetal.,1997;seereviews DAreleaseisalsoassociatedwiththeprocessofattachingsignif-

by Berridge and Waterhouse, 2003; Chamberlain and Robbins, icancetostimuli(saliency)regardlessofemotionalvalence,rather

2013).TheNAsystemhasalsobeenimplicatedinshiftingattention thancontributingspecificallytopositiveemotionalityorapproach

fromoneperceptualdimensiontoanother(Kehagiaetal.,2010; behavior(Oades,1985;Berridge,2007;Salamoneetal.,1997).In

RobbinsandRoberts,2007;Taitetal.,2007),inprovisionofatten- fact,contrarytothenotionofDAasa“neurotransmitterofplea-

tioninitsphasicmodeandindistractibilityinitstonicmodein sure”,appetitivestimulienhanceactivityinthemesocorticalDA

nonhumanprimatesperformingago/no-govisualattentionaltask systemtoalesserdegreeandmoretransientlythandoaversive

(Aston-JonesandCohen,2005).AnexcessinNAcanalsocompro- stimuli (see Seamans and Robbins, 2009 for a review). Multiple

mise performance as it increases distractibility by novel stimuli. reportshavedescribedDAincreaseduringreactionstothecircum-

AninteractionbetweenDAandNAappearstoregulatetheopti- stanceofdefeat(Puglisi-AllegraandCabib,1990),aversivestimuli

mallevelofNA-inducedarousal,inmodulatingthestrengthofthe (Horvitz,2000),stress(Anismanetal.,1993;Puglisi-Allegraetal.,

signalanditsinterferencefromdistractingevents(Arnsten,1997; 1990;TideyandMiczek1996),footshock(Salamoneetal.,1997;

Durstewitz and Seamans, 2006). Kehagia, Murray and Robbins Thierryetal.,1976),highlysalientvisualstimuli(Redgraveetal.,

(2010)reviewedevidenceofdifferentialimpactsofcortical5-HT 1999),motorreadiness(BrownandRobbins,1991),andparanoia,

andNAsuggestingthatPFCNAlikelymediatesahigherorderflex- repetitiveorstereotypedbehavior(TuckerandWilliamson,1984).

ibility during attentional set-shifting, consistent with its role in AnexcessofDAcombinedwithadeficitin5-HThasbeenhypoth-

orientationwhereas5-HTintheorbitofrontalcortex(OFC)medi- esizedtocauseobsessive-compulsivedisorder(Denysetal.,2004;

atesthelowlevelflexibilityrequiredofreversallearning. Kooetal.,2010;Szechtmanetal.,1998).Investigatorshavefound

A review of experimental evidence and dynamical modeling similarresultsforavarietyofstressors,includinghandling,forced

of the functionality of NA and DA neurons in LC using a target swimming,tailpinch,socialdefeat,conditionedaversivestimuli,

detection task suggested their different role in exploration and andpharmacologicalanxiogenesis(SeamansandRobbins,2009).

exploitation of behavioural alternatives (Aston-Jones and Cohen, AroleofDAD2receptorstimulationin“salience-labelling”can

2005;McClureetal.,2005;Reyetal.,2007).Usingthisfunctional beseeninitsassociationwithschizophrenia(Coyle,2006;Gray,

distinctiontheseauthorscametoaconsensusthatwhileDAiscor- 1998; Kapur, 2003) and psychoticism (Corr and Kumari, 2000),

relatedwithresponseexploitation,NAreleaseiscorrelatedwith both linked to an excess of dopamine. People with these condi-

explorationprocesses.The“exploration”conceptisinlinewiththe tions over-attribute significance to common details and objects

“orientation”componentofactionsdescribedinmodelsofkinesiol- in the environment, and show a poor ability to suppress non-

ogyandpsychophysiology(seeTable1).Bothconceptsdealwithan importantinformation.Studiesofconditionedblocking,prepulse

expansionofbehavioralalternatives,especiallynotedundercon- inhibition(PPI)andlatentinhibition(LI)(asanabilitytosuppress

ditionsofnovelorunpredictableevents. aresponsetoirrelevantstimuli)haveindicatedthatbothPPIand

(sometimes)LIarereducedinschizophrenia(Gray1998;Helmsley

4.3. Theroleofdopaminereleaseinprioritizingstimulussalience 1987;Swerdlowetal.,1992;Weiner1990)andinnormalindivid-

andactionproduction ualswhoscoredhighonpsychoticismorschizotypyscales(Baruch

et al., 1988; Kumari et al., 1997). Helmsley (1987), Oades et al.

StriatalDAiswell-knowntohaveimportantrolesinincentive- (1996)observedthatanexperimentalincreaseofDAmaycompro-

motivation and reinforcement learning, as well as behavioral mise latent inhibition (which results in attention not being paid

activation and cognitive and motor output, whilst being modu- to irrelevant stimuli) and conditioned blocking, (which prevents

latedbythereciprocalinfluenceofprefrontalDA(seee.greview redundantinformationbeingprocessed),andthereforecausesan

by Robbins 2010). There is consensus concerning the role of DA individualtopayattentiontoandassignsignificancetoevenirrele-

systemsinbehavioralplasticityandmotorperformance(Seamans vantstimuli.WhenDAisreleasedduringapleasurableexperience

andRobbins,2009;SeamansandYang,2004;YinandKnowlton, it may amplify the significance of events and objects associated

2006).Plasticityinvolvesthesimultaneousactivationandsuppres- withpleasurableeffects.SuchamplifyingeffectsofDAreleasehave

sionofseveralscriptsofactions,theintegrationofanewprogramof beendescribedasincentivesensitization(Berridge,2007)oralter-

actions(includingeffectsofrewardandincentivemotivation)and nativelyasenhancedconditionedreinforcement(Robbins,2010).

the sequencing of instrumental behavior, including pre-learned Inadditiontoalteringprioritiesinperceptionthatcontribute

habits.StriatalDAsystemsarekeyplayersinbehavioralplasticity: to a final programming of actions, DA release affects motor out-

DAprojectionstothePFCaswellasthestriatumhavebeenshown put,mediating“motorreadiness”duringresponsepreparationby

toprovidenotonlybottom-upactivation,butalsotop-downreg- thestriatum(BrownandRobbins,1991;SeamansandYang,2004;

ulation,i.e.sequencingandgoal-directionality,ofbehavior(Costa YinandKnowlton,2006).Inthecaudatenucleusitamplifiesthe

etal.,2006;Graceetal.,2007;SeamansandYang,2004;Yinand significance of actions, helping both to sequence and to switch

Knowlton,2006).ThePFCreceivesmoreDAinnervationcompared between them (Seamans and Robbins, 2009). In studies on non-

with other cortical regions, especially in rodents, and such het- humanprimatesacontributionof5-HTwasconsistentwithatonic

erogeneity is characteristic only of DA projections as all other component of behavior to enable reversal learning, whereas the

ascendingmonoaminergicprojectionsaremoreevenlydistributed deficientcontributionofPFCDAwasconsistentwithcompromised

amongcorticalregions.SuchpredominanceofDAprojectionsinthe abilityforprioritizationofactionsresultingininappropriateperse-

PFC,the“programmingareaofthebrain”(StussandKnight,2002) verationduringextinctionoflearnedprogramsofaction(Walker

suggestsitskeyroleinthemodulationofimportantcognitiveand etal.,2009).TheseresultssuggestthatDAplaysakeyroleininte-

executiveprocessesinvolvedinplanning,organizationandreason- gration(includingprioritization,sequencingandprogramming)of

ing.Itisalsonoteworthythatthestriatum,hasverylittleNAinput actions.

suggestingagainquitespecificrolesofitsDAinnervation.Thishas Such diverse roles for DA release in behavioral regulation

ledmanyneuroscientiststobelievethattheascendingDAsystem haveonefeatureincommon:allofthemprioritizeandtherefore

providesaspectrumoffunctionshelpingtoprioritizeandprepare facilitate the choice of behavioral alternatives necessary for the

aprogramofactions:frommarkingthesignificanceofstimulito integration of subsequent actions (whether perceptual-cognitive

makingchoices,topreparingmotoractionsandcognitiveoutputs ormotor).Infact,arecentstudyontheroleofDAD2receptorsin
I.Trofimova,T.W.Robbins/NeuroscienceandBiobehavioralReviews64(2016)382–402 391

reinforcementlearningreportedthataD2receptorantagonistdid asfacilitationofbehavioraloutputbycoordinatingautonomicand

notdisruptlearning,butratherinducedprofoundimpairmentsin neuro-endocrinefunctionandbyaconcomitantgeneralsuppres-

choiceperformance(Eiseneggeretal.,2014).Ithasbeenalsoshown sionofafferentinputfromsensorychannels(Hensler,2006;Jacobs

thatD1andD2receptorsmaybestimulatedoptimallyatdifferent andFornal,2010).Asupervisoryroleof5-HTintheregulationof

levelsofDApresynapticactivity,whichmayimprovesomeaspects physicalendurancecanbeseenfromtheanatomicallocationof5-

ofcognitionandhinderothers(FlorescoandMagyar2006;Seamans HTcellsinallinternalorgans:infact,thebrainhasonly1–2%of

andRobbins2009). theserotoninofthebody(Azmitia,2010;Hensler,2006).Despite

this,the5-HTsystemiswidelyrepresentedinmanywell-defined

4.4. Neurotransmittersystemsformaintenanceofbehavioural brain structures, and the main source of 5-HT neurons, the dor-

arousal salandmedianraphénuclei(RN),havethelargestandthemost

complexefferentsystemincomparisontoanyotherstructurein

Whenweusetheterm“maintenanceofactions”weacknowl- thebrain(Azmitia,2010).Suchawideandstructured5-HTneuron

edgethefluidnatureofactions,andBernstein’s(1947/1996)idea organizationmightwellreflectitsdiversefunctions.

thateveryactionisbeingconstructedanew,basedonpreviously

tried and constructed units. Maintenance of actions therefore is 4.5. Functionalinteractionsbetweenneurotransmittersystems

understoodhereasmaintenanceofthatconstructionprocess,with

all necessary variations required by changing situations or by LinksbetweenMAandAChreleaseandspecificformsofarousal

decreasing executive capacities in repetitive activities. There are havebeendescribedheretoillustratetheideathatneurotransmit-

atleastthreeancientanddistinctneurotransmittersystemsthat tersdonotsimplymediateorinhibitbehavioralarousal.Instead,

provideformaintenanceofbehavior: they likely have functional differentiations that provide various

aspectsofarousal.Moreover,ensemble-likemutualregulationof

- neuropeptides, that act slowly but with great plasticity and in MAsystemsoccursthroughco-localizationoftheirprojectionson

tune with the metabolic state of the body (Mains and Eipper, the same neurons within various limbic structures and in their

2006).Outof100+knownneuropeptideswejustpointhereto mutualinteractions.

theabovementionedroleoforexins,andalsotoGrowthHormone Thus,undertheconditionsofsignificance(whichmightbeasso-

thatwasimplicatedinthemaintenanceofphysicalendurance; ciated with high DA release) an orientational component (likely

- acetylcholine, that in addition to its fast transmission mecha- associated with NA release) should be activated. This is indeed

nisms in muscle control, has a slow-acting G-protein coupled observedasaco-releaseofDAandNA(DevotoandFlore,2007).

receptorsystememployedinitskeyroleintheparasympathetic NA-DAinteractionsappeartobecomplex,asDAispresentinNA

system,vigilanceofbehaviorandsustainedattention(Everittand neurons,beingthebiochemicalprecursorofNAandlikelyacting

Robbins,1997;Sarteretal.,2001) as a physiological ligand of NA receptors (Zhang et al., 2004). It

- serotonin system, that appeared to have a key role in repeti- hasbeensuggestedthatinthecerebralcortexaconsistentfrac-

tiveaspectsofbehaviorsuchasbasicmovement,caloricintake, tion of extracellular DA is recaptured into NA terminals by NA

sleep-wakecircadianrhythms,tonicmotoractivity,modulation transporter,andacompetitionforthesametransportercanbea
of neuroend ocrine fu nction, ap petit e, and trophic functions − mechanism regu la tingreciproca lsu ppr ession ormutuala ctiva tio n

contributionsbeingnotedinalmostallorganisms,fromplants ofDAandNArelease(DevotoandFlore,2007;Moronetal.,2002;

tovertebrates(Azmitia,2010;Hensler,2006). Pozzietal.,1994;YamamotoandNovotney,1998).IfNArelease

isassociatedwithorientationandDAreleasewithselectionand

The arousal of the 5-HT system differs from general awake- prioritization (i.e. with reduction) of these alternatives, then we

arousal provided by the hypothalamic neuropeptides, from the wouldpredictthatDAsystemsmayleadtoasuppressionofNA

reactive physiological arousal provided by the hypothalamic- release,inordertoenablebehavioraloutput.Thisindeedwhatwas

pituitaryaxis(HPA)andfromthetonic-vigilancearousalprovided observedinexperimentalstudiesshowingthatanimbalance,i.e.

by the ACh system. 5-HT-controlled arousal is more plastic and eitherinsufficientorexcessiveDAD1receptorstimulation,leadsto

selectiveinnatureandsupportstherepetitionofbehavioralunits anincreaseinNAsynthesisthatcompromisesattentionandwork-

thatwereproventobebeneficial.Azmitia(2010)describedthat ingmemorythrougheffectsonstress(Arnsten,1997;Brokawand

uninvolved 5HT neurons are generally either silent or highly Hansen,1987;Oades,2002).Complementarily,thecentralNAsys-

rhythmicallyactiveandatfirstmakeindiscriminateconnections. temappearstohavemechanismsforsuppressingDArelease,inline

Their activity is gradually synchronized with neurons that are withtheideathattheorientationalcomponentofbehaviouralreg-

synchronousandiseliminatedforneuronswhoseactivityisasyn- ulationshouldhaveawaytosuppressexistingprogramsofactions
chronous.Int hiss en sethetonic ar ousaloft he5-HT neuron sw orks (see Re y et al. , 2007 for r ev iew) − th e proces s that is i m portant

like a glue binding the most synchronous elements. During this inshiftingbetweenactionsandstoppingalreadyinitiatedactions

integration process 5-HT fibres also grow out to the periphery (BariandRobbins,2013).Inacutebrainslicesfromthemidbrain

ofaparticularCNStargetsiteandthenawaitsomesignalbefore PaladiniandWilliams(2004)haveobservedaninhibitoryeffectof
th e finalinfiltr ation takes plac e.On cea functio nalgr oupis estab- NAonDA neu ronactiv itythro ugha ctivation of(cid:2) 1-NArece ptors. In

lished, 5-HT maintains their specific arousal. Jacobs and Azmitia theGrenhoffetal.(1993)invivostudyofanesthetizedrats,stimula-

(1992) pointed out that 5-HT neurons spontaneously discharge tionoftheLCproducedalong-lastingdepressionofDAcellactivity

withanextraordinarytonicregularityandarestronglyactivated intheventraltegmentalarea(VTA)andsubstantianigra(SN).Stud-

duringrhythmicactivities,suchasfeeding,licking,grooming,pos- ies with the catecholamine stimulant d-amphetamine (Darracq

turalcontrol,swimming,butinhibitedduringalertstatesrequiring etal.,1998)andNAreceptorantagonists(Shietal.,2000;Linner

orientation. et al., 2001) have also shown that NA alpha2- adrenergic recep-

Yet, as Jacobs and Fornal (2010) concluded, 5-HT neuronal torslikelyhaveanindirectcontrolovertheDAoutflow.Behavioral

activity supervises a process of integration and maintenance of experimentsshowedthatNAplaysanimportantroleinalerting

actionsratherthansolelybuildingparticularmotoractsoractivat- responses(inlinewiththehypothesisaboutitsroleinattention

ingmusclegroups.Inthissense5-HTprovidesadifferentialand tonovelty),butthisroleisassociatedwithinhibitionofpreviously

plastictypeofmaintenanceofestablishedbehavioralunits.Sev- learned responses and stopping action for which execution was

eralauthorssummarizedtheprimaryfunctionofthe5-HTsystem alreadyinitiated(BariandRobbins,2013).