The Combinatorial Creature: Cortical Phenotypes within and across Lifetimes

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Krubitzer, L.A. and Prescott, T.J. orcid.org/0000-0003-4927-5390 (2018) The

Combinatorial Creature: Cortical Phenotypes within and across Lifetimes. Trends in

Neurosciences, 41. pp. 744-762. ISSN 0166-2236

https://doi.org/10.1016/j.tins.2018.08.002

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SpecialIssue:TimeintheBrain

Review

The

Combinatorial

Creature:

Cortical

Phenotypes

within

and

across

Lifetimes

Leah

A.

Krubitzer

* and

Tony

J.

Prescott

Theneocortexisoneofthemostdistinctivestructuresofthemammalianbrain, yetalsooneofthemostvariedintermsofbothsizeandorganization.Multiple processes havecontributedtothis variability,includingevolutionary mecha-nisms(i.e.,alterationsingenesequence)thatalterthesize,organization,and connectionsofneocortex,andactivity dependentmechanisms thatcanalso modifythesesamefeatures. Thus,changestotheneocortexcan occurover differenttime-scales,includingwithinasinglegeneration.Thiscombinationof genetic and activity dependent mechanisms that create a given cortical phenotypeallowsthe mammalianneocortex torapidly andflexibly adjust to differentbodyandenvironmentalcontexts,andinhumanspermitscultureto impactbrainconstruction.

Brain,Body,andEnvironmentInteractions

Inthisreviewwediscusstheevolutionanddevelopmentofmammalianneocortex.Weexamine

thecombinatorialnatureofcorticalphenotypes,explorethedifferenttime-scalesoverwhich

theneocortexcanchange,andconsiderhowrelationshipsbetweenthebrain,thebody,and

theenvironmenthaveshapeddifferentphenotypes,includingourown.Ourreviewisbasedon

threepropositions.

Thefirstisthatallbehaviorisgeneratedbytheembodiedbrainwhichtiessensationtoactionin

aloopthroughtheworld[1,2].Thus,anychangeinbehaviorcanbelinkedtoalterationsinthe

brain,thebody,ortheenvironment.Thebrainisnotdirectlyexposedtotheenvironmentand

theonlyinformationabouttheexternalworldthatisdeliveredtothebrainduringdevelopment,

andthroughoutalifetime,isderivedfromarestrictedsetofsensoryinputsfromtheeyes,ears,

skin,musclesandjoints,nose,andtongue.Thebodyanditssensoryreceptorarraysmake

behaviorpossible,buttheyalsoconstrainwhatkindsofbehaviorscanbegenerated.Moreover,

theformofthebodyitselfsimplifiestheproblemofmotorcontrolforthebrainbymakingcertain

kindsofbehavior easier(walking, running,grasping), andother typesof behavior (flying in

humans)difficult orimpossible[3].Forexample,legs have dynamical properties suitedfor

walking,wheretheyoperatelikeinvertedpendulums,creatinganintrinsicallystablegaitthat

needsonlylimitedactivecontrol[4];theconfigurationofthehandenablescertainsynergetic

grasppositionsthatreducesthedegreesoffreedomofmovement,makingcontrolofgrasping

easier[5].Theenvironmentcreatesaffordancesforbehavior[6,7];apoolaffordsdrinkingor

swimming,atree –climbing,andthiskeyboard –typing.Therelationshipbetween brains,

bodies and the environment are thus reciprocal and each shapes the others on a

moment-by-momentbasisandoverlongerperiodsoftime.

Thesecondpropositionisthattherearemultipletimescalesthatarerelevantforunderstanding

howanyextantbrainphenotypeemerges.Brainscanchangeacrosslarge,evolutionarytime

scalesofthousandstomillionsofyears;acrossshortertimescalessuchasgenerations;and

Highlights

Therearemultipletime-scalesthatare relevantforunderstandinghowagiven phenotype emerges. Brains change acrosslarge,evolutionarytime-scales, shortertime-scalessuchas genera-tions,andwithinthelifeofanindividual.

Anygivenphenotypeisacombinationof genesinvolvedinbrainandbody devel-opment, behavior, and the environment in whichanindividualdevelops.Asimilar phenotypeindifferentspeciesmaybe duetohomology,butcanalsobethe result of a different combination of factors.

Thereareseveralconstraintsthatrestrict theavenuesalongwhichevolutionofthe brainandbodycanproceed.Oneof theseconstraintsisthecontingentnature in which genes are deployed during development. Another constraint is genetic pleiotropy;a singlegenecan beexpressedindifferentportionsofthe nervous system at different times in developmentandcanbeinvolvedin dif-ferentaspectsofbrainandbody organi-zation. Finally, the laws of physics constrainbrainevolution.

Thehumanneocortexhasan extraor-dinarycapacitytoadaptbasedon con-text, allowing for rapid phenotypic changeevenwithinasinglegeneration. Ourspecieshasalsoevolveda remark-ablyfluidbrain/bodyinterfacewiththe environment, such that tools and machines can be incorporated into ourbodyschema,whichextendsour embodimentandperipersonalspace.

1_{CenterforNeuroscienceand} DepartmentofPsychology,University ofCalifornia,Davis,Davis,CA95616, USA

2_{SheffieldRoboticsandDepartment} ofComputerScience,Universityof Sheffield,Sheffield,UK

*Correspondence: [email protected] (L.A.Krubitzer).

Glossary

Apoptosis:naturallyoccurringcell deathduringdevelopment.

Cellcyclekinetics:thecycleof processesthroughwhichcells duplicatethemselves.For neurogenesisofthemammalian neocortex,thisoccursinthe ventricularandsubventricularzone.

Corticalarealization:theprocess bywhichcorticalfieldsemerge duringdevelopment.

DNAmethylation:anepigenetic mechanismthatcanchangegene expressionwithoutalteringthe underlyingDNAsequence.

Epigenetic:thestudyofheritable changesinthephenotypethatdo notinvolvedirectchangesinDNA sequences.

Histoneacetylation:anepigenetic mechanismthatregulatesgene expression,primarilybysuppressing genetranscription.

Homology:phenotypic

characteristicsthatareinheritedfrom acommonancestor.

Self-organization:thecapacityof complexdynamicsystems,including bodiesandnervoussystems,to spontaneouslycreateintrinsicorder.

Subventricularzone:alayered structureinthevertebratecentral nervoussystemcontainingprogenitor cellsthatgiverisetonewcortical neuronsduringbraindevelopment.In mammalsbothanouterandaninner ventricularzonehavebeenidentified.

acrossthelifeofanindividual:day-by-day,withinhours,minutes,andevenonatimescaleofa

second.Thus,yourbrainisdifferentnowthanwhenyoufirstbeganreadingthisreview.

A finalpropositionisthat any extantphenotypeis aunique ‘combinatorialcreation’ofthe

genetic cascadesinvolved in brainconstruction and the wider embryological, bodily, and

environmental context in which development happens [8,9,95]. Genes are the heritable

components of evolutionand essential agents in the developmental processesthat build

brains.Althoughgenesareinstrumentalinshapingthebrain,they co-varywiththesemore

proximaltargetsofselection(Figure1)[10],andhowgenescontributetocomplexbehavioris

nuanced.

Whilethesepropositionscanapplytoanyconsiderationofbrainevolution,thespecificfocusof

ourreviewisonthemammalianneocortexbecauseofitsimportantcontributiontoperception,

cognition,andvolitionalmotorcontrol.Itisoneoftheportionsofthebrainthathaschanged

most dramaticallyover the course of mammalianevolution, including, in some mammals,

expansions inrelative size compared to other parts of the brainsuch as the spinal cord,

hindbrainandmidbrain[11].In thisreviewwefirstprovideabriefbackgroundonthebasic

patternoforganizationandconnectivityoftheneocortexthatallmammalspossessandthe

typesofchanges thathaveoccurredto thispatternoverthe courseofevolution. Wethen

considerfactorsthatconstraintheevolutionofthebrainandthebody,themechanismsby

whichphenotypictransformationsoccur,andthetimecoursesoverwhichchangeispossible.

Finally,we discusshow understandingthese factorscan provide insight intohow cultural

evolutionimpactscorticalorganizationandbehavior.Thisisespeciallyrelevantgiventherapidly

changingsocialmilieuinwhichcontemporaryhumanbrainsdevelopandbehave.

ABasicPlan andAlterationstoThisPlan

Theneocortexisparticularlylargeinnon-humanandhumanprimates.Wehaveknownsince

theearlystudiesofBrodmann(1909)andcolleagues(e.g.,[12,13];see[14]forreview)thatitis

notsimplytheexpansionofthecorticalsheetthataccountsforsomeofourremarkableabilities,

buttheincreaseinthenumberofcorticalfieldsthatcomposetheneocortexandtheirpatterns

of connections. The fossil record indicates that the first mammals had a relatively small

neocortexin termsof proportionalvolume[15],and comparative studies indicatethat the

earliestmammalianbrainsweresimplyorganizedandlikelycontained15–20corticalfields,

similartotheneocortexofashort-tailedopossum(Figure2).However,thenumberofcortical

fieldsinmodernlivingmammalsrangesfrom15toover200(inhumans,atleastaccordingto

somedefinitions)[16].Howdidtheneocortexevolvefromasimplestructurewithafewcortical

fields,presentinourcommonancestor200 millionyearsago,to themuchmorecomplex

structurewithmultipleinterconnectedareasthatareobservedinthelarger-brained,

modern-day mammals? This question is difficult to address because brains do not fossilize, and

modern-daybrains are theresult of an accumulation ofchanges that have occurredover

millionsofyears.

Fortunately,wecancircumventproblemsassociatedwithunderstandingbrainevolutionintwo

importantways:comparativestudiesanddevelopmentalstudies.Incomparativestudieswe

examinetheproductsoftheevolutionaryprocess(e.g.,brainsandbodiesofdifferent

modern-daymammals)tounderstand‘what’evolutionhasproduced.Thistypeofanalysisallowsusto

uncover common features of brain organization that are present in all mammals due to

inheritancefromacommonancestor(homology;seeGlossary),aswellasunique

special-izationsthatdifferentmammalspossess.Whilecomparativestudiesoftheneocortexareuseful

Targets of selecƟon

Shallow extended

Steep restricted

Shallow extended

Steep restricted Small Large

Poor Good

Few Many Few Many

Low High

Restricted Up Down

Small

Large Small

Large

Small Large Increase

Decrease

Slow Fast Short Long

Small Large

Up Down

Expanded

High energy prey with disnct auditory emission

Number of photons Wind velocity

Slope of Pax 6 gradient Auditory discriminaon

Response me to changes in air pressure

Size of S1

Size of V1 Size of A1

Slope of Emx2 gradient

Spaal extent of Prx1 expression in forelimb

Proximal to distal limb growth Regulaon of gremlin

Regulaon of BMPs

Apoptosis of interdigit membrane

Interdigit membrane size

Length of forelimb

Genec event

Developmental process

Genec event Corcal phenotype

Body

Brain

Environmental context

Opmal phenotypic characterisc within a populaon

Genec profile that co-varies with phenotype/developmental event Current genec profile/

phenotype Inherited genec profile/

selected phenotype

Gaussian distribuon within a populaon

theyarelimitedsincethey donottellus‘how’thesephenotypictransformationsoccur.To

understandhowthesetransformationshappened,onecanstudyneuraldevelopment,since

theevolutionoftheneocortexis,inpart,theevolutionofthedevelopmentalmechanismsthat

giverisetothecorticalphenotype[17].

Ma

rsupia

_ls

Sinodelphys szalayi (125 mya)

P

la

ce

n

ta

ls

Morganucodon (205 mya)

Short-nosed echidna (tachyglossus aculeatus)

Duckbill platypus (ornithorhynchus ana nus)

Brush-tailed possum (trichosurus vulpecula)

Virginia opossum (didelphis virginia)

Living monotremes

Mo

no

tre

m

es

Early mammals

Living marsupials

Short-tailed opossum (monodelphis domes ca)

Dipr otod

on a

D id

elp himo

rp hia

Common ancestor

Primary somatosensory area (s1)

Primary auditory area (a1) Primary visual area (V1)

Somatosensory areas

Auditory areas Visual areas

Frontal myelinated area

Mul modal cortex

1mm

V1 V1

S1 S1

A1 A1

Cingu late c

ortex

RSC

FM

F

ENT

Pyriform cortex Olfactory bulb

Comparativestudiesinavarietyofmammalsallowustoappreciatethat,notwithstandingthe

wide variety of patterns of neocortical organization across mammalian brains, there is a

fundamental plan thatall mammalssharewithour commonancestor (see[18] for review;

Figure3). Thisconstellation of homologous corticalareas includes primary sensory areas (S1,V1,A1;seeTable1),secondsensoryareas(S2/PV,V2,rostralauditoryarea),and,atleast

ineutherians(placentalmammals),separatemotorareas(e.g.,M1,PM,SMA).Thesecortical

areas have thalamocortical and corticocortical connections which have been maintained

across species (e.g., geniculocortical pathways); but these networks have also been

elaboratedin differentlineages with the addition ofnew fields. Interestingly, even when a

sensoryreceptorarraygoesintodisuse,suchastheeyesintheblindmolerat,aspectsofthis

Primary somatosensory area (S1)

Primary auditory area (A1) Primary visual area (V1)

Somatosensory areas Visual areas

Posterior parietal cortex (PPC)

Monotremes Marsupials

Placentals

Echidna Platypus

Flying fox Ghost bat

Galago

Opossum Cat

Mouse

Squirrel Macaque

Chimpanzee

Ti monkey

Hedgehog Tenrec

Human

Insecvores

Chiroptera Carnivores Afrosoricida

Rodents

Old world monkeys New world

monkeys

Hominds Great apes

Primates

Prosimians

Common

ancestor

homologousnetwork,includingthepresenceofaV1andthegeniculocorticalpathway,canstill

beobserved([19,20],[21] Figure4). Ratherthan processingvisualinformation, the‘visual’

structuresoftheblindmolerathavebeenco-optedbytheauditorysystem,suggestingthatthe

cortexisnotconstrainedbythemodalityofsensoryinput,andthatitistheinput,ratherthan

intrinsicfactors,thatdeterminesultimatefunction(seebelow).

Comparativestudieshavealsouncoveredanumberofsystemslevelchangesthathavebeen

madetothiscommonplanofneocorticalorganizationinmammals,andalterationstothisplan

oftentakeasimilarform([22],Figure5).Themostobviousalterationisachangeinthesizeofthe

corticalsheetthatcanscalewiththesizeofthebodyorbecomeenlargedrelativetotherestof

thebrainorbody.Mammalianbrainsvaryinsize(andaccordinglyweight) byfiveordersof

magnitude,rangingfromafractionofagraminsomeshrewstonearly10kginspermwhales

(see[23]forreview).

Table1.ListofAbbreviations

A1 Primaryauditoryarea

AAF Anteriorauditoryfield

AC Auditorycortex

AD Anterodorsalnucleus

AV Anteroventralnucleus

CT Caudotemporalarea

ENT Entorhinalcortex

F Frontalcortex

FM Frontalmyelinatedarea

LD Lateraldorsalnucleus

LGd Dorsallateralgeniculatenucleus

LP Lateralposteriornucleus

M1 Primarymotorarea

MM Multimodalarea

OT Optictract

PM Premotorarea

PPC Posteriorparietalcortex

PV Parietalventralarea

RSC Retrosplenialarea

S1 Primarysomatosensoryarea

S2 Secondsomatosensoryarea

SMA Supplementarymotorarea

V1 Primaryvisualarea

rV1 Reorganizedprimaryvisualarea

V2 Secondvisualarea

VL Ventrolateralthalamicnucleus

Thereisalsowidevariabilityintheamountoftheneocortexdevotedtoprocessinginputsfroma

particularsensorysystem(sensory domainallocation).Forexample,inecholocating,

micro-chiropteranbats’auditorycortexisgreatlyenlarged,whereasinrodentswithasimilarsized

neocortex,somatosensorycortexdominatesthecorticalsheet([24,25]Figure8C). Another

alterationisthemagnificationofbehaviorallyrelevantsensoryreceptorarrays.Forexample,in

thesomatosensorysystemthiscouldincludeanincreasedsizeintherepresentationofthebill

ofaplatypus,thehand ofaprimate, andthevibrissaeof amouse.Therehave alsobeen

changesintherelativesizeofcorticalfields,incorticalfieldnumbers,andintheconnectionsof

corticalfields,allofwhichcancontributetodifferencesinbehavior.

TheCombinatorialCreature:DiversityintheFaceofConstraint

Twoimportantquestionsthatarisefromtheseobservationsare:What factorscontributeto

thesesystemslevelmodificationstotheneocortex?And,whatisthetimecourseoverwhich

thesealterationsemerge?Itistemptingtohuntfor ‘the’waybywhichsomeaspectofthe

phenotypeismodified:Whatis‘theway’inwhichthecorticalsheetcanincreaseinsize?What

1mm

Blind mole rat

Neocortex

S1

V1

AC

m

r

is‘theway’inwhichthesizeofacorticalfieldisdetermined?Andwhatis‘theway’inwhich

connectionsofacorticalfieldarealtered?However,thereisnosingleprocessbywhichany

given aspect of the corticalphenotype can be modified. There are multiple mechanisms

throughwhichagivencharacteristiccouldbeassembled,includingthosethatdirectlyalter

theneocortexitself,thosethatalterthebody,those thatimpactboth (e.g.,throughglobal

changesindevelopmentaltiming[26]),andthosethataltercellularmechanismsthatallowthe

environmentinwhichthebraindevelopstoimpactnervoussystemconstruction.However,the

waysinwhichthebraincanbealteredare,nevertheless,limited.

Oneofthemostsignificantconstraintsthatrestrictstheavenuesalongwhichevolutionofthe

brainandbody canproceed isthe contingentnatureinwhichgenes aredeployed during

development. For example, there are transcription factors (e.g., Pax6) expressed during

developmentintheneocorticalepithelialprogenitorcellsthatplayanumberofrolesincortical

development,suchasestablishingpatterningandregulatingneurogenesis.Theyalsoeither

promote or repress the transcription of a number of downstream targets including other

Modificaons to the neocortex

(A) Size of corcal sheet

(B) Sensory domain allocaon

(C) Relave size of corcal fields

(D) Magnificaon of behaviorally

relevant body parts

(E) Number of corcal fields

(F) Connecons of corcal fields

S1 A1 V1 Modules in V1

Specialized body part in S1 Other somatosensory areas

transcriptionfactors,celladhesionmolecules,andaxonguidancemolecules,whichcontinue

theprocessofconstructingthenervoussystem(see[27]forreview).Experimentalmanipulation

oftheexpressionofearlypatterninggenes(e.g.,Pax6,COUP-TF1)alterstherelativesizeand

theconnectionsofcorticalfieldsaswellastherelativelocationsofcorticalfields(see[28]and

Figure6).Thistypeofcontingentdeploymentservesasamajorconstraintforfutureevolution

since altering early events affects subsequent events, which may result in a non-viable

offspring.Thus,someaspectsofcorticalorganizationpersistevenintheabsenceofapparent

use(e.g.,thepresenceofaV1evenintheabsenceofvision;Figure4).Thisreflectsageneral

rulethatthemolecularregulatorsandtheresultinganatomicalstructuresthataregenerated

veryearly in development are generally notsensitive to sensory inputand other potential

selectiveevolutionarypressures.

Thesameholdstrueforgenesthatareinvolvedintheconstructionofthebody.Homeobox

genes(Hox)arealargefamilyofgenesthatguidetheconstructionofthehindbrain,spinalcord,

(A)

Normal corcal organizaon

COUP-TF1

COUP-TF1 -/- Emx2

-/-Emx2 Pax6

Pax6

-/-LGd

VP VP LGd

Emx2 +/+ Emx2

-/-V1 A1

S1

M1

(B)

Altered corcal organizaon

(C)

Altered thalamocorcal connecons

Parietal cortex Occipital cortex

neck,bodyandlimbsduringearlyembryonicdevelopment.Theyarehighlyconservedfromflies

tomammals,directthedeploymentofdownstreamgenesinvolvedinlimbconstruction,and

constrainthetypesofalterations thatcanbemadetothebody.Whileevolutionhas

trans-formedbasiclimbstructureintohands,wings,hoovesandflippers(Figure7),everymammalis

constrainedbyabasicbodyplancontrolledbytheseHoxgenes.Aswithtranscriptionfactorsin

theneocortex,alterationsinthetemporalandspatialpatternofHoxgenescanalterforelimb

developmentinratherradicalways,asdemonstratedincomparativestudiesoflimb

develop-mentinbatsandmice([29–31];see[32]forreview;Figure8).Themorphologicalstructureofthe

forelimbineachofthesespeciesisremarkablydifferent,whichseemstoimplythattheremust

bemajordifferencesingenesinvolvedintheconstructionofthelimbs.Infact,thisisnotthe

case;therearealterationsinspatiotemporalpatternsofexpressionofahandfulofgenes,orin

the suppression of some genes, that can account for these morphological difference

(e.g.,[31,33,34]).Thus,notwithstandingtheapparentvariabilityinforelimbmorphologyand

use,mammalsremaintetrapodswithabasicbodyplan,andhavenotevolvedextralimbs,or

evendigits.

Humerus

Ulna Radius Carpals Metacarpals

Phalanges

Forelimb diversity mammals

Human

Whale

Bat

Cat

Horse

2 mm

Cretekos et al., 2008

Cretekos et al., 2001

V1

A1

S1

S1

_V1

A1/aud

Ba

t

Mouse

E10.5 E11 E12 E12.5 E13.5

14E 15E 16 E16L 17L

Bat

Mouse

Bat

Wise et al., 1986 Mouse

Woolsey, 1967

d1 d2 d3 d4

d5

d1

d2 d3

d4 d5 dis fl

dis hl

pr fl

pr hl

dis fl

pr fl

pr hl

dis hl

(A)

Embryonic development of the forelimb: expression of

Prx1

(B)

Adult forelimb morphology

(C)

Adult neocortex: magnificaon of forelimb representaon

M

R

Thelaws of physicsalso constrain the evolution of sensory systems. For example,while

photonsaredistributeddifferentlyinaquaticandterrestrialenvironments,theyhaveimmutable

characteristics;specifically,theyarediscretequantaofelectromagneticenergythatarealways

inmotionandtravelatthespeedoflightinavacuum.Likewise,regardlessofthemedium(solid,

liquid,orgas),soundwavestravelthrougheachofthesemediabyvibratingmoleculeswithin

them.Whilethedensityofthemediuminwhichananimallivescanchangethespeedatwhich

soundtravels,theauditorysystemmustadapttooptimallycapturethissourceofenergy.This

constrainstheevolutionofsensoryorgansandtheirreceptorsthatmusttransducethisenergy,

whichthenervoussystemwillultimatelytranslateandactupon.

Despitetheserather largeconstraints imposedon brainandbody construction, there are

multiplewaysinwhichany givenaspectofthecorticalphenotypecanbealtered;herewe

providethreedistinctexamples.First,alterationsintheoverallsizeofthecorticalsheetmightbe

achievedthroughanumberofmechanismsthataltercellcyclekinetics,orprogenitorpools

from whichneuronsarise. Previousstudieshave shown that duringcorticalneurogenesis,

macaquemonkeys,whichhave alargecorticalsheet, havean extendedperiodofcortical

neurogenesiswithanincreasedrateofcelldivisioncomparedtomice[35,36].These

dissim-ilaritiescan account for some of the differences in cortical sheet size exhibited by these

mammals. Anotherpossible way in which the size of the neocortex can be altered isby

theaddition of extraneurogenic cells (intermediate progenitors)within the subventricular

zoneofthedevelopingbrain[37–39].Inadditiontointermediateprogenitors,therearealso

increasesinthenumberofouterradialglialprogenitorsthatundergoself-renewing,symmetric

divisions(e.g.,[40]).Finally,subpopulationsofGABAergiccellscanbegeneratedinavarietyof

differentlocations,includingtheganglioniceminence,thedorsaltelencephalon[41]andthe

embryonicpreopticarea[42].

Asecondexampleisthatofcorticalfieldsize.Ithasbeendemonstratedthatgenesintrinsicto

thedevelopingneocortex canalterthe relative sizeof corticalfields(Figure6; see[28] for

review).Inaddition,corticalfieldsizecanberegulatedbyalteringtheoverallsizeofthecortical

sheet[43],bychangesinthesizeofthalamicnuclei,andbydifferencesinspontaneousand

sensorydrivenactivity presentduringearly development[28,44].A finalexampleisthatof

corticocorticalandthalamocorticalconnections,whichcanbechangedbyalteringthe

expres-sionofgenesintrinsictotheneocortex(Figure6;[28,45–47]),byalteringthesizeofthecortical

sheet[43],bychangesinthedevelopingthalamus(see[28]forreview),byearlyexposureto

toxinssuchasethanol[48],orbyalteringtheratioofincomingsensorydrivenactivityearlyin

development.Importantly,thesemodificationscanbelinkedtoalterationsinsensorymediated

behaviorasexploredlater.

TimescalesofEvolutionandDevelopment

In the previous section, we discussedthe different factors that contribute to the cortical

phenotype;but howandwhy dothesechanges comeabout?Evolutionarytheory tells us

thatphenotypic changeresults from naturalselection acrossvariationwithin a population.

Variationcantaketheformofgeneticchange,forinstance,alterationsinDNAsequencedueto

substitution,insertionordeletion,orthroughgenetic(allelic)drift.Contemporaryevolutionary

biologyhashighlightedthecomplementaryroleofexperienceinshapingdevelopment and

producingphenotypicdifferencesforselectiontoactupon(see[8]forreview).Indeed,ithas

becomeincreasinglyclearthatthesuccessofthemammalianbrainarchitecture,inadaptingto

awiderangeofhabitats,hasoccurredbyavoidingover-specificationofthenervoussystemin

thegenome, andby invokingdevelopmental mechanisms that respondadaptivelyto both

animal’senvironmentalniche[9,17].Computersimulationofthesemechanisms(e.g.,[9,49])is

essentialtoourunderstandingofhowthebrainself-assemblesandtoidentifyinghowabalance

between genetic specification, self-organization of network structure, and sensitivity to

internaland externalfeedback hasgiven rise to the diversityof neocortical forms thatwe

observeinextantmammals.

Whilechangesinthegenomethatinducephenotypicvariationinbrainorganizationaccumulate

andspreadthroughthepopulationovermanygenerations,phenotypictransformationsinbrain

organizationandconnectivitycanalsooccurwithinthelifetimeofanindividual.The

mecha-nismsbywhichthelatteroccurarevaried.Forexample,environmentallyinducedchangesin

histoneacetylationandDNAmethylationcanalterwhereandwhengenesareexpressed

[50],whichinturncanalterconnectivityofabrainarea.Likewise,alterationsinintracellularand

synapticmechanismsinvolvedlearning,memory,andplasticity(e.g.,pre-andpostsynaptic

NMDAreceptors[51,52])cangeneratelargechangesinhowinformationisprocessedinthe

brainandthebehaviorthatthebrainultimatelygenerates.

WehaveknownsincethestudiesofWaddingtonthatagivengenotypeiscapableofcreatinga

rangeofphenotypes[53];howeverwhatwedonotknowishowfarwecanexperimentallypush

agenotype.Canweinducemassivechangesincorticalorganizationandconnectivitywithin

individual lifetimes, likethose produced throughout the course of evolution, or is the final

phenotypic outcome more constrained? To address how early sensory context impacts

corticalorganizationand connectivity,andultimately thebehavior thatthe brainproduces,

wedescribeaseriesofexperimentsinwhicheitherthesensoryreceptorarray,the

environ-mentalcontext,ortheexposuretosensoryinputhasbeenmodifiedveryearlyindevelopment.

Tocompletelyloseasourceofafferentsensoryinputisoneofthemostdevastatingthingsthat

canhappentoadevelopingbrain.Whilerareinnature,themannerinwhichtheneocortex

respondstosuchatraumaprovidesagoodindicationofitsadaptivecapability,whichmaybe

hardertoseewithmoresubtleinterventionsthatbetterreflectchangesinthebodythathappen

morefrequentlyinnaturalconditions.Asanexample,todeterminetheeffectofacomplete

sensorylossoncorticalorganization,theKrubitzerlaboratorymadebilateralenucleationsinthe

SouthAmericanshort-tailedopossumbeforeretinalandthalamicprojectionshadreachedtheir

targetsandpriortotheonsetofspontaneousactivity[54].Thisdrasticallychangedtheratioof

incomingsensoryinputstothedevelopingneocortexandresultedinalterationsinthesize,

connectivity,andthefunctionalorganizationofV1(thetargetedsensorysystem)andS1(the

sparedsensorysystem).V1wasreducedtohalfofitsnormalsize,neuronsinthereorganized

V1(rV1)respondedtosomatosensoryandauditorystimulation,andrV1receivedinputsfrom

somatosensory and auditory regions of the dorsal thalamus and neocortex ([55,56] see

Figure9).Similareffectswerefoundfollowingdifferenttypesofexperimentallyinducedsensory

loss including congenital deafness [57,58], decreased sensory-driven activity [59,60],and

peripheral lesions [54,61,62]. Importantly, these experiments suggest that the cortical

phenotypeis capable of remarkable change when inputs from different sensory systems

arealtered,underscoringtheimportanceofspontaneousandsensorydrivenactivityfornormal

developmentatalllevelsofthenervoussystem.Interestingly,notonlyaretheconnectionsof

the re-organized visual cortex altered, but the neural response properties, receptive field

characteristics,andcorticalandsubcorticalconnectionsoftheprimarysomatosensorycortex

alsoundergochanges[63].RecentworkintheKrubitzerlaboratoryalsoindicatesthatthese

functionalandneuroanatomicalalterationsintheneocortexareaccompaniedbyan

Asecondseriesofstudiescomparedthesizeofcorticalfieldsinnocturnalrodents(rats)to

diurnal rodents (tree squirrels, ground squirrels and Nile grass rats), and also compared

laboratoryratstowildcaughtrats[65].Thisstudyaddressesthequestionofhowachange

inlifestyleorhabitatimpactsthedevelopingbrain.Thesestudiesdemonstratedthatdiurnal

rodentshadsignificantlylargervisualareas(V1,V2andOT)whereasnocturnalrodentshad

significantlylargersomatosensory(S1,S2)andauditoryareas(A1+AAF).Similarexpansions

ofvisualcortexhavealsobeenobservedindiurnalversusnocturnalprimates[66,67].Especially

interestingwas theobservation that thesame speciesof rat(Rattusnorvegicus) reared in

differentenvironments(wildversuslaboratory)hadsignificantdifferencesinthesizeofprimary

auditoryandsomatosensorycortex,althoughthemagnitudeofthedifferenceinthesizeof

somatosensoryandauditorycortexwasmuchsmallerthanthatdescribedaboveforearlyblind

animals(10%and27%,respectively).Inaddition,thereweresignificantdifferencesinbrainto

bodyratios(wildcaughtratshadarelativelybiggerbrain)andinthepercentageofthebrain

V1 (area 17)

CT S1

A1 V2

Ar ea 17

CT S1

A1

1 mm

Normal opossum

_{Bilaterally enucleated at P4}

VL VP S1

V1 injecon MM

CT

ER

LGd LD

LP V2

Cortex

Thalamus

Area 17 injecon MM

CT

ER

LGd LD

LP X

Cortex

Thalamus

AD AV

VL

A1 Other

M

R

(A)

Funconal organizaon

(B)

Corcal and thalamic connecons

Primary somatosensory area (S1) Primary auditory area (A1) Primary visual area (V1)

Somatosensory areas Auditory areas Visual areas

Frontal myelinated area Aud + som + vis Aud + som

Industrial revoluon Most recent known

Neanderthal remains Neanderthal Humans Human/ne ander thal p opula o ns spli t 370 kya 300 kya

100 kya - 40 kya

Figurave art FOXP2 undergoes intronic non-coding changes 400 kya Earliest anatomically modern humans Environment/social context Morphology

Emergence of true culture

Smaller, standardized tools Spears and knives in shas and handles Composite tool manufacture Cultural tradions

Linguisc diversity

Personal ornaments Use of pigments Burials 28 kya

Hominins Neanderthal Human 35 kya Polished, drilled, perforated bones

Projecles Sophiscated blades

Increased populaon Large dispersal of populaon 70 - 50 kya

Hand producon to machines Chemical manufacturing Iron producon Improved water power

1760 - 1820

100 kya

Panini (chimpanzees)

Hominins

6 mya Many features of modern hand 3.2 mya

Archaic hyoid 1.6 mya Anatomical capacity of ear/cochlea for modern paerns of sound transmission

800 kya 700 kya

3.4 mya

Stone tool assisted consumpon of food ung

2.5 mya Culture supporng communicaon Enhanced

communicaon tool use tradion

Control of fire 1 mya

1.5 mya

FOXP2 2 changes in proen coding sequence

1.6 mya

Large cung tools Modern hand

and muscular morphology

Modern hyoid

1900’s Nuclear power

1886 Automobiles 1903 Air powered flight 1957 First satellite in space 1950 Electronic computer

1990’s World wide web, electronic mail, texng 2000’s Electronic social networking

260 - 300 kya

Daily and prolonged interacons with machines

occupiedby the neocortex (wild ratshad relatively large cortices).Subsequent studies of

cellularcompositionrevealedthatwildratshadalargerpercentageofneuronsandagreater

densityofneuronsinV1comparedtolaboratory-rearedanimals[68].Perhapsthesefindings

arenottoosurprising,sincelaboratoryrearedanimalsarehighlydeprivedintermsofboth

sensoryinputandmovementoptions.Theyalsodemonstratetheneedtoinvestigatethebrains

ofanimals inmore enriched environmentsto get a deeper understandingof natural brain

developmentandfunction[69].

Afinalseriesofstudiesinthemonogamousprairievoleunderscorestheimportanceofearly

sensoryexperienceinconstructingacorticalphenotype.Prairievolesarebiparentalandboth

parentscontributetoinfantcare,whichisrelativelyrareamongmammals.Importantly,voles

naturallyengageindifferentrearingstylesinwhichtheamountoftactilecontact(high, HC

versuslow,LC)deliveredtotheinfantsbytheparentsisnormallydistributed[70];andinfants

adopt the rearing style of their parents. The Krubitzer lab took advantage of this natural

variabilityandexaminedboththesizeofcorticalfieldsandtheconnectionsofsomatosensory

cortexinhighversuslowcontactinfantsandfoundthathighcontactanimals(females)hada

relativelylargemotorcortex[71],andthatthecorticalandcallosalconnectionsof

somatosen-sorycortexdifferedbetweenthetwocontactgroupsinboththedensityofconnectionsandthe

locationofitsinputsfromdifferentcorticalfields[72].Thesestudiesdemonstratethat,withina

singlelifetime,aspectsoflifestyleor‘culture'canimpactcorticalfieldsizeandconnectivity.

Thesethree seriesofstudiesindicate thatsensoryinputandenvironmentalcontext playa

criticalroleinphenotypicoutcome.Webelievethattheseaspectsofthephenotypegenerated

bysensoryinputandtheenvironmentwillpersistacrossgenerationsifthecontextis

main-tained,andthatthephenotypecanundergorapidchange,fromgenerationtogeneration,ifthe

environmentishighlyvariable.Thus,fromourperspective,whatneedstobebetterstudiedand

explainedistheevolutionofthedevelopmentalmechanismsthatallowsuchstrikingsensitivity

tocontextovershorttime-scales.

ConcludingRemarksandFuturePerspectives

Inthisreview,wediscussedmultiplemechanismsbywhichthesamephenotypiccharacteristic

(e.g.,size of a corticalfield; connectionsof a corticalfield) can be altered.These include

traditionalevolutionary mechanisms that operate directly onthe neocortexand body, and

activitydependentmechanismsthatcanalterthefunctionalorganizationandconnectionsof

thebrain,andthebehaviorthatthebraingeneratesinthecourseofalifetime.Thus,radical

changestothephenotypeoccuroverbothlongandshorttimescales.Changesoccurringover

shortertimescalesare likely drivenbythe long-termevolutionofsynaptic,cellular,and/or

epigeneticmechanismsthatallowthedevelopingorganismtoconstructacorticalphenotype

thatisadaptedtoitsenvironmentalcontext.

Withrespecttoourownspecies,webelievethatweshouldconsidersociallearning,culture,

andlanguageascomplexpatternsofmultisensoryactivityimpingingonthedevelopingnervous

system.Thesesocialconstructscanfundamentallyalteranumberofaspectsoforganization,

including size of corticalfields, corticaland subcortical connections, and neural response

properties,whichinturnaltersbehavior.Supportforthissuppositioncomesfromstudiesof

humanevolution.Anatomicallymodernhumanshaveexistedfor260–350thousandyears[73]

andfeaturesofthemodernhandthatcouldsupporttooluse[74],andofasupralaryngaltract

thatcouldsupportspeech[75,76]evolvedmuchearlier.Yet,ourmost complexbehaviors,

such as the ability to craft complex artifacts, and our capacity for spoken language as

evidencedbytracesofsymbolicactivity,haveemergedmorerecently[77].Wehypothesize

OutstandingQuestions

Whataretheunderlyingmechanisms thatallowthedevelopingbraintobe shapedbytheenvironment?

Howdo alterationsinthe brain co-evolvewithalterationsinthebody?

Howflexibleisthegenomein produc-ingawiderangeofphenotypes?

thatalthoughthefirstmodernhumanshadbrainsandbodiesthatwerecapableofcomplex

physicalandsocialinteractionswiththeworld,theemergenceofhumanculture,beginning

some200 thousandyears ago[77],likely played animportant roleinshapingthe modern

humanbrain.Inrecentmillennia,culturalevolutionhasseenacceleratinggrowth(Figure10).For

example,theindustrialrevolutionoccurredlessthan300yearsago;airpoweredflight,nuclear

technologiesand electroniccomputers are allless than a centuryold; and oursocial and

technicalinteractionswithmachine-generatedvirtualworldsbeganless thanthreedecades

ago.Theimplicationisthatifourbehaviorandtheenvironmentsthatweinhabithaveradically

alteredoverrelatively shorttimescales(centuriesto decades),then featuresofthe human

corticalphenotypemustalso haveundergonerapid andpossiblydramaticchanges within

recenthistory.Infact,wewouldarguethathumanshaveanextraordinarycapacitytoconstruct

our neocortex based oncontext, over the course of a prolonged infancy and childhood,

allowingforrapidphenotypicchangewithinevenasinglegeneration.Our specieshasalso

evolved aremarkably fluid brain/body interface with theenvironment, such that tools and

machinescanbeincorporatedintoourbodyschema[78,79],extendingourembodimentand

peripersonalspace,andexpandingtheloopbetweenourbrains,ourbodies,andtheworld.

Thiseventualityhasmadeusintouniquelybiohybridcreatures[80,81]whosebrainsadaptand

bootstrapthemselveswiththetechnologiestheyhavegivenriseto,andwithwhomourfutures

areincreasinglyentwined.

Acknowledgements

WethankScottSimon,DrewHalley,MaryBaldwin,andCynthiaWellerfortheirhelpfulcommentsonthismanuscript.Leah Krubitzer,andsomeoftheworkdescribedinthisreview,issupportedbytheJamesS.McDonnellFoundationand NICHHD(R01HD084362-01A2).TonyPrescott’scontributiontothiscommentarywassupportedbytheEuropeanUnion Horizon2020program,throughtheHumanBrainProject(HBP-SGA2,785907),andbytheSageCenterfortheStudyof MindDistinguishedFellow’sprogram.

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