Ancestral Exposure to Stress Generates New Behavioral Traits and a Functional Hemispheric ...

13 Pages·2016·5.18 MB·English

CerebralCortex,March2017;27:2126–2138
doi:10.1093/cercor/bhw063
AdvanceAccessPublicationDate:10March2016
OriginalArticle
ORIGINAL ARTICLE
Ancestral Exposure to Stress Generates New Behavioral
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Traits and a Functional Hemispheric Dominance Shift n
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Mirela Ambeskovic1, Nasrin Soltanpour1, Erin A. Falkenberg1, Fabiola C. fro
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R. Zucchi1,2, Bryan Kolb1 and Gerlinde A.S. Metz1 h
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1CanadianCentreforBehaviouralNeuroscience,UniversityofLethbridge,Lethbridge,AB,CanadaT1K3M4 ://a
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and2DepartmentofPhysiologicalSciences,UniversityofBrasilia,Brasilia,DF70910-900,Brazil ad
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AddresscorrespondencetoGerlindeA.Metz,CanadianCentreforBehaviouralNeuroscience,UniversityofLethbridge,4401UniversityDrive,Lethbridge, ic
AlbertaT1K3M4,Canada.Email:[email protected] .o
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Abstract rc
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Inacontinuouslystressfulenvironment,theeffectsofrecurrentprenatalstress(PS)accumulateacrossgenerationsandgenerate r/a
newbehavioraltraitsintheabsenceofgeneticvariation.Here,weinvestigatedifPSormultigenerationalPSacross4generations rtic
le
differentiallyaffectbehavioraltraits,laterality,andhemisphericdominanceinmaleandfemalerats.Usingskilledreachingand -a
skilledwalkingtasks,3findingssupporttheformationofnewbehavioraltraitsandshiftedlateralitybymultigenerationalstress. bs
First,whilePSintheF1generationdidnotalterpawpreference,multigenerationalstressintheF4generationshiftedpaw trac
preferencetofavorleft-handednessonlyinmales.Second,multigenerationalstressimpairedskilledreachingandskilled t/2
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walkingmovementabilitiesinmales,whileimprovingtheseabilitiesinfemalesbeyondthelevelsofcontrols.Third,theshift /3
/2
towardleft-handednessinmultigenerationallystressedmaleswasaccompaniedbyincreaseddendriticcomplexityandgreater 1
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spinedensityintherightparietalcortex.Thus,cumulativemultigenerationalstressgeneratessexuallydimorphicleft- 6/3
handednessanddominanceshifttowardtherighthemisphereinmales.Thesefindingsexplaintheoriginsofapparently 05
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heritablebehavioraltraitsandhandednessintheabsenceofDNAsequencevariationswhileproposingepigeneticmechanisms. 3
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Keywords:behaviorallaterality,braindominance,dendriticmorphology,dexterity,finemotorskills,Golgi–Coxstaining, by
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handedness,multigenerationalprenatalstress,neuroplasticity,parietalcortex(Par1),sexdifferences,sexualdimorphism, u
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spinedensity s
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A
Introduction p
Earlylifeexperience,suchasprenatalstress(PS),modifiesthe motorreflexdevelopment(Patinetal.2004),andreducedmotor ril 20
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developingbrainandbehaviorwithpotentiallylife-longconse- abilityandstrengthinlaterlife(Kofman2002;Canuetal.2007; 9
quences.SeverePSmayresultinreducedhippocampalvolume Caoetal.2014)inbothexperimentalanimalsandhumans.
(Lemaireetal.2000)andalteredfunctionofprefrontalstructures Growing evidence suggests that programming by PS may
suchasanteriorcingulatecortex(ACC)andorbitalfrontalcortex affect subsequent generations of offspring. Studies involving
(OFC) (Murmu et al. 2006; Muhammad et al. 2012; Mychasiuk the Dutch famine birth cohorts havesuggested that prenatal
etal.2012).PSanimalsoftenshowreduceddendriticspinedensity undernutritioncansignificantlyaffectthehealthofchildren
anddendriticatrophyinbothACCandOFC(Murmuetal.2006). andgrandchildren(Roseboometal.2001;Kattietal.2002,2007;
TheseanatomicalchangesinducedbyPSareassociatedwithcog- RoseboomandWatson2012).Furthermore,prenataltoxinsand
nitive impairments, such as learning and memory deficits steroidhormonesmayalterbehavioralfunctionsacrossseveral
(Lemaireetal.2000;WelbergandSeckl2001;Bowmanetal.2004; subsequentgenerations(Anwayetal.2006;Skinneretal.2011;
Weinstock 2008; Glover 2011; Harris and Seckl 2011), delayed Vyssotski2011;Iqbaletal.2012;MatthewsandPhillips2012).
©TheAuthor2016.PublishedbyOxfordUniversityPress.Allrightsreserved.ForPermissions,pleasee-mail:[email protected]
MultigenerationalStressPromotesDendriticReorganizationandLeft-Handedness Ambeskovicetal. | 2127
Recently,ourlaboratoryhasshownthatstressduringpregnancy
altersmaternalbehaviorandnewborndevelopmentacrosssev-
eralgenerations,withpronouncedchangesinducedbycumula-
tive effects of recurrent stress (Yao et al. 2014). Our findings
indicatedthatmultigenerationaladverseexposuremayresult
in behavioral traits that may vary across generations (Ward
etal.2013).Behavioralvariationsacrossgenerationsmaybeex-
plainedbyepigeneticmechanisms(Skinner2008;Meaney2010;
Dunnetal.2011;MigicovskyandKovalchuk2011;Skinneretal.
2011;Babenkoetal.2012)thataretransmittedandpotentiallyac-
cumulatedacrossgenerations.Thus,throughepigeneticregula-
tion, a continuously stressful environment may result in
multigenerationalbehavioralchangesandpotentiallygenerate
D
newbehavioraltraitsthroughalteredneuroplasticity. o
w
Aprominentbehavioraltraitwithpotentiallyancestralori- n
gins is handedness. Handedness reflects cerebral asymmetry loa
d
and has been linked to specific gene functions (Scerri et al. ed
2011).Geneticmodelshavebeenusedtoexplaingreaterinci- fro
denceofleft-handednessinmales(McManus1991).However,a m
h
recentgenome-wideassociationstudyfoundnogeneticlinkages ttp
(pAarsmseoduornetthraolu.g2h01th4)e.mNaottearbnlayl,lilnefeta-hgeanradtehdenrethssansteheempsatteornbael s://a
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a
lineage(McManus1991;Annettetal.1996).Transgenerational d
e
epigenetic programing by adverse maternal experience may m
thereforeprovideamechanismforapparentlyheritablepatterns ic.o
inhandednessandlateralityintheabsenceofgeneticchanges. up
Here, we tested if a single versus acontinuouslystressful .co
m
environment, induced by exposure to multigenerational PS
Figure 1. Multigenerational and transgenerational stress model. Pregnant /c
across4generations,canleadtochangesinmotorlaterality, dams (P0) were stressed to generate F1 prenatally stressed offspring. The erc
tcTauelhtrreeaerlbaeprtxailoaplnseatsrsiicyimnimtyefimnnotfeeptswraeyarn,isseaotndardielmscaiooglrttnteoeerrxedsd(kPtinaollresui1,np)rvoianenwsaatpldigrmuealftoteermrpesahntlorceeelosa,sgan-yndindifndesmutrracuaetclsde-. tgtsrhtearenenesmsrsgaaetltiineonernenraafagotlieloglonrwweaaaletsd–sgtpbrreryeosandsto-ulgnicrnesaetdnraedgbsmesyopwstrtahersegensrpsahrinonadcdgiuebpcseerteedongngfsreatonrnmeetsrsamtehtedoe.tahTplerhienresnemaaitgnuaell4ltiyingceswotnnrheesirsceashcteuidootnniFvlaye1l or/article-a
generations(F0,F1,F2,F3)toproducethestressedF4generation.Maternalstress b
Fti1ongeanlearnadtiomnusl,teigxepnoesreadtitoonPaSl,PvSerinsutshtehFe4egffeencetsraotfiotrna.nTshgeenfienrda-- (erxepderairmroewn,triendvollevtetedrst)heocFc1urgreendedrautriionngogfenstoantisotnreaslsdeady(sF11-2N–1)8a.nTdhperepnraetsaelnlyt strac
ingsrevealedthatmultigenerationalexposuretoPSexceeded stressed (F1-S) offspring, and the F4 generation of nonstressed offspring t/2
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theeffectsofsinglegenerationPSandpromotednewbehavioral (F4-NNNN),transgenerationallystressedoffspring(F4-SNNN),andmultigenerationally /3
traits.Importantly,multigenerationalexposuretorecurrentPS stressedoffspring(F4-SSSS). /21
2
induces a shift of brain lateralization toward the right hemi- 6
/3
sphereandleft-handednessinmales,butnotinfemales.These nonstressconditions.Parentalfemaleratswereeitherstressed 0
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functionalchangeswereaccompaniedbyneuromorphological duringlategestation(S)orremainedunstressed(N).Inthemulti- 6
3
changesintherightparietalcortex. generationalstresslineage,theirpregnantF1daughters(F1-S),F2 07
granddaughters(F2-SS),andF3great-granddaughters(F3-SSS) by
werestressedagainduringpregnancy(Skelinetal.2015;Erickson gu
MaterialsandMethods e
et al. 2014; Yao et al. 2014). A lineage of yoked controls was s
Animals bredwitheachgeneration(nonstresspregnantF0,F1-N,F2-NN, t on
F3-NNN).Dependingonlittersize,amaximumof6offspring 1
0
ThisstudyinvolvedgenerationsofLong-Evanshoodedratsbred perlitterofeachsexwererandomlyselectedtobeincludedin A
p
avnivdarriauimse.dTahteth15e2CaadnualdtiraantsCseunbtjreectfotroBthehisasvtiuoduyrawlNereeuhroosucsieedncine tfrhoemex4pdeirffimereennttsli.tEtearcsh. experimentalgroupincludedoffspring ril 20
groups(malesinpairs,females3percage)undera12:12hlight/ TheF1generationincluded“prenatallystressed”(F1-S)ani- 19
darkcyclewithlightstartingat07:30handtheroomtemperature malsandnonstressedcontrols(F1-N),andtheF4generationin-
setat22°C.Priortobehavioraltraining,ratswerefooddeprivedto cluded“transgenerationallyprenatallystressed”ratswithstress
reach90–95%oftheirbaselineweight.Tomaintainthisweight, limitedtotheF0generation(F4-SNNN)and“multigenerationally
ratsreceivedstandardchowfoodintheirhomecages5hafter prenatallystressed”ratsinwhichstresshadoccurredin4succes-
completionofdailyskilledreachingtrainingsessions.Ratswere sivegenerations(F4-SSSS)toinvestigatetheinfluenceofprenatal,
weigheddaily.AllprocedureswereapprovedbytheUniversityof transgenerational,andmultigenerationalstressonmotorfunc-
LethbridgeAnimalCareCommitteeincompliancewiththeguide- tionandbrainlaterality.TheexperimentsincludedthemaleF1
linesbytheCanadianCouncilonAnimalCare. generation (males: n=41 [F1-S=20, F1-N=21]) and males and
females from the F4 generation (males: n=55 [F4-NNNN=21,
F4-SNNN=12, F4-SSSS=22]; females: n=56 [F4-NNNN=24,
ExperimentalDesign
F4-SNNN=8,F4-SSSS=24]).Thegroupsweretrainedandtested
Twodifferentlineagesofratswerebredunderstandardizedcon- in a skilled reaching and a skilled walking task to determine
ditions(Fig.1),whereSreferstoprenatalstressandNrefersto dexterityandpawpreference.Sincethemultigenerationalstress
2128 | CerebralCortex,2017,Vol.27,No.3
(F4-SSSS)showedthemostsignificantdifferenceforpawpreference representedatotalmissand6representedacorrectlimbplace-
andlaterality,thebehavioralandneuronalanalysisfocusedonthis ment.Anerrorwasdefinedasalimbplacementthatreceived
generation.Follow-upstudiesinvolvedbehavioraltestsofmaleand scoreof0,1,or2points.
femaleanimalsexposedtomultigenerationalstressattheageof6
months(malen=21 Pawpreferencescores.Toconfirmpawpreferenceasdeterminedin
[F4-NNNN=11, F4-SSSS=10]; female n=24 [F4-NNNN=13, F4- theskilledreachingtask,pawusagewasmeasuredforinitiation
SSSS=11]).Animalswerethenrandomlyassignedtoneuromor- ofsteppingcycles.Rightpawdominanceinreachingwasaccom-
phologicalanalyses(malen=12[F4-NNNN=6,F4-SSSS=6];female paniedbyinitiatingasteppingcyclewiththerightforelimb90%
n=12[F4-NNNN=6,F4-SSSS=6]). ofthetime.Rightpawpreferenceinskilledreachingcloselycor-
relatedwithrightpawdominanceinsteppingontheladderrung
PrenatalStress walkingtask.
Fromgestationaldays12–18,pregnantdamsweresubjecteddaily
torestraintinaPlexiglascylinderfor20minandforcedswim- HistologicalProcessingforGolgi–CoxStaining Do
w
mrecinegiviendwbaortmhswtraetsesr(p2r2o°cCe)dfuorre5smeainch(Ydaaoyeitnaal.s2e0m14i)r.aTnhdeoamniomrdaelsr Awfittehrabnehoavveirodroalsteeostfinpgenwtaosbacorbmitpalleatenddtwheeraeniinmtaralscawredriealtlryeapteerd- nloa
d
eitherinthemorningorafternoonhours. fusedwith0.9%saline.Thebrainswereremovedandpreserved ed
in Golgi–Cox solution for 14 days in a dark location (Ramon- fro
BehavioralTesting Moliner1957).Thebrainswerethenplacedin30%sucrosefor m
h
SkilledReachingTask 28days.Avibratome(Leica,BuffaloGrove,IL,USA)wasusedto ttp
Aprnoitmocaolslswdeersecrtirbaeindepdreavnidoutesslyte(dMientzskainlldedWrheiaschhaiwng2a0c0c0o).rdBirniegfltyo, cgueltattihne-cboraatiendssalitde2s0.0Inµtmheafinndaltshteeps,litcheesbwraeirnesmweoruenstteadinoend s://aca
accordingtotheprocedurepublishedbyGibbandKolb(1998).Ac- d
ratswerepretrainedtoreachasymptotelevelsinskilledreaching e
cordingtoourpreviouslypublishedprocedures,theentireden- m
success. ic
dritesofindividualneuronswerestained,includingthedistal .o
u
Rseecauchtiinvgesduacycse.ssInsceoarcehs.sPeesrscieonnt,sruatcscewsesrweaasllorewceodrdteodrefoarch14focro2n0- soeuggmhleynststa.Dineenddraintidcswegitmhoeunttsotvheartlampewttihthecarnitoetrhiaeorfdbeenindgrittheoorr- p.com
foodpellets(45mg,Bioserv,Inc.,NJ,USA).Thesuccesspercent bloodvesselwereincludedintheexamination.Varioustypesof /c
(%)wascalculatedusingthefollowingformula: spinesweredrawn andincludedintheanalysisaccordingto erc
Success percent¼nnuummbbeerr ooff sauttcecmespstess×100 p2F0irge0.Pv32yi;AoWrua)meswlleismdrteuaaldsneice2lees0lcl0st(1Re;fdorBbofriomonrwsaolnannyeaetlayranslIid.sII2.0KAo0of5cltba;hWme1ei9lprb9aa9er;rluieeKcttioadallabl.cm2oe0tro1tue1axn)l..t(e2Pd0a0ro01n,; or/article-a
b
Onday15ofbehavioraltesting,theperformancewasvideotaped aGomlgiic–rCoosxcostpaeinwedasbruasineds(tFoigt.r2aBc,eC).inAdtiovtiadluoafl1n0ecuelrlosn(5spferormhemthie- strac
withadigitalvideocamcorder(PanasonicWV-BP330,Panasonic, sphere)weretracedat×200magnification(GibbandKolb1998).In t/2
7
Minato-ku,Tokyo,Japan),andanexperimenterblindtotheex- thecurrentstudy,60cellsweretracedpergroup(10peranimal,6 /3
perimental conditions performed the qualitative analysis of animalspergroup)across4experimentalgroups(i.e.,240cellsin /21
2
videorecordings. total).Neuromorphologicalmeasurementsincludedapicaland 6
/3
Qualitative reaching performance was based on 11 main basilarShollanalysis(anestimateofdendriticlengthderived 0
5
movement components and 35 subcomponents (Metz and fromdendriticbranchesthatintersectconcentriccirclesspaced 63
Whishaw,2000).Threesuccessfulreachespereachratwereana- 25µmapart),apical,andbasilardendriticbranchorder(anesti- 07
lyzedandaveragedtoassessthequalitativefeaturesofmove- mationofdendriticcomplexitybasedonthenumberofbranch by
ments.Themaximumreachingmovementscorewas35points. bifurcations)andspinedensity(thenumberofspineprotrusions gu
ona50-µmsegmentofdendritetracedat×1000magnification; es
Pawpreferencescores.Pawdominancewasdeterminedbypre- GibbandKolb1998;Fig.2D).Theexactlengthofthesegment t on
ferredpawusewhenreachingforafoodpellet.Rightpawdomin- was calculated and expressed as the number of spines per 10
ancewasrecordedifananimalusedtherightpawtoin>90%of 10µm(Mychasiuketal.2013). A
p
rpeaawchiens,>l9e0ft%paowf rdeoamchineas.ncAemwbaidserxetcroorudsedanfoimruaslasguesoefdtheeithleefrt ril 20
rightorleftpawfor40–60%ofthetime. StatisticalAnalysis 19
StatisticalanalysiswasperformedusingSPSS20forWindows
SkilledWalkingTask 11.5.0(IBMCorporation,Armonk,NY,USA).Three-wayanalysis
The horizontal ladder rung walking apparatus (Metz and ofvariances(ANOVAs)withStress,Sex,andHemisphereasfac-
Whishaw2002)wasusedtoassessskilledwalkingperformance. torswererun,andrevealednomaineffectofHemisphere,except
Briefly,pretrainedanimalsweretested3timesineachtestses- forspinedensity.Thus,two-wayANOVAswithStressandSexas
sionandvideorecordingswerecollected.Therecordingswere factorswererunforbehavioraltasks(pelletreachingtaskand
analyzedbyablindexperimenteraccordingtoourpreviously skilledwalkingtask)andneuromorphologyoftheparietalcortex
publishedratingscale(MetzandWhishaw2002). (Par1).Unpairedsamplet-testswereusedforallposthocana-
lyses.χ2testswereperformedtorevealpossibleassociationsbe-
Skilledwalkingscores.Thequantitativeanalysisincludedtheaver- tweentreatmentandpawpreference.Exactbinomialconfidence
agenumberoferrorsforleftandrightforelimbsandleftandRHL limits and proportions were calculated for nominal variables
asaratioofthetotalnumberofsteps.Forqualitativeanalysis,the (pawpreference).Pearson’scorrelationswereusedtoexamine
limbplacementwasscoredonascalerangingfrom0to6,where0 possiblerelationshipsbetweenbehaviorandneuromorphology
MultigenerationalStressPromotesDendriticReorganizationandLeft-Handedness Ambeskovicetal. | 2129
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Figure2.MorphometryofGolgi-stainedpyramidalneuronsintheparietalcortexPar1.(A)Schematicdiagramofcoronalsectionsthroughtherighthemisphereillustrating ttp
s
thelocationoftheparietalcortexPar1(shadedarea)accordingtostandardcytoarchitecturalcriteria.Indicatedisthepositionrelativetobregma(PaxinosandWatson ://a
1998);(B)Photomicrographasseenthroughthecameralucida;(C)Representativepyramidalneuronshowingapicalandbasilardendrites;(D)High-powerimageofa c
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dendriticsegmentwithdendriticspines. d
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Figure3.Effectsofprenatalstressacrossgenerationsonhandedness.Percentageofratsdisplayingpawpreferenceinthereachingtask.(A)Pawpreferenceinmaleswas /3
slightlyaffectedbybothprenatalstress(F1-S)andtransgenerationalstress(F4-SNNN),andsignificantlyalteredbymultigenerationalstress(F4-SSSS)incomparisonwith /21
nonstressed(F4-NNNN)animals.(B)Transgenerationalstress(F4-SNNN)modifiedhandednesstosimilardegreesinbothmalesandfemales.(C)Multigenerationalstress 26
significantlyshiftedpawpreferencetowardleft-handednessinmales;nonstressedmales(n=21)had19%absoluteleftpawpreferencewhilemultigenerationallystressed /3
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males(n=22)preferredtheleftpaw50%ofthetime.However,multigerationallystressedfemalesshowedonlyaslightshiftinleftpawpreference(34%inF4-NNNNto46% 5
6
inF4-SSSS). 3
0
7
b
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(spinedensity)basedonhemisphericdominance(ipsilateraland pawpreferenceinmalerats(n=20)comparedwithnonstressed gu
contralateralhemisphere).Pawpreferencefromeachanimalwas (F1-N)controls(n=21;χ2(1)=1.33,P=0.25).However,thepropor- es
usedtodeterminehemisphericdominance,andthereforespine tionofleftpawpreferenceinF1-Sanimalswasslightlylarger t o
n
densityfromeachhemispherewasassignedtotheipsilateralor (35%or0.35with95%confidencelimitsof0.15and0.60)thanin 1
0
contralateralside.Forexample,forananimalwithrightpaw nonstressedcontrols(19%or0.19withconfidencelimitsof0.05 A
p
pofretfheerelenfctehaenmdislepfhtehreemwiassphlaebreicleddocmonintaranlcaete,rtahle(is.ep.i,nceondternaslaitty- apnrodp0o.r4t0io;nFigo.f3lAef)t.RpeacwurprerenftePreSnacceroisnsFg4e-nSeSrSaStiomnasleinscfrreoamsed35thtoe ril 20
eraltothepreferredlimb).Reachingscoresinindividualanimals 50%(0.5with95%confidencelimitsof0.28and0.717;χ2(1)=0.03, 19
werecorrelatedtotheircontralateralandipsilateralapicalspine P=0.33;Fig.3A).Interestingly,theexperienceofbothtransgenera-
densitymeasurement.Theresultsareshownasthemeans± tional(F4-SNNN)andmultigenerational(F4-SSSS)stressaffected
standard error of the mean (SEM). Asterisks indicate signifi- pawuse(Fig.3B)whencomparedwithanimalsexposedtoPSin
cances:*P<0.05,**P<0.01,***P<0.001. theF1generation.Theratioofpawpreferenceinskilledreaching
amongmaleandfemaleratsrevealedasexuallydimorphiceffect
ofmultigenerationalPS;multigenerationalPS(F4-SSSS)signifi-
Results cantlyincreasedleftpawpreferenceinmales(χ2(1)=4.53,P<0.05,
MultigenerationalandTransgenerationalStressPromote Fig.3C)butnotinfemales(χ2(1)=0.78,P=0.37,Fig.3C)incompari-
sonwithnonstressedcontrolanimals.
LeftPawPreference
Nonstressed(F4-NNNN)malerats(n=21)weremorelikelyto
Basedonskilledreachingperformance,ratsweretestedforpaw beright-handed(81%or0.8with95%confidencelimitsof0.58
useintermsofleft,right,andambidextroustraits.Theexperience and0.95)thantobeleft-handed(19%;Fig.3C).Multigenerational
ofPSintheF1generation(F1-S)hadnosignificantconsequenceon PS(F4-SSSS)decreasedtheproportionofrightpawpreference
2130 | CerebralCortex,2017,Vol.27,No.3
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Figure4.Effectsofmultigenerationalprenatalstressonskilledreachingperformance.Multigenerationalstressaffectedskilledreachingsuccessandmovement m
trajectoriesinasexuallydimorphicmanner.(A)Femalesperformedskilledreachingmovementswithoverallhighersuccessratesandhigherqualitativemovement /c
e
scores.Multigenerationalstressinmales(n=10)reducedsuccessratesandqualitativemovementscorescomparedwithnonstressedmales(n=11).Incontrast, rc
Pmmhouovltteoimggereannpethracstooimofnrpaeoplnrseetrnseetsnwstaaintsivpfeeemrafioamlremmse(odnv=beme1t0te)enirntsbcyfroefraesmeeaadclheressaetchxhaainnngdmsgaurloecucse.psA.sTdahdnietdiiollqnuuasaltlrlyiat,tamiotinuvlestihmgoeownvesermtahteaiontntaanslccsoetrsreterssasclonsmtergepasatsriveceadluywsaeitfdhfetcnhtoeendasimmtreatsloessebdewfahetimlaeagiltreebsaet(nneer=fia1tne0gd).uf(leBam)rTpaholesesita.ii(omCn) or/artic
towardthepelletinmales(seearrow).Asterisksindicatesignificances:*P<0.05.Alldatamean±SEM. le-a
b
s
tra
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amongmales(n=22)to50%,comparedwithnonstressedrats movementsrevealedamaineffectofsex(F1,35=50.37,P<0.001), t/2
(F4-NNNN, n=21; Fig. 3C). Among nonstressed females as females generally performed better than males (P≤0.001; 7/3
(F4-NNNN,n=24)theright:leftratiowas66%(0.66with95%con- Fig.4A).Theaveragescoreinfemaleswas30pointscompared /2
1
fidencelimitsof0.45and0.84)right-handedand34%(0.34with withanaverageof24inmales.Furthermore,therewasasignifi- 26
95%confidencelimitsof0.15and0.55)left-handed.Multigener- cant Sex×Stress interaction (F1,35=7.30, P<0.05), as F4-SSSS /30
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ationalPSinfemales(F4-SSSS;n=24)changedthisratioto54% femalesperformedbetterthannonstressedF4-NNNNfemales 6
3
(0.54with95%confidencelimitsof0.45and0.84)right-handed (P≤0.05).Furthermore,F4-SSSSmalesperformedslightlyworse 0
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and46%(0.46with95%confidencelimitsof0.15and0.55)left- thanF4-NNNNmales(P=0.50;Fig.4A).Notably,stressexerted b
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handed.Anotablebutnonsignificantshiftinleftpawpreference sex-specificeffectsontheaimcomponent.F4-SSSSmalesre- g
u
wasobservedintransgenerationallystressed(F4-SNNN)males vealedimpairedaimofthepawdirectedtowardthepelletwith es
(χ2(1)=1.82,P=0.178,andfemales(χ2(1)=0.62,P=0.40).Interest- a greater supination of the paw toward the reaching side t o
n
ingly,F4-SNNNanimalsshowedashiftinpawpreferencetoward (Fig.4B,C).Furthermore,incomparisonwithF4-SSSSfemales, 1
theleftlimbfrom19to41%(0.41with95%confidencelimitof0.26 wheninitiatingareachF4-SSSSmalesdisplayedweightshiftto- 0 A
p
amnodre0.l6ik3e),lysitmoiblaerletfot-Fh4a-nSdSSedS(a6n6i%moarls0..F646-wSNitNhN95f%emcoanlefisdwenecree wthaerpdatwhefirrormeatchheinflgoofor.rTelhimisbcoamsipfotnoeunstewthaeslbeoftdiynttoacatiidniFn4l-iSftSinSSg ril 2
0
limitsof0.22and0.95)thanright-handed(34%or0.34withcon- femalesincomparisonwithcontrols(Fig.4C). 19
fidencelimitsof0.04and0.77)incomparisonwithF4-NNNNfe-
males,whichwereratherright-handed(66%).AsF4-SSSSmales
demonstratedthemostsignificantshiftinpawpreferenceand MultigenerationalStressIncreasedSkilledWalking
ErrorsOnlyinMales
laterality,thisgroupwasusedforsubsequentbehavioraland
neuromorphologicalexaminations. Theerrorratesinskilledwalkingrevealedasignificantmain
effectofSex,asfemaleratsoverallmadefewerforelimb(left
forelimb:F =15.37,P<0.001;rightforelimb:F =22.67,P<
MultigenerationalStresshadSexuallyDimorphicEffects 1,40 1,40
0.001)andhindlimb[lefthindlimb:F =5.24,P<0.05;right
onSkilledLimbuse 1,40
hindlimb(RHL):F =8.78,P<0.005]errorsthanmales(Fig.5).
1,40
AlthoughtherewasnomaineffectofSex,Stress,oranyinter- Furthermore,RHLerrorsrevealedamaineffectofStressinthe
action for percent success, there were significant changes in F4generation(F =4.58,P<0.05)andasignificantSex×Stress
1,40
movementtrajectories,asrevealedbyqualitativeanalyses.The interactionforRHLerrors(F =8.52,P<0.01)andforleftforelimb
1,40
averagequalitativereachingmovementscoreforskilledreaching errors (F =4.32, P<0.05). Multigenerational PS had sexually
1,40
MultigenerationalStressPromotesDendriticReorganizationandLeft-Handedness Ambeskovicetal. | 2131
parietalcortices;malesgenerallyhadalargerspinedensitythan
females(P≤0.05;Fig.6D).Similarly,malesshowedasignificantly
greaterspinedensityintheleftparietalcortexapicalfieldincom-
parisonwithfemales(F =12.23,P<0.01).Importantly,multi-
1,20
generationalPSdecreasedspinedensityintheright (P<0.05)
andleftparietalcortexapicalfieldsinmales(Fig.6D).Figure7il-
lustratesthat,incontrasttononstressF4-NNNNmales,themul-
tigenerationallystressedF4-SSSSmalesrevealedsignificantly
morecomplexdendriticbranchingpatternsandlowerdendritic
spinedensityintherightparietalcortex.
MultigenerationalStressisAssociatedwithSignificant
RelationshipsBetweenSkilledMotorAbilityandSpine D
o
DensityinMales w
n
Correlationanalysisrevealedasignificantrelationshipbetween loa
d
thespinedensityoftheparietalcontralateralhemisphereand ed
skilledreachingperformanceamongmalesinboththeF4multi- fro
Figure 5. Effects of multigenerational prenatal stress on skilled walking generationalPSandcontrolconditions.F4-NNNNratswithgreat- m
paesrefoxrumalalyncdei.mMourlpthigiecnmeraantinoenra.lSptrreenssaetadlfsetmreassleaslt(eFr4e-dSSsSkSil)lesdhowwaelkdinhgigahbeilritfyooint ethredpenardireittaiclcsoprinteexdsehnoswiteydinhitghheercoqnutarlaitlaattievrealrehaecmhiisnpghsecroereosf https
placementaccuracythanstressedmales(F4-SSSS).Ahistoryofstressinmales (r=0.76,P<0.05;Fig.8A).Additionally,therewasasignificantre- ://a
increasedtheerrorrateswithreducederrorrateserrorsintheRHL,indicating c
thattheirbrainlateralitywasmodified.Incontrast,footplacementaccuracyin lationship between ipsilateral hemisphere and the reaching ad
e
stressedfemales(F4-SSSS)wasnotaffected.Alldatamean±SEM. scores(r=0.83,P<0.05;Fig.8A)inF4-NNNN.Importantly,there m
wasapositiverelationshipbetweenreachingmovementscores ic.o
anddendriticspinedensityinthecontralateralhemispherein up
dimorphiceffectsonskilledwalkinginRHLerrorsasstressedF4- F4-SSSS-stressedmales(r=0.82,P<0.05;Fig.8B).Norelationship .co
SSSSmalesmademoreerrorsthannonstressedF4-NNNNmales(P was found between the ipsilateral hemisphere and reaching m
≤0.05).Incontrast,thestressedF4-SSSSfemalesmadeslightly movement performance in F4 SSSS animals. Thus, rats with /ce
fewererrorsthannonstressedF4-NNNNfemales(P=0.35;Fig.5). higherspinedensityinthecontralateralhemisphereshowed rco
betterreachingperformance.However,nosignificantcorrelation r/a
wasfoundbetweentheipsilateralorcontralateralhemispheres rtic
MultigenerationalStressAlteredSpineDensityand le
andreachingperformanceinfemales(Fig.8C,D).Additionally, -a
DendriticComplexityinParietalCortexinaSexually b
our results revealed a positive correlation between dendritic s
DimorphicManner lengthintherightapicalfieldandskilledwalkingerrorscores trac
Afamilyhistoryofstressrevealedtobeasignificantdeterminant in F4-SSSS-stressed males (r=0.88, P<0.05; data not shown). t/2
7
ofneuronalplasticity.Athree-wayANOVArevealedamaineffect Thesefindingssuggestthatimprovedskilledreachingandwalk- /3
ofStress(F2,40=5.0,P<0.001)andSex(F2,40=7.3,P<0.001)butno ingabilityoftheleftpawwereassociatedwithlargerdendriticre- /212
main effect of Hemisphere (F =1.6, P>0.05). In general, modelingoftherighthemisphereinmales,furtheremphasizing 6
2,40 /3
females had longer dendrites with more elaborate branching pronouncedlateralityandhemisphericshiftinmultigeneration- 0
5
thanmales.Males,ontheotherhand,hadgreaterspinedensity allystressedmales. 6
3
thanfemales.Stressincreaseddendriticlengthandbranching 07
ebfuftecdteocfreHaesemdisspphinereedfeonrssiptyin.eNodteanbsliyt,y.thTehreerwigahstahesimgnisipfihcaenret Discussion by gu
revealed a significantly higher spine density in both apical PSrepresentsapowerfulimpactonbehaviorandneuronalmorph- es
(F =4.9, P<0.05), and basilar dendrites (F =4.0, P<0.05). ology.Thepresentstudyexpandsthispreviousresearchbyinves- t o
1,40 1,40 n
Using two-way ANOVAs, branch orders of the parietal cortex tigating if recurrent PS across 4 generations aggravates the 1
0
(Par1)intherightandleftapicalfieldsrevealedasignificant consequencesofPSinasinglegenerationtopromotethedevelop- A
p
mThaeirneeaflfseoctwoafsSatnreisnscirneatsheeiFn4dgeennderriatitciobnra(nF1c,h23in=g4.i1n0b,oPt≤h0r.i0g5h)t. mseexnutaollfyndeiwmobrephhaivciomraalntnraeirt.sTbhyeshpirfetisnegnbteshtuadvyioprarlolvaitdeersal3itymianina ril 20
(F1,20=7.39,P<0.05)andleft(F1,20=7.44,P<0.05)apicalneurons findings.First,multigenerationalPSshiftedpawdominancein 19
ofmultigenerationallystressF4-SSSSmaleandfemaleanimals malesbutnotinfemales.Second,multigenerationalPScompro-
(Fig.6A,B).Inthebasilarfields,femalesoverallshowedsignifi- misedskilledmovementtrajectoriesandskilledwalkingability
cantlylongerdendritesintheright (F =9.93,P<0.005)and in males. In contrast, a family history of PS rather improved
1,20
left (F =5.96,P<0.05)parietalcortexcomparedwithmales theseabilitiesinfemales.Third,corticaldendriticmorphologyin-
1,20
(Fig.6A,C).Furthermore,femaleshadsignificantlylongerden- dicatedthatmultigenerationalPSdecreasedmultisynapticplasti-
dritesintheapicalfieldintherightparietalcortexcompared cityinmalesbutincreaseditinfemales.Notably,theshifttoward
withmales(F =8.96,P<0.01). left-handednessinstressedmaleswasaccompaniedbyincreased
1,20
Thedendriticlengthinthebasilarfieldintheleftparietal dendriticcomplexityintherightparietalcortex.Therefore,the
cortexrevealedasignificantSex×Stressinteraction(F =4.00, presentdataindicatethatmultigenerationalPSpromotesdysmas-
1,20
P<0.05). Multigenerational PS reduced dendritic length in fe- culinizationinbehaviorandbrainmorphologyamongmales.
malesandincreasedthesameinmales(Fig.6A,C).Asignificant Thepresentstudyconfirmsthenotionthatalteredbehavioral
effectofSexwasfoundfordendriticspinedensityinthebasilar traits caused by PS vary between males and females. PS and
fieldoftheright(F =6.57,P<0.05)andleft(F =9.74,P<0.05) chronic stress exposure was shown to be associated with
1,20 1,20
2132 | CerebralCortex,2017,Vol.27,No.3
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Figure6.Neuroanatomicalpathologyoftheparietalcortexinresponsetomultigenerationalprenatalstress.Ahistoryofmultigenerationalstressaltereddendritic
morphologyintheparietalcortex.(A)CameralucidadrawingofapicalandbasilarpyramidalcellsinthePar1ofstressedF4-SSSSandnonstressedF4-NNNNmale
andfemalerats.(B)Dendriticbranching,(C)dendriticlength,and(D)MeanspinedensityinthePar1regionofbothrightandlefthemispheresinmaleandfemalerats
exposedtomultigenerationalstress.Notethatmultigenerationalstressalteredneuronalmorphologyoftheparietalcortexinsex-specificmanner.Asterisksindicate
significances:*P<0.05.Alldatamean±SEM.
reductioninhippocampal(McEwenandMagarinos1997)and DarnauderyandMaccari2008).Humanstudieshavereported
corticalplasticityinmales(Brownetal.2005;Radleyetal.2006, greater motor deficits in male than the female PS offspring
2013;Shanskyetal.2009)andanincreaseinfemales(Schmitz (Patinetal.2004;Caoetal.2014).Importantly,aparticularout-
etal.2002;MuhammadandKolb2011;Mychasiuketal.2012). comeofPSmayaffectbehaviorallateralityinasexuallydimorph-
Additionally,PSinducesmemoryandlearningimpairmentsin ic manner, with males being more susceptible to laterality
males,whileitimprovesthesecognitivefunctionsinfemales changesthanfemales(Alonsoetal.1991,1997;TangandVersty-
(Lemaire et al. 2000; Bowman et al. 2004; Son et al. 2006; nen2002).Theseexperimentaldataaresupportedbyhuman
MultigenerationalStressPromotesDendriticReorganizationandLeft-Handedness Ambeskovicetal. | 2133
(1930)reportedthatratsgenerallyprefertherightpawoverthe
left. Distribution of rat paw preference is similar to that of
humanhandednessinmales(right80%vs.20%left),whereas
infemalesthisdistributionappearsratherequallydistributed
(TsaiandMaurer1930;TangandVerstynen2002;Guvenetal.
2003).However,thereareinconsistentresultsintheliteraturere-
gardinghandedness.AccordingtoTangandVerstynen(2002),
theseinconsistenciescanbeexplainedintermsofdifferences
amongtestingmethods.Furthermore,environmentandearly
life experiences may modify handedness and associated
neuromorphology.
Changesinhandednessareusuallyreflectedbyalteredneur-
onalmorphology.Forexample,chronicstressandmoderatePS
D
exposurewereshowntodecreasespinedensityinthemedial o
w
prefrontalandorbitofrontalcortices(Brownetal.2005;Radley n
lo
etal.2006, 2013).Incontrast,mildPSdecreasedspinedensity a
d
inmedialprefrontalcortexanddidnotaffectspinedensityin ed
the orbitofrontal cortex (Kolb et al. 2012; Muhammad et al. fro
2012).Furthermore,Radleyetal.(2013)reportedthatchronicvari- m
h
ablestress(CVS)after14daysinmalesinducedsynapticdestabil- ttp
ipzraetfiroonntianltchirecuhiytp.Tothheaylafomuon-dpitthuaittaCrVy-Saddrimenianlis(hHePdA)thinehdiebnitsoirtyy s://a
c
a
ofstubbyspinesinbasilardendritesandthinspinesinapical d
e
andoveralldendritesoftheanteriorbednucleiofthestriatermi- m
nalis (aBST)-projecting prelimbic area neurons (Radley et al. ic.o
2013).Thiswasaccompaniedbyaselectivedepletionofmature up
mushroom spines in aBST-projecting neurons (Radley et al. .co
Figure7.Computer-assistedreconstructionofGolgi-stainedneuronsandapical 2013).However,Blossetal.2011reportedthatmaturemushroom m
spinesinlayerIIIoftheparietal1cortex(Par1).Imagesdepictrepresentative spinesarethemoststableduringenvironmentalchallengessuch /ce
neuronsintheleft (A)andright (B)hemispheresofnonstressedF4-NNNN rc
asstress.Sincethisstudyanalyzedonlyonetimepointfollowing o
msstpraienlseesse;ddneeFnu4s-riStoySnSsinSinmthtaheleersilg.ehNftto(htCee)mtahniesdpinrhicgerhreetas(oDefd)mhdeuemlntdiigsrepitnhiceerrcaeotsmioopnflamelxluyitlytsitgarenensdsederadetcimroenaaalselelsdy, tohreschhrirnoknaicgestroefssmeuxsphorsouorme, istpiisnensotisclreeasrpiofntshibeleelifmorintahteiosne r/article
whichaccompaniedtheshifttowardleft-handedness. alterations(Radleyetal.2013).Theliteraturesuggeststhatgluco- -a
corticoid-dependentmechanismsinfluencedbyenvironmental bs
findingswherematernalstressat18weeksofpregnancypre- factors are behind the elimination of mushroom spines in trac
dictedatypicalhandednessthatwasmoreprominentinmales aBST-projecting prelimbic area neurons and the observed t/2
7
(Gloveretal.2004).Specifically,left-handednesswasobserved morphologicalshift(Radleyetal.2013). /3
toincreaseinresponsetoPSexposureonlyinmales(Elis1991). Avarietyofenvironmentalandexperientialfactorscanalso /21
Thepresentfindingsexpandtheseobservationsbysuggesting shifttheratioofhandednessandhemisphericdominance.Cor- 26
/3
that PS recurring across generations of the maternal lineage ticaldevelopmentinparticularissusceptibletoavarietyofenvir- 0
5
will program vulnerability to facilitate a shift in handedness onmentalfactors(Geschwindetal.2002;Kolbetal.2012).The 6
3
andbrainlateralizationinthemaleoffspring. maturationofhemisphericdominanceisinfluencedbythetime 07
For a long time, lateralized brains were believed to be a ofexposure,intensityoftheexperience,developmentalstage, by
uniquelyhumanfeature(Diamondetal.1981;Campetal.1984; andsex(Michelsenetal.2007;MuhammadandKolb2011;Kolb gu
Alonsoetal.1991;TangandVerstynen2002).However,asym- etal.2012).Thepresentdataconfirmpreviousobservationsthat es
metriesinbrainandbehaviorweredescribedinmanyotherspe- stressaltersbraindominanceandhandpreference.Themostpro- t o
n
cies,suchasrat,cat,rabbit,andnonhumanprimates(Kolbetal. foundmodificationsaregenerallyfoundinmales,wheretheirab- 1
0
1982;Campetal.1984;Alonsoetal.1991;Rogers2000;Tangand solute hand preference may decrease from 80:20 right-hand A
p
Vdeesrsctryibneednb2e0h0a2v;iGoaraoladnedficZithsaansgso20c0ia8t)e.dFowriethxarmigphlteh,eramtisstpuhdeieres detoaml.in19a3n0c;eTianntghaencdonVterrosltypnoepnul2a0t0io2n;Gtouv6e0n:4e0t(aTls.a2i0a0n3;dGMaoauarnedr ril 20
1
lesions,whichwerenotpresentinanimalswithalefthemi- Zhang 2008). In contrast, in rats the female paw dominance 9
spherelesion(RobinsonandCoyle1980;Kolbetal.1982;Kirkland tendstobesmallerwith60:40rightpawdominance(Tsaiand
etal.2008).Therapeuticbenefitsafterbrainlesionalsodiffer Maurer1930;Guvenetal.2003),whichisalsoobservedinthe
depending on hemispheric dominance (Nikkhah et al. 2001; humanpopulation(Alonsoetal.1991;TangandVerstynen2002).
VyazovskiyandTobler2008).Furthermore,both humansand Brainorganizationandmotorfunctionsthatdependonhand-
ratsdisplayahighdegreeofhemisphericspecializationwithin edness may be differentially expressed in males and females
theparietalcortex(Rushworthetal.1997,2001,2003;Schluter (CulhamandValyear2006;Culhametal.2006;Gardeneretal.
etal.2001;Culhametal.2006;Mentoetal.2010).Thislateraliza- 2009;TomasiandVolkow2012).EvidencesuggeststhatPSregu-
tiondifferencesupportstheoverallpreferenceoftherightupper latesfundamentalepigeneticmechanismsandendocrinepat-
limbs(KolbandWhishaw2003;Whishawetal.2003). ternsacrossgenerationstopromotedemasculinization(Morgan
Pawpreferenceandhandednessreflectmorepreciseuseand andBale2011),andthesefactorsmayalsoshiftlateralizationin
individualpreferenceofonelimbovertheother,whichisideally behaviorandbrainfunction.Itispossiblethatearlylifeadversity
testedinskilledreachingorobjectmanipulationtasks.Using modifies cerebral asymmetry trough general neuromodulatory
standardizedreachingtasks,earlystudiesbyTsaiandMaurer systems(TangandVerstynen2002).Inparticular,testosteroneis
2134 | CerebralCortex,2017,Vol.27,No.3
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Figure8.Relationshipbetweenskilledreachingperformanceandspinedensity.Correlationbetweenmeanspinedensityintheapicaldendritesoftheipsilateraland 6/3
contralateralhemispheresandmeanqualitativemovementscorefor(A)nonstressed(F4-NNNN)males,(B)stressed(F4-SSSS)males,(C)nonstressed(F4-NNNN) 0
5
females,and(D)stressed(F4-SSSS)females.Astrongpositivecorrelationbetweenqualitativereachingscoreandmeanspinedensitywasfoundfornonstressed 6
3
malesinthelefthemisphere,andforstressedmalesintherighthemisphere.Thisshiftindicatesthatmultigenerationalstressmodifiedbrainlateralityinmales. 0
7
Additionally,nonstressedmalesreachingscoreandmeanspinedensityoftheipsilateral(right)hemispherewerenegativelycorrelated.Nocorrelationwasfoundin b
femalerats.Asterisksindicatesignificances:*P<0.05. y g
u
e
s
alikelycandidatetoinfluencecorticallateralizationandpawpref- Furthermore, females in general seem more resistant than t o
n
erence(Flemingetal.1986;StewartandKolb1988;Wisniewski malestostress-inducedimpairment(Zuenaetal.2008).Improved 1
0
1998;Guvenetal.2003).Thus,themultigenerationalPSinthepre- stresstoleranceorresilienceinfemalesmaypromotebothsen- A
p
steesnttosstteurdoynmelaeyveallste,rtheuasrlayfcfeecretibnrgalmdaelveelpoapwmpernetfevrieanrceedumcotiroensien- soryThanedsemxoutaolrlyasdpimecotsrpohfisckcilhleadnmgeosvienmseenntspoerrimforomtoarnpceer.form- ril 20
1
verelythanfemalelaterality(StewartandKolb1988;Geschwind ancewereaccompaniedbyneuromorphologicaladaptationsin 9
etal.2002;Culhametal.2006).Similarmechanismsmaybere- afunctionallymeaningful area,the parietalcortex. Although
sponsibleforreducingmaleskilledreachingperformanceaswell. therearenopreviousdataontheeffectsofmultigenerational
The present results revealed that multigenerational PS af- PSoncorticalneuromorphology,earlierstudiesinPSconfirm
fectedmaleandfemaleskilledreachingandwalkingabilitiesdif- thepresentfindings.Muhammadetal.(2012)reportedthatPS
ferently. While multigenerational PS reduced skilled reaching causedadecreaseinbasilarorbitofrontalcortex(angularinsular
performance in males, it seemed to promote performance cortex,dorsalpart)inbothmalesandfemales(Muhammadetal.
amongthestressedfemales.Notably,theimpairmentsinskilled 2012). Furthermore, PSdiminished dendritic growthinmales
walkingweregreaterforthenondominantlimb.Itispossiblethat (Bustamanteetal.2013)withreductioninbranchingoftheapical
successfulskilledreachingmotorperformanceamongfemalesis dendritesinlayerII/IIIpyramidalneuronsoftheparietalcortex
linkedtoimprovedrecoveryfromstress(JadavjiandMetz2008; (Bustamanteetal.2013)andincreasedcorticalspinedensity(Mu-
Knielingetal.2009),ortocopingwithPS(Bowmanetal.2004;Mar- hammadandKolb2011,2012).Accordingly,corticalspinedensity
roccoetal.2012).RecurrentPSacrossgenerationsmayparticular- intherighthemisphereandskilledreachingmovementperform-
ly favor the development of stress tolerance or resilience. ance were positively correlated in stressed males but not in
MultigenerationalStressPromotesDendriticReorganizationandLeft-Handedness Ambeskovicetal. | 2135
females.OtherstudieshaveshownthatPSexposuremodifiesthe Alonso SJ, Navarro E, Santana C, Rodriguez M. 1997. Motor
neuronalmorphologyofhippocampusandnucleusaccumbens lateralization, behavioral despair and dopaminergic brain
aswell(Mychasiuketal.2012).Thus,theeffectsofmultigener- asymmetryafterprenatalstress.PharmacolBiochemBehav.
ationalstressmaynotbelimitedtotheparietalcortexandmay 58(2):443–448.
affectavarietyofotherareasandbehaviors. AnnettM,EglintonE,SmytheP.1996.Typesofdyslexiaandthe
Alterationsinneuronalplasticitymaybeduetotoxiceffects shifttodextrality.JChildPsycholPsychiatry.37(2):167–180.
of excess circulating glucocorticoids (McEwen and Magarinos AnwayMD,LeathersC,SkinnerMK.2006.Endocrinedisruptor
1997;Takahashi1998;Wellman2001;CookandWellman2004; vinclozolin induced epigenetic transgenerational adult-
SecklandMeaney2004;Brownetal.2005)andprolongedHPA onsetdisease.Endocrinology.147(12):5515–5523.
axisresponse(Koeniget al. 2005; Shanskyet al. 2009; Radley ArmourJA,DavisonA,McManusIC.2014.Genome-wideassoci-
etal.2013).Mechanismshavebeenproposedthatcontributeto ationstudyofhandednessexcludessimplegeneticmodels.
neuronaldamageafterexposuretoPS.First,increasedcortico- Heredity.112:221–225.
steronecirculationisassociatedwithstress-induceddecrease BabenkoO,GolubovA,IlnytskyyY,KovalchukI,MetzGA.2012.
D
inneurotrophins,particularlybrain-derivedneurotrophicfactor Genomicandepigenomicresponsestochronicstressinvolve o
w
in various brain regions (Smith et al. 1995; Murakami et al. miRNA-mediatedprogramming.PLoSOne.7(1):1–17. n
lo
2005;Uysaletal.2011;Bustamanteetal.2013).Second,PSmay BabenkoO,KovalchukI,MetzGA.2015.Stress-inducedperinatal a
d
alter microtubule-associated protein 2 synthesis in the brain and transgenerational epigenetic programming of brain ed
(Barrosetal.2006),resultinginimpairedsynaptogenesisand development and mental health. Neurosci Biobehav Rev. fro
neurite outgrowth (Bustamante et al. 2013). Additionally, the 48:70–91. m
h
mechanismthatexplainssexdifferencesmayinvolvesuppres- BarrosVG,Duhalde-VegaM,CaltanaL,BruscoA,AntonelliMC. ttp
smioannoeftlaalt.e2p0r0e4n).aAtallteterasttiiocunlsairnananddrorogegnensehcorremtioonneinsmduarliensg(Beaorwly- 2th0e06a.dAulsttrroatcybtrea-inn.eJuNroenurvousclnieRreasb.i8li3t(y5):t7o87p–r8e0n0a.tal stress in s://a
c
a
developmenthaveprofoundeffectsonbraindevelopment,fem- BlossEB,JanessenWG,OhmDT,YukFJ,WadsworthS,SaardiKM, d
e
inizingmalesandmasculinizingfemales(Bowmanetal.2004; McEwenBS,MorrisonJH.2011.Evidenceforreducedexperi- m
Zuenaetal.2008).Sincerecentgenome-widesequencingfailed ence-dependentdendriticspineplasticityintheagingpre- ic.o
toidentifyanyconclusivelinkagetoaspecificlocusassociated frontalcortex.JNeuroendocrinol.31:7831–7839. up
withhandedness(Armouretal.2014),theimportanceofenviron- BowmanRE,MacLuskyNJ,SarmientoY,FrankfurtM,GordonM, .co
m
mentalfactorsandassociatedepigeneticprograming,suchas LuineVN.2004.Sexuallydimorphiceffectsofprenatalstress
/c
geneexpressionregulationthroughmicroRNAsandDNAmethy- oncognition,hormonalresponses,andcentralneurotrans- e
lation(ReltonandDavey-Smith2010;Yaoetal.2014;Babenko mitters.Endocrinology.145(8):3778–3787. rco
seitzaeld..20T1h5e),pofresseexn-stpsetcuifidcybtrhaeinredfoerveelsouppmpeonrttsisthfuertohbesreermvapthioan- BrowalnteSrsMd,eHnednrnitiincgmS,oWrpehlolmloagnyCinL.r2a0t0m5.eSdhiaolt-ptreerfmro,nmtailldc-ostrrteesxs. r/article
thatleft-handednessispassedonthroughthematernallineage CerebCortex.15:1714–1722. -a
b
(McManus1991;Annettetal.1996)intheabsenceofDNAmodi- Bustamante C, Henríquez R, Medina F, Reinoso C, Vargas R, s
fications(Armouretal.2014). PascualR.2013.Maternalexerciseduringpregnancyamelio- trac
Thepresentstudysuggeststhat4generationsofdirectexpos- ratesthepostnatalneuronalimpairmentsinducedbypre- t/2
7
uretoPSisassociatedwithahemisphericdominanceshiftto natalrestraintstressinmice.IntJDevNeurosci.31(4):267–273. /3
favorleft-handednessinmales,thusgeneratingamomentum CampDM,RobinsonTE,BeckerJB.1984.Sexdifferencesintheef- /21
2
todevelopnewbehavioraltraits.Thesetraitsmaybepassedon fectsofearlyexperienceonthedevelopmentofbehavioral 6
tosubsequentgenerationsthroughthematernallineageeven andbrainasymmetriesinrats.PhysiolBehav.33(3):433–439. /30
5
intheabsenceofrecognizablePSandintheabsenceofDNAse- CanuMH,DarnaudéryM,FalempinM,MaccariS,ViltartO.2007. 6
3
quencechanges.Thus,transgenerationalepigeneticinheritance Effectofhindlimbunloadingonmotoractivityinadultrats: 07
may provide a primary mechanism for heritable patterns in impactofprenatalstress.BehavNeurosci.121(1):177–185. by
handednessandlaterality. CaoX,LaplanteDP,BrunetA,CiampiA,KingS.2014.Prenatalma- gu
e
ternalstressaffectsmotorfunctionin5½-yearoldchildren: s
Funding projecticestorm.DevPsychobiol.56(1):117–125. t on
Cook SC, Wellman CL. 2004. Chronic stress alters dendritic 1
The authors acknowledge support by the Alberta Innovates- morphology in rat medial prefrontal cortex. J Neurobiol. 0 A
H“PeraelttehrmSBoilrutthioannsdHIneateltrhdyisOciuptlcionmareys”T(Gea.Am.S.MGr.)a,ngtran#2ts0f0r7o0m05A9l5- Cul6h0a:m236JC–,2P4r8a.tesi-CavinaC,SinghalA.2006.Theroleofparietal pril 20
bertaInnovates-HealthSolutions(G.A.S.M.),theNaturalSciences 1
cortexinvisuomotorcontrol:whathavewelearnedfromneu- 9
and Engineering Research Council of Canada (B.K., G.A.S.M.), roimaging?Neuropsychologia.44(13):2668–2684.
andtheCanadianInstitutesofHealthResearchgrant#102652
CulhamJC,ValyearKF.2006.Humanparietalcortexinaction.
(G.A.S.M.).G.A.S.M.isanAHFMRSeniorScholar. CurrOpinNeurobiol.16:205–212.
DarnauderyM,MaccariS.2008.Epigeneticprogrammingofthe
Notes
stressresponseinmaleandfemaleratsbyprenatalrestraint
TheauthorsthankCathyCarollandByronDentforexcellentas- stress.BrainResRev.57(2):571–585.
sistancewiththeexperiments.ConflictofInterest:Nonedeclared. Diamond MC, Dowling GA, Johnson RE. 1981. Morphologic
cerebral cortical asymmetry in male and female rats. Exp
Neurol.71(2):261–268.
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