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2025 CONFERENCE

The Changing Brain

August 18 – 20, 2025 Irvine, California, USA

• The Evolving Brain

• The Learning Brain

• States of the Brain

• The Developing Brain

• The Dynamic Brain

• The Disordered Brain

Paola Arlotta, Harvard University

Xiangmin Xu, University of California, Irvine

Confirmed Speakers: Conference Organizers:

Ishmail Abdus-Saboor, Columbia University

Paola Arlotta, Harvard University

Carlos Brody, Princeton University

Beth Buffalo, University of Washington

Edward Chang, UCSF

Anne Churchland, UCLA

Yang Dan, University of California, Berkeley

Catherine Dulac, Harvard University

Guoping Feng, MIT

Zhigang He, Harvard University

Hailan Hu, Zheijang University, China

Josh Huang, Duke University

Sten Linnarsson, Karolinska Institutet, Sweden

Liqun Luo, Stanford University

Hongkui Zeng, Allen Institute for Brain Science

Guillermina López-Bendito, UMH-CSIC, Spain

Liqun Luo, Stanford University

Michelle Monje, Stanford University

John Ngai, National Institutes of Health

Tom Nowakowski, UCSF

Vanessa Ruta, Rockefeller University

Bernardo Sabatini, Harvard University

Nelson Spruston, Howard Hughes Medical Institute

Karel Svoboda, Allen Institute for Neural Dynamics

Li-Huei Tsai, MIT

Pierre Vanderhaeghen, Leuven Brain Institute of Technology

Hongkui Zeng, Allen Institute of Brain Science

Larry Zipursky, UCLA

Editor-in-Chief

JulioLicinio, StateUniversityofNewYork,UpstateMedicalUniversity,Syracuse,NewYork13210,USA

PublishingManager

Ma-LiWong, StateUniversityofNewYork,UpstateMedicalUniversity,Syracuse,NewYork13210,USA

EditorialBoard

SchahramAkbarian, IcahnSchoolofMedicineatMountSinai,NewYork,NewYork10029,USA

DanielBarbosa, MedicalUniversityofSouthCarolina,Charleston,SouthCarolina29425,USA

TatianaBarichello, TheUniversityofTexasHealthScienceCenteratHouston,Houston,Texas77054,USA

HilaryBlumberg, YaleSchoolofMedicine,NewHaven,Connecticut06510,USA

StefanR.Bornstein, TUDDresdenUniversityofTechnology,01307Dresden,Germany

EmilianaBorrelli, UniversityofCalifornia,Irvine,California92697,USA

PaoloBrambilla, UniversitàdegliStudidiMilano,20122Milan,MI,Italy

JoshuaC.Brown, HarvardMedicalSchoolandMcLeanHospital,Belmont,Massachusetts02478,USA

AnnamariaCattaneo, UniversitàdegliStudidiMilano,20133Milan,MI,Italy

UdoDannlowski, UniversityofMünster,D-48149Münster,Germany

HamedEkhtiari, UniversityofMinnesotaMedicalSchool,Minneapolis,Minnesota55454,USA MassimoFilippi, Vita-SaluteSanRaffaeleUniversity,20132Milano,MI,Italy

KostasN.Fountoulakis, SchoolofMedicine,AristotleUniversityofThessaloniki,Thessaloniki,Greece SamGandy, IcahnSchoolofMedicineatMountSinai,NewYork,NewYork10029,USA

RubenGur, UniversityofPennsylvania,Philadelphia,Pennsylvania19104,USA

CaseyH.Halpern, PerelmanSchoolofMedicine,UniversityofPennsylvania,Philadelphia,Pennsylvania19104,USA

AlanG.Harris, NewYorkUniversityGrossmanSchoolofMedicine,NewYork,NewYork10016,USA

IanB.Hickie, UniversityofSydney,BrainandMindInstitute,Camperdown,NewSouthWales2050,Australia

AtsushiKamiya, JohnsHopkinsSchoolofMedicine,Baltimore,Maryland21287,USA

KeithM.Kendrick, UniversityofElectronicScienceandTechnologyofChina,Chengdu,China

RonaldC.Kessler, HarvardMedicalSchool,Boston,Massachusetts02115,USA

AdrienneCarolLahti, UniversityofAlabamaatBirmingham,Birmingham,Alabama35294,USA

TatiaM.C.Lee, TheStateKeyLaboratoryofBrainandCognitiveSciences,UniversityofHongKong,HongKongSAR JohnMantsch, MedicalCollegeofWisconsin,Milwaukee,Wisconsin53226,USA

ValeriaMondelli, InstituteofPsychiatry,PsychologyandNeuroscience,King’sCollege,London,SE59RT,UK

RuthO’Hara, StanfordUniversity,Stanford,California94305,USA

AnilkumarPillai, UniversityofTexasHealthScienceCenteratHouston,Houston,Texas77054,USA

JelenaRadulovic, AlbertEinsteinCollegeofMedicine,Bronx,NewYork10461,USA

GavinReynolds, Queen’sUniversityBelfastandSheffieldHallamUniversity,UK

MarisaRoberto, TheScrippsResearchInstitute,LaJolla,California92037,USA

IsabelleM.Rosso, HarvardMedicalSchoolandMcLeanHospital,Belmont,Massachusetts02478,USA

ZoltanSarnyai, MargaretRoderickCentreforMentalHealthResearch,JamesCookUniversity,Townsville,Queensland4811,Australia

JonathanSavitz, LaureateInstituteforBrainResearch,Tulsa,Oklahoma74136,USA

AkiraSawa, JohnsHopkinsSchoolofMedicine,Baltimore,Maryland21287,USA

HelenBlairSimpson, ColumbiaUniversityandNewYorkStatePsychiatricInstitute,NewYork,NewYork10032,USA

NunoSousa, SchoolofMedicine,UniversityofMinho,4710-057Braga,Portugal

WeihongSong, WenzhouMedicalUniversity,Wenzhou,325015,ChinaandUniversityofBritishColumbia,Vancouver,BritishColumbiaV6T1Z3,Canada Li-HueiTsai, PicowerInstitute,MassachusettsInstituteofTechnology,Cambridge,Massachusetts02139,USA

KueiY.Tseng, UniversityofIllinoisChicago–CollegeofMedicine,Chicago,Illinois60612,USA

LucinaUddin, UniversityofCalifornia,LosAngeles,California90095,USA

GuidovanWingen, UniversityofAmsterdam,Amsterdam,1100DD,TheNetherlands

RogerWalz, UniversidadeFederaldeSantaCatarina,Florianópolis,SantaCatarina88040-970,Brazil

YunleiYang, AlbertEinsteinCollegeofMedicine,Bronx,NewYork10461,USA

Wei-DongYao, StateUniversityofNewYork,UpstateMedicalUniversity,Syracuse,NewYork13210,USA

KeqiangYe, ShenzhenInstituteofAdvancedTechnology,ChineseAcademyofSciences,Shenzhen,518055,China

AllanH.Young, InstituteofPsychiatry,PsychologyandNeuroscience,King’sCollegeLondon,London,SE58AF,UK

TifeiYuan, ShanghaiMentalHealthCenter,BrainHealthInstitute,200030Shanghai,China

MoneZaidi, IcahnSchoolofMedicineatMountSinai,NewYork,NewYork10029-5674,USA

BrainMedicine ispublishedbyGenomicPress.

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BrainMedicine

Volume1 Number2 March2025

EDITORIAL

Medication-inducedsteroldisruption:Anoverlookedthreattobraindevelopmentandpublichealth

INNOVATORS&IDEAS:RISINGSTARS

MunirGunesKutlu:Exploringtheneuralmechanismsoflearningand socialbehaviors–Ascientist’sjourneyandperspective

AlessandraBorsini:Whatneuroinflammationhastodowithdepressionandhownutritioncanplayabeneficialrole

UdoDannlowski:Brainstructureandfunctioninthelong-termcourseofmentaldisorders

VickiL.Clifton:Stress,sex,andtheplacenta:itsroleinfetalandchilddevelopment

VickiL.Clifton

EuripedesC.Miguel:Riskfactorsforobsessive-compulsiveandothermentalhealthdisordersandtheirtreatmentandpublicpolicy implications

AnnamariaCattaneo:Threemainquestions:Stress,mental,andphysicalhealth:Isthegutmicrobiomethekey?Whicharethebiological mechanismsdrivingperinataldepression,andhowdotheyaffectthe mentalandphysicalhealthoftheoffspring?Pharmacologicaland non-pharmacologicalinterventionsinreducingtheriskofdevelopingmooddisordersorinimprovingsymptomatology:Isinflammationthe keydriver?

NancyJaneRothwell:Braininflammationandthepathtoleadership

Sterolbiosynthesisdisruptionbycommonprescriptionmedications:criticalimplicationsforneuraldevelopmentandbrainhealth

Maternalimmuneactivationimpairshippocampalpyramidalneuronexcitabilityinnewbornratoffspring:Implicationsfor neurodevelopmentaldisorders

CoverArt

Aconceptualvisualizationdepictingtheimpactofmaternalimmuneactivationonhippocampalneurondevelopment.Alaboratoryratisshownholding atransparent modelofabrainwithvisibleneuralpathways,symbolizingtherelationshipbetweenmaternalinfectionduringpregnancyandalteredneuronalexcitabilityinoffspring.The warmambertonesoftheratcontrastwiththetranslucentpink-huedbrainmodel,representingthedelicatebalanceofneurotransmissionaffectedbyprenatalimmune challenges.Theetherealglowextendingfromthebrainhighlightstheglutamatergicpathwaysparticularlyvulnerabletomaternalimmuneactivation,withconnections illustratedflowingintocrucialhippocampalregions.Thisimagereflectsthefindingspresentedin“Maternalimmuneactivationimpairshippocampalpyramidalneuron excitabilityinnewbornratoffspring:Implicationsforneurodevelopmentaldisorders”byLuciaMoravcikovaetal.onpages46-52inthisissue.

Coverdesigngeneratedthroughextensiveanditerativehuman-AIcollaborationusingClaudebyAnthropicandGrok(createdbyxAI)AIassistants.Thefinalcoverislicensed underCreativeCommonsAttribution-NonCommercial-NoDerivatives4.0InternationalLicense(CCBY-NC-ND4.0).Thiscovermaybereproducedwithoutpermissionunder thetermsofthislicense,providedappropriatecreditisgiventoGenomicPressandthecontentisnotmodifiedorusedforcommercialpurposes. Copyright©2025GenomicPress.Allrightsreserved.

Thisissueisnowavailableat https://url.genomicpress.com/2p895a75

EDITORIAL

Medication-inducedsteroldisruption:Anoverlookedthreattobraindevelopment andpublichealth

©TheAuthor(s),2025.ThisarticleisunderexclusiveandpermanentlicensetoGenomicPress

BrainMedicine March2025;1(2):1–3;doi: https://doi.org/10.61373/bm025d.0041

Scientificprogressoftendemandsthatwerevisitcomfortableassumptions.Occasionally,newdatadomorethaninform—theyprovoke.ThearticlebyKoradeandMirnicsinthisissueof BrainMedicine isarareand necessaryprovocation(1).Itunveilsasilenthazard:thatabroadarray ofwidelyprescribeddrugs,developedandapprovedfordisparateconditions,mayconvergeonasharedoff-targettoxicity.Thesemedications disruptsterolbiosynthesis—anessentialmetabolicprocessunderpinningneuraldevelopment—anddosoinwaysthatmirrorthebiochemical footprintofdevastatinggeneticsyndromes.

Cholesterol,amoleculethathascaptivatedscientificinquiryfor generations,standsamongthemostintenselystudiedcompoundsin history—asevidencedbythethirteenNobellaureateswhosedistinguishedcareersweresignificantlydevotedtounravelingitsmysteries(2).

Whileclinicaldiscourseoftenportrayscholesterolasacardiovascularvillain,itsroleinthebrainrevealsaprofoundlydifferentnarrative.Withinthisdelicateneurallandscape,cholesterolemergesnotas anadversarybutasanindispensableelement—afundamentalcornerstoneofcerebralarchitecturewithoutwhichlifeitselfcouldnotexist. Thebraincontainsadisproportionate25%ofthebody’scholesterol,despiteaccountingforonly2%oftotalmass(3).Thisisnotincidental—itis themolecularscaffoldinguponwhichbrainarchitectureandconnectivityarebuilt.Cholesteroliscentraltosynapseformation,axonalguidance,dendriticarborization,andmyelinintegrity.Cholesterolandsphingolipids,embeddedwithinmembraneraftmicrodomains,serveascritical signalingmoleculesthatfacilitateneuronaldifferentiationandsynaptogenesis,makingtheirpropermetabolismessentialformaintainingbrain functionandpreventingneurologicalandneurodegenerativediseases (4).Itisactuallyfascinatingthattwodecadesagotherewasaracetoidentifyaglia-derivedfactorthatstronglypromotessynapsedevelopmentin culturesofpurifiedCNSneurons.MauchetalpublishedapaperinScience in2001identifyingthisfactorascholesterolcomplexedtoapolipoprotein E-containinglipoproteins(5).Itisthereforenotsurprisingthatcholesterolhomeostasisissocriticalthatthebrainmaintainsanautonomous cholesteroleconomy,isolatedbytheblood-brainbarrierfromsystemic fluctuations.

Fromearlygestationtolateadulthood,thisself-containedbiosyntheticmachinerysustainscognitiveandneuralfunction.Geneticdisruptionsofthispathway—suchasinSmith-Lemli-OpitzSyndrome(SLOS), lathosterolosis,desmosterolosis,CDPX2,CHILDsyndrome,SC4MOLdeficiency,andHEMdysplasia,allcausedbypathogenicvariantsincriticalsterolbiosynthesisgenes—producecatastrophicdevelopmental outcomes(6, 7).Thishaslongservedasawarning:perturbingsterol homeostasisinthedevelopingbrainisnotcompatiblewithhealth.

KoradeandMirnicshaveastrongrecordinthisarea(8)andwhat theirworkhashighlightedisprofoundlyunsettling.Over30FDAapproveddrugs—amongthem,psychiatricmainstayssuchasaripiprazole,trazodone,haloperidol,andcariprazine—havebeenshowntoinhibit DHCR7.Thisinhibitionraisesthelevelsof7-dehydrocholesterol(7-DHC), suppressescholesterolsynthesis,andgeneratesasterolprofileindistinguishablefromthatseenincongenitalmetabolicdisorders.Thisisnota

Received:25March2025.Revised:3April2025.Accepted:5April2025. Publishedonline:22April2025.

hypotheticalconcern—itisempiricallyvalidatedincelllines,rodentmodels,andhumanbloodsamples.Notably,acomprehensive,systemicreview byBollandandTatonettiinvestigatedthefetaloutcomesfollowingprenatalexposuretoDHCR7modulators,andconcededthat “first-trimester exposuretoDHCR7inhibitorsresultedinoutcomessimilartothoseof knownteratogens” inhumans(9).

Evenmorealarmingisthefactthat7-DHCisnotinert.Itisbiochemicallyvolatile—themostoxidizablelipidknowninhumanswithareactivity 200timesgreaterthancholesterol.ItsaccumulationresultsintheformationoftoxicoxysterolssuchasDHCEO,whichimpairneuriteoutgrowth, altercellularmorphology,anddamagethefundamentalarchitectureof neuronalconnectivity(7, 10, 11).Thesearenotesotericmoleculardetails. Thesearemechanismsofharm.

Thescenariobecomesevenmoreconcerningwhenoneconsidersthe effectofpolypharmacy.Inexperimentalsystems,combinationsoftwoor moreDHCR7-inhibitingdrugselevate7-DHCtolevelsmorethan15times abovecontrol(12, 13).Pregnantwomentakingmultiplesuchmedications exhibitedthehighestconcentrationsof7-DHCintheirblood.Theseeffectsarenotadditive—theyareoftensynergistic.Andtheyarehappening undertheradarofourregulatorysystems.

Here,weencounterapivotalfailureinmodernpharmacology:regulatorydrugapprovalisbasedalmostexclusivelyonsingle-agentsafety data,despitetheclinicalrealitythatithasbecomeincreasinglycommon forpatientstorelyontheuseofmultipleprescriptionmedications(14, 15).Preclinicaltoxicology,clinicaltrials,post-marketingsurveillance—all assumethatmedicationswillbetakeninisolation.Butthatassumption collapsesinreal-worldclinicalsettings.Mostpatients—especiallythose withchronicpsychiatricormedicalconditions—takemultipledrugssimultaneously.Yetthesecombinationsaretypicallynottestedtogether, noteveninanimals,letaloneinpregnantwomenorinfants.Thisisablind spotofbreathtakingscale.

WhatKoradeandMirnicsrevealisespeciallydisturbinginthiscontext. Ifindividualdrugscanmimicametabolicdisorder,whatarewetomake oftheirinteractions?Weareprescribingmolecularcocktailswithnoempiricalknowledgeofhowtheyalterdevelopmentalneurochemistry.The combinationsthataremostcommoninclinicalpracticearealsotheleast studied.Thisisnotanoversight.Itisasystemicdesignflawinhowwe evaluatedrugsafety(see Fig.1).

Andthevulnerablepopulationsarenothypothetical.Atleast1–3%of thegeneralpopulationcarrysingle-alleleDHCR7mutations(16).These individualsaretypicallyasymptomatic,buttheyliveontheedgeofsterol balance.Asingleprescriptioncantipthatbalance.Twoormoremaysend themintoabiochemicalstatethatresemblesSLOS.Neithertheclinician northepatientwouldeverknow.

Moreover,thedevelopmentalwindowsofvulnerabilityextendwell beyondgestation.Myelination,glialproliferation,synapticpruning,and hormonalshiftsoccurthroughinfancy,childhood,andadolescence(17). Thesestagesaremarkedbyhighdemandforsterol-derivedsignaling andmembranecomponents(18).Thesterol-disruptingeffectsofdrugs administeredduringtheseperiodsmaymanifestnotasmalformations

Figure1. Medication-induceddisruptionofsterolbiosynthesisposessignificantriskstobraindevelopmentandfunction.Atthetopcenterofthisschematic lies thecholesterolmolecule—ananchorofneurobiologicalintegrity—flanked bythestructureofhaloperidolembeddedwithinthebrain,exemplifying oneofover 30FDA-approvedcompoundsknowntoinhibitDHCR7.Theseagents,manyofwhichareorallyadministeredandprocessedthroughthegastrointestinal–hepatic axis,initiatebiochemicaldisruptionsattheleveloffirst-passmetabolism,alteringsterolhomeostasisbeforethecompoundsevenreachthecentralnervous system.Theresult:accumulationoftoxicprecursorssuchas7-dehydrocholesterol(7-DHC)andtheirconversionintohighlyreactiveoxysterols(topright),with well-establishedneurotoxicpotential.Ontheleft,aDNAstrandsignalsgeneticvulnerability,whichcanamplifythesepathologicalcascades—particularlyduring periodsofneurodevelopmentalsensitivity(lowerright).Thediversearrayofmedications(pills,upperleft)underscoresthewidepharmacologic footprintof thisoff-targeteffect,raisingseriousconcernsaboutadditiveorsynergistictoxicityinthecontextofpolypharmacy.Takentogether,thismechanism—once overlooked—demandsurgentattentionasapressingpublichealthconcern,particularlyfordevelopingbrainsandgeneticallysusceptiblepopulations.

butassubtler,chronic,functionalimpairments:cognitivedelay,emotionaldysregulation,behavioraldisturbance.Wearenottrackingthese outcomes.Wearenotevenlooking.

Theimplicationsareimmense.Thepharmaceuticalindustrymustimmediatelyincorporatesterolbiosynthesisscreeningintoalldevelopmentalsafetyassessments.Regulatoryagenciesmustabandonthefictionof monotherapytestingandrequireatleastsomemodelingofcommondrug combinations.Clinicaltrialdesignsmustevolvetoreflectthemessyreal-

ityofmodernmedicine.Andpost-marketingsurveillancemustincludenot onlyshort-termadverseeventsbutalsolong-termdevelopmentaland behavioralendpoints.

Clinicians,too,mustrespondwithheightenedvigilance.Genetic testingforDHCR7pathogenicvariants(andotherpost-lanosterol biosynthesisenzymes)shouldbeconsideredinwomenofchildbearingagewhorequiremedicationsknowntodisruptsterolsynthesis. Polypharmacyinvolvingsuchdrugsshouldbeavoidedduringpregnancy

wheneverpossible.Patientcounselingmustincludediscussionsofthese risks—especiallyinpsychiatriccare,wherethesemedicationsareoften initiatedearlyandcontinuedlong-term.

KoradeandMirnicsarenotofferingamerecaution.Theyarechallengingtheveryarchitectureofhowwethinkaboutdrugsafety.Theproblem theyhighlightisnotthatafewdrugshaveanunfortunatesideeffect.Itis thatourentiresystemofmedicationevaluationignoresthecomplexities ofdevelopmentalbiology,geneticsusceptibility,andreal-worldprescribingpatterns.

Wemustnolongerregardsterolbiosynthesisasanobscuremetabolic pathway.Itisacentralaxisofbraindevelopment.Andthedisruption ofthataxis—whetherbymutation,medication,orboth—hasconsequencesthatareprofound,irreversible,andavoidable.Despitedecades ofpharmaceuticaldevelopment,welackacomprehensivecatalogueof FDA-approvedmedicationswithsterol-inhibitingsideeffects—acritical knowledgegapthatmayobscureiatrogenicdisruptionsofthisessential pathway.

Thisisacalltoaction.Notsomeday.Now.

References

JulioLicinio1

1 Editor-in-Chief, BrainMedicine,GenomicPress,NewYork, NewYork10036,USA

e-mail: julio.licinio@genomicpress.com

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16.Witsch-BaumgartnerM,LofflerJ,UtermannG.MutationsinthehumanDHCR7gene. HumMutat.2001;17(3):172–82.DOI: 10.1002/humu.2.PMID:11241839

17.SpearLP.Adolescentneurodevelopment.JAdolescHealth.2013;52(2Suppl2):S7–13. DOI: 10.1016/j.jadohealth.2012.05.006.PMID:23332574;PMCID: PMC3982854

18.PeeplesES,MirnicsK,KoradeZ.Chemicalinhibitionofsterolbiosynthesis. Biomolecules.2024;14(4):410.DOI: 10.3390/biom14040410.PMID:38672427; PMCID: PMC11048061

Publisher’snote: GenomicPressmaintainsapositionofimpartialityandneutralityregardingterritorialassertionsrepresentedinpublishedmaterialsandaffiliationsofinstitutionalnature.Assuch,wewillusetheaffiliationsprovidedbytheauthors,withouteditingthem.Suchusesimplyreflectswhattheauthorssubmitted tousanditdoesnotindicatethatGenomicPresssupportsanytypeofterritorial assertions.

OpenAccess. ThisarticleislicensedtoGenomicPressundertheCreativeCommonsAttribution-NonCommercial-NoDerivatives4.0InternationalLicense(CCBY-NC-ND4.0).Thelicensemandates:(1)Attribution:Credit mustbegiventotheoriginalwork,withalinktothelicenseandnotificationofany changes.Theacknowledgmentshouldnotimplylicensorendorsement.(2)NonCommercial:Thematerialcannotbeusedforcommercialpurposes.(3)NoDerivatives: Modifiedversionsoftheworkcannotbedistributed.(4)Noadditionallegalortechnologicalrestrictionsmaybeappliedbeyondthosestipulatedinthelicense.Public domainmaterialsorthosecoveredbystatutoryexceptionsareexemptfromthese terms.Thislicensedoesnotcoverallpotentialrights,suchaspublicityorprivacy rights,whichmayrestrictmaterialuse.Third-partycontentinthisarticlefallsunderthearticle’sCreativeCommonslicenseunlessotherwisestated.Ifuseexceeds thelicensescopeorstatutoryregulation,permissionmustbeobtainedfromthe copyrightholder.Forcompletelicensedetails,visit https://creativecommons.org/ licenses/by-nc-nd/4.0/.Thelicenseisprovidedwithoutwarranties.

INNOVATORS&IDEAS:RISINGSTAR

MunirGunesKutlu:Exploringtheneuralmechanismsoflearningand socialbehaviors–Ascientist’sjourneyandperspective

©GenomicPress,2024.The“GenomicPressInterview”frameworkisprotectedundercopyright.Individualresponsesarepublishedunderexclusive andpermanentlicensetoGenomicPress.

BrainMedicine March2025;1(2):4–7;doi: https://doi.org/10.61373/bm024k.0136

Keywords: Learningandmemory,socialcognition,dopamine,striatum, computationalmodeling,learningtheory

Dr.Munir“Gunes”Kutlu,AssistantProfessorattheCenterfor SubstanceAbuseResearch(CSAR)andtheDepartmentofNeural SciencesatTempleUniversityLewisKatzSchoolofMedicine, investigatestheneuralmechanismsunderlyingassociativelearning, mainlyfocusingonreward,fear,andsocialinteraction.Drawingfrom hiscomputationalneurosciencetrainingatDukeUniversityand postdoctoralworkatTempleandVanderbiltUniversities,Dr.Kutlu combinessystemsneuroscience,computationalapproaches,and behavioralanalysistounderstandhowourbrainsprocess environmentalassociationsandhowtheseprocessescanbecome maladaptiveindiseasestates.Hislaboratory,dedicatedto“bridging thebrain-behaviorgap,”fostersacollaborativeenvironmentthat nurturesthenextgenerationofneuroscientistswhilepursuing innovativeneuralcircuitanalysisapproachesinrewardandaversive learningcontexts.InthisGenomicPressinterview,Dr.Kutlushareshis insightsonthesefascinatingaspectsofbehavioralneuroscienceand hislaboratory’smissiontoadvanceourunderstandingofneural circuitfunctioninhealthanddisease.

Part1:MunirGunesKutlu–LifeandCareer

Couldyougiveusaglimpseintoyourpersonalhistory,emphasizing thepivotalmomentsthatfirstkindledyourpassionforscience?

Igrewupwithanaturalcuriosityabouthowthingswork,butmytruepassionforsciencewasignitedduringmyundergraduatestudieswhenItook myfirstneurosciencecourse.There,Iwasfascinatedbythecomplexities ofthebrainandthepotentialtounderstandbehaviorsthroughneural mechanisms.Eachstepofmyjourney,fromobtainingmyPh.D.throughmy postdoctoraltrainingtostartingmyownlab,hasbeenfueledbyadesire touncoverhowthebraindrivesbehavior.Iconductedmyfirstresearch projectonunderstandinglearningmechanismsinhumans.Thisexperienceshowedmethepowerofcombiningbehavioralanalysiswithcomputationalmodeling,shapingmyfutureresearchpathtowardunderstandingtheneuralcircuitsunderlyinglearningandmemory.

Wewouldliketoknowmoreaboutyourcareertrajectoryleadingupto yourcurrentrole.Whatdefiningmomentschanneledyoutowardthis opportunity?

IgrewupinIstanbul,Turkiye,whereIreceivedmybachelor’sdegreein psychologyatBilgiUniversity.AtBilgi,Iconductedathesisprojectonthe mathematicalmodelsofassociativelearningasanundergraduate.Followingmyinterestinthetheory,IdidmyPh.D.atDukeUniversityunder mymentor,Dr.NestorSchmajuk,studyingthetheoryandcomputational modelsoflearningandmemory.Thesecondpivotalmomentinmycareer wasmypostdoctoraltrainingunderDr.ErinCalipariatVanderbiltUniversity,whereIwastrainedinin-vivoneuralrecordingtechniques,which allowedmetoexaminetheneuralcircuitssupportingthelearningand

Received:30December2024.Accepted:2December2024. Publishedonline:17December2024.

memorymechanismsIpreviouslystudiedatthetheoreticalandbehaviorallevels.Asaresult,inmylabatTempleUniversityLewisKatzSchool ofMedicine,Istudylearningandmemoryaswellassocialbehaviorsin severaldifferentanalyticallevels,suchasfromtheorytobehaviorand circuitbiology.

Pleasesharewithuswhatinitiallypiquedyourinterestinyour favoriteresearchorprofessionalfocusarea. Myfascinationwiththebrain’sabilitytoencodeinformationbeganduringmyundergraduatestudieswhenIwasintroducedtoassociativelearningmodelsliketheRescorla-WagnerandPearce-Hallmodels.Exploring howthesemodelspredictlearningthroughassociationsbetweenstimuli andresponsessparkedmycuriosityabouttheneuralmechanismsunderlyingtheseprocesses.Ilikedtheideathatcomplexbehaviorscouldbe

Figure1. MunirGunesKutlu,PhD,TempleUniversityLewisKatzSchoolof Medicine,USA.

understoodthroughrelativelysimplemathematicalframeworks,which ledmetodelvedeeperintohowthebrainimplementsthesecomputationalprinciples.Thisearlyexposuretoassociativelearningtheorieslaid thefoundationformyresearch,whichfocusesonunderstandinghowthe brainencodes,processes,andretainsinformation,especiallyinthecontextofreward-basedlearningandsocialinteractions.Itwasadefining momentthatsetthecourseformyfutureworkinneuroscience.

Whatimpactdoyouhopetoachieveinyourfieldbyfocusingon specificresearchtopics?

TheprimaryimpactIhopetoachieveinmyfieldistouncoverhowour brainsperformfundamentalcalculationsaboutoursurroundings,particularlyinmakingdecisionsaboutrewardsanddangers.Myresearch aimstodecodetheneuralprocessesthatenableustoassessourenvironment,predictoutcomes,andmakeadaptivedecisions.Byfocusing onassociativelearningandneuralencodingmechanisms,Istrivetounderstandhowthebraintransformssensoryinputsintomeaningfulpredictionsthatguidebehavior.Ultimately,mygoalistorevealhowneural circuitsintegrateinformationtoevaluaterisksandrewards,shedding lightontheunderpinningsofdecision-makingprocesses.Thisresearch hasthepotentialtoinformourunderstandingofmentalhealthconditionswherethesecomputationsgoawry,suchasanxiety,addiction,and socialdysfunction,pavingthewayfornewtherapeuticstrategies.

Pleasetellusmoreaboutyourcurrentscholarlyfocalpointswithin yourchosenfieldofscience?

Mycurrentscholarlyfocuscentersonassociativelearning,specifically howmemoriesareencodedandmaintainedinthebrainandhowthese processesinfluencedecision-makingwheninteractingwithourenvironmentsandothersinsocialsettings.Ourprimaryfocusistodiscoverwhere fundamentallearningandmemorycomputationssuchasnovelty,predictionerror,saliency,andattentionareencodedinthebrain.Wehavepublishedaseriesofmanuscriptsexaminingtheroleofdopaminereleasein thestriatumanditsroleinencodingpredictionerrorandsaliencyduringassociativelearning.Challengingthecurrentdogmaofdopaminergic informationencoding,wefoundthatdopaminereleaseinthenucleusaccumbenscoresignalsperceivedsaliency,anassociativelearningtermfor howsalientexternalstimuliareperceivedindependentoftheirphysical saliency.Similarly,weidentifiedvalence-freeinformationencodingpropertiesofD1andD2mediumspinyneuronsinthenucleusaccumbens.I continuethislineofworkinmylabandexpandittootherneurotransmittersystems,suchasacetylcholineandsingle-cellneuralensembles.

Iamalsoparticularlyinterestedinunderstandinghowneuralcircuits, includingthoseinthestriatum,adapttoexperiencesofsocialcompetitionandhowtheseadaptationsinfluencebehavioranddecision-making. Additionally,Iamexploringtheroleofdrugsofabuseinalteringthese processes.Stimulantssuchascocaineandnicotinecanprofoundlyaffect howmemoriesareformedandhowsocialdecisionsaremade,oftenleadingtomaladaptivebehaviorsthatimpairsocialfunctioning.Byexamining howthesesubstancesdisruptneuralplasticityandrewardsystems,my researchaimstouncoverthemechanismsthatunderlieaddictionandits impactonsocialcognition.Istudyhowsocialhierarchiesareestablished throughbehavioralparadigmsandhowenvironmentalandpharmacologicalfactorscanmodifythem.Bycombiningthesebehavioraltoolswith advancedneurotechnologies,suchasfiberphotometryforreal-timemonitoringofneurotransmitterrelease,Iaimtogainadeeperunderstanding ofhowassociativenaturalanddrug-inducedchangesinfluencelearning andmemoryprocessesinbrainfunction.Thisresearchhasbroadimplicationsforunderstandingaddiction,competition,andtheneuralbasisof socialbehavior.

Whathabitsandvaluesdidyoudevelopduringyouracademicstudies orsubsequentpostdoctoralexperiencesthatyouupholdwithinyour researchenvironment?

Duringmyacademicstudiesandpostdoctoralexperiences,Ideveloped asolidcommitmenttorigorouslyanalyzingdatafromvariousperspec-

tivesandanalyticallevelsbeforereachingconclusions.Thisapproach ensuresthatourfindingsarebothreliableandrobustwhilefostering adeeperunderstandingofthequestionsweseektoanswer.Inmyresearchenvironment,wechallengeourselvesnottoacceptcurrentdogmasaboutthebrainandbehavioratfacevalue.Instead,wecritically evaluatetheseprevailingideasthroughthelensofourdata,questioningassumptionsandexploringalternativeinterpretations.Thismindset encouragesinnovationandhelpsusuncoverinsightsthatmaydisrupt conventionalthinking.Byintegratingrigorousanalysiswithawillingness tochallengeestablishednorms,westrivetocontributetoamorenuancedandaccurateunderstandingofthebrainanditsrelationshipto behavior.

AtGenomicPress,weprioritizefosteringresearchendeavorsbased solelyontheirinherentmerit,uninfluencedbygeographyorthe researchers’personalordemographictraits.Arethereparticular culturalfacetswithinthescientificcommunitythatwarrant transformativescrutiny,oristhereacausewithinsciencethatdeeply stirsyourpassions?

Freethinkingisthecornerstoneofallscientificprogress.Theabilityto question,challengethestatusquo,andpushboundariesdrivesinnovationandleadstobreakthroughs.However,forsciencetotrulythrive,we mustensurethatfreethinkingisnotconfinedtoaselectgroupbutis accessibletoindividualsacrossborders,culturalidentities,andsocioeconomicboundaries.Transformativescrutinywithinthescientificcommunityisneededtodismantlebarriersthatlimitparticipation.Thereare untappedperspectivesandideasinregionsandcommunitiesthatneed accesstoresourcesoropportunitiestoengageinscientificdiscourse.By creatinganenvironmentwheremeritandcuriosityarethedrivingforces, weempowerindividualstocontributetheiruniqueinsightsandcreativity.Thisdiversityofthoughtenrichesthescientificprocessandensures thattheprogressweachievebenefitsallofhumanity,notjustaprivileged few.

Whatdoyoumostenjoyinyourcapacityasanacademicorresearch risingstar?

WhatImostenjoyinmyroleasanacademicandresearcheristhefreedom tobecreative,tothinkdeeply,andtoaskmeaningfulquestions.Theacademicenvironmentprovidesauniquespacewherecuriosityiscelebrated, allowingustoexplorenovelideas,challengeestablishedperspectives, andpursuequestionsthatinspireinnovativeapproaches.Thatsaid,this freedomisnotwithoutitschallenges.Fundingconcernscansometimes hindertheextenttowhichbold,exploratorysciencecanbepursued.The needtoalignresearchwithfundingprioritiesortosecureresourcesoftenimposescertainconstraintsoncreativeexploration.However,these challengesalsoinspireresilienceandingenuity,drivingmetofindinnovativewaystobalancecreativitywithpracticality.Evenwithintheselimitations,theabilitytoaskquestionsandseekanswersremainsoneofthe mostrewardingaspectsofmywork,fuelingmypassionfordiscoveryand progress.

Outsideprofessionalconfines,howdoyouprefertoallocateyour leisuremoments,orconversely,inwhatmannerwouldyouenvision spendingthesemomentsgivenachoice?

Outsideofmyprofessionallife,Ienjoyengaginginphysicalactivitiesthat challengebothmybodyandmind,suchasrockclimbing,asshownin Figure2.Itisarewardingwaytostayactiveandhealthywhilepushingmyselftoovercomeobstacles.IamalsoabigfanofTurkishsoccer,andasa proudsupporterofGalatasaray,Ilovefollowingtheirgamesandcheering themon.Aboveall,themostfulfillingwayIspendmytimeiswithmykids andfamily.Whetheritisplaying,exploring,orsimplyrelaxingtogether, thesemomentsbringmethegreatestjoyandhelpkeepmegrounded.My familyismybiggestsourceofhappinessandinspiration,andtheymake everydaymeaningful.

Figure2. GunesKutluscalingrockfacesinUtah’sdramaticlandscape.Beyondthelaboratory,hefindsbothchallengeandclarityinclimbing–apursuitthat demandsthesamefocusanddeterminationhebringstohisneuroscienceresearch.

Part2:MunirGunesKutlu–SelectedquestionsfromtheProust Questionnaire1

Whatisyourideaofperfecthappiness? Knowingmykidsarehappyandhealthy.

1 Inthelatenineteenthcentury,variousquestionnaireswereapopulardiversion designedtodiscovernewthingsaboutoldfriends.Whatisnowknownasthe35questionProustQuestionnairebecamefamousafterMarcelProust’sanswersto thesequestionswerefoundandpublishedposthumously.Proustansweredthequestionstwice,atages14and20.In2003Proust’shandwrittenanswerswereauctioned offfor$130,000.Multipleotherhistoricalandcontemporaryfigureshaveanswered theProustQuestionnaire,includingamongothersKarlMarx,OscarWilde,ArthurConanDoyle,FernandoPessoa,StéphaneMallarmé,PaulCézanne,VladimirNabokov, KazuoIshiguro,CatherineDeneuve,SophiaLoren,GinaLollobrigida,GloriaSteinem, Pelé,Valentino,YokoOno,EltonJohn,MartinScorsese,PedroAlmodóvar,Richard Branson,JimmyCarter,DavidChang,SpikeLee,HughJackman,andZendaya.The ProustQuestionnaireisoftenusedtointerviewcelebrities:theideaisthatbyansweringthesequestions,anindividualwillrevealhisorhertruenature.WehavecondensedtheProustQuestionnairebyreducingthenumberofquestionsandslightly rewordingsome.Thesecuratedquestionsprovideinsightsintotheindividual’sinner world,rangingfromnotionsofhappinessandfeartoaspirationsandinspirations.

Whatisyourgreatestfear?

Mygreatestfearisfacingasituationwhere,nomatterwhatIdo,Icannot preventanegativeoutcomeformylovedones.

Whichlivingpersondoyoumostadmire?

IdonothaveasinglepersonIadmirethemost,butratheramultitude ofindividualsacrossdifferentfieldswhoinspiremedeeply.Inscience, Igreatlyadmirethosewhochallengeestablisheddogmasandpushthe boundariesofconventionalthinking,drivinginnovationandprogress.In sports,Irespectathleteswhodemonstrateexceptionaltalent,resilience, anddedicationtotheircraft.Theseindividualsinspiremeindifferent ways,remindingmeofthepowerofperseveranceandboldnessinachievingmeaningfulchange.

Whatisyourgreatestextravagance?

Mygreatestextravaganceistraveling.Ideeplyvaluetheexperiencesand memoriesthatcomefromexploringnewplaces,immersingmyselfindifferentcultures,andbroadeningmyperspectiveontheworld.Itisan indulgencethatenrichesbothmypersonalandprofessionallife.

Whatareyoumostproudof?

Iammostproudofmyfamily.Reflectingonmyjourney,Iseewehave comealongwayfromverymodestbeginnings,grapplingwithfinancial

challengesandanuncertainfuture.Tohavebuiltastablelifeandcareerthatenablesmetosupportandprovideformyfamilyisaprofoundly cherishedachievement.Theirloveandpresencearemymostsignificant sourceofprideandfulfillment.

Whatisyourgreatestregret?

TherearecertainlymomentsinmylifewhereIcouldhavemademore informeddecisions,butIstrivetolivewithoutdwellingonpastactions. Instead,Ifocusonlearningfromthoseexperiencesandmovingforward withamindsetofgrowthandself-improvement.

Whatisthequalityyoumostadmireinpeople? Grit.

Whatisthetraityoumostdislikeinpeople?

ThetraitImostdislikeinpeopleisalackofambitionorasenseof purpose—whensomeonehasnogoalorpursuittostrivefor.

Whatdoyouconsiderthemostoverratedvirtue?

Inmyopinion,blindobedienceorunquestioningcomplianceisthemost overratedvirtue.Whiledisciplineandrespectforauthorityhavetheir place,progressisdrivenbycuriosity,criticalthinking,andthecourage tochallengeestablishednorms.Withquestioningandreevaluating,true growthandinnovationbecomemoreaccessible.

Whatisyourfavoriteoccupation(oractivity)?

Watchingsocceror“futbol”aswecallitinTurkish.

Wherewouldyoumostliketolive?

SomewhereonthecoastoftheMediterraneanSea.

Whatisyourmosttreasuredpossession?

Asaphysicalobject,mymosttreasuredpossessionisaGalatasarayjersey signedbytheentireteam.Beyondthejersey,however,mymostcherished “possessions”arethememoriesandexperiencesIhavesharedwithmy family,whichbringjoyandmeaningtomylifedaily.

Whenandwherewereyouhappiest?Andwhyweresohappythen?

Rightnow,Iamhappiest.Havingmykidsaroundmeandspendingtime withthemfillsmylifewithjoyandmeaning.Iknowthatin10–20years,I willlookbackonthesedayswithfondnessandnostalgia,cherishingthe momentswesharenow.KnowinghowpreciousandfleetingitisisafantastictimeinlifethatIsincerelyappreciate.

Whatisyourcurrentstateofmind?

Mycurrentstateofmindisfocusedanddetermined.Iamfullydedicated tobuildingmylabandfosteringitsgrowth.Thisphaseisexcitingand challenging,filledwithopportunitiestolaythefoundationformeaningfulresearchandtocreateacollaborativeenvironmentthatsupportsdiscoveryandinnovation.

Whatisyourmostmarkedcharacteristic?

Mymostmarkedcharacteristicismydetermination—whenIfocusona problem,IdonotletitgountilIhavefoundasolution.Thispersistence drivesmetodigdeeper,exploreeveryangle,andkeeppushingforward, nomatterhowchallengingthetaskmaybe.

Amongyourtalents,whichone(s)give(s)youacompetitiveedge?

Amongmytalents,mygritanddeterminationgivemeacompetitiveedge. OnceIsetmysightsonagoal,Iamrelentlessinmypursuit,overcomingobstaclesandstayingfocuseduntilIachieveit.Thisresilienceallows metonavigatechallengesandmaintainmomentum,eveninthefaceof adversity.

Whatdoyouconsideryourgreatestachievement?

Inmycareer,mygreatestachievementisestablishingmylabatatopresearchinstitution,whereIcancontributetoadvancingscienceandmentoringthenextgenerationofresearchers.Inmypersonallife,mygreatestachievementisundoubtedlymyfamily—theyaremysourceofjoy, support,andinspiration,andnothingbringsmegreaterfulfillmentthan beingwiththem.

Ifyoucouldchangeonethingaboutyourself,whatwoulditbe? IfIcouldchangeonethingaboutmyself,itwouldbetoworrylessabout imaginedproblems.Sometimes,Ioverthinksituationsthatmaynever happen.Iwanttofocusmoreonthepresentandtacklechallengesasthey come.ThisissomethingIamactivelyworkingontoimprove.

Whatdoyoumostvalueinyourfriends? Loyalty.

Whoareyourfavoritewriters?

Duringmyteenageyears,AminMaaloufwasmyfavoriteauthor.Ireadall ofhisbooksandwascaptivatedbyhisabilitytoseamlesslyweavehistorywithfiction.Thesedays,Ileanmoretowardnon-fiction.WhileIdo nothaveasinglefavoriteauthor,IenjoyreadingworksbyNiallFerguson, MalcolmGladwell,andYuvalNoahHarari,allofwhomofferfascinating insightsintohistory,society,andhumanbehavior.

Whoareyourheroesoffiction?

Idonotbelieveinheroes,especiallyfictionalones.

Whoareyourheroesinreallife?

WhileIamskepticaloftheheroconcept,IresonatedeeplywithAlbert Camusandhisworldview.

Whataphorismormottobestencapsulatesyourlifephilosophy?

“Thestruggleitselftowardstheheightsisenoughtofillaman’sheart. OnemustimagineSisyphushappy.”—AlbertCamus, TheMythofSisyphus andOtherEssays

Philadelphia,Pennsylvania,USA 30November2024

MunirGunesKutlu1 1 CenterforSubstanceAbuseResearch,DepartmentofNeuralSciences,Temple UniversityLewisKatzSchoolofMedicine,Philadelphia,Pennsylvania19140,USA e-mail: gunes.kutlu@temple.edu

Publisher’snote: GenomicPressmaintainsapositionofimpartialityandneutrality regardingterritorialassertionsrepresentedinpublishedmaterialsandaffiliations ofinstitutionalnature.Assuch,wewillusetheaffiliationsprovidedbytheauthors, withouteditingthem.Suchusesimplyreflectswhattheauthorssubmittedtousand itdoesnotindicatethatGenomicPresssupportsanytypeofterritorialassertions.

OpenAccess. The“GenomicPressInterview”frameworkiscopyrightedtoGenomicPress.Theinterviewee’sresponsesarelicensedtoGenomicPressundertheCreativeCommonsAttribution-NonCommercialNoDerivatives4.0InternationalLicense(CCBY-NC-ND4.0).Thelicensemandates: (1)Attribution:Creditmustbegiventotheoriginalwork,withalinktothelicense andnotificationofanychanges.Theacknowledgmentshouldnotimplylicensorendorsement.(2)NonCommercial:Thematerialcannotbeusedforcommercialpurposes.(3)NoDerivatives:Modifiedversionsoftheworkcannotbedistributed.(4) Noadditionallegalortechnologicalrestrictionsmaybeappliedbeyondthosestipulatedinthelicense.Publicdomainmaterialsorthosecoveredbystatutoryexceptionsareexemptfromtheseterms.Thislicensedoesnotcoverallpotential rights,suchaspublicityorprivacyrights,whichmayrestrictmaterialuse.Thirdpartycontentinthisarticlefallsunderthearticle’sCreativeCommonslicenseunless otherwisestated.Ifuseexceedsthelicensescopeorstatutoryregulation,permissionmustbeobtainedfromthecopyrightholder.Forcompletelicensedetails,visit https://creativecommons.org/licenses/by-nc-nd/4.0/.Thelicenseisprovidedwithoutwarranties.

INNOVATORS&IDEAS:RISINGSTAR

AlessandraBorsini:Whatneuroinflammationhastodowithdepressionandhow nutritioncanplayabeneficialrole

©TheAuthor(s),underexclusivelicensetoGenomicPress2024

BrainMedicine March2025;1(2):8–10;doi: https://doi.org/10.61373/bm024k.0037

Keywords: depression,neuroinflammation,neurogenesis,nutrition, mind-bodyinterface

AlessandraBorsiniisaLecturerinPsychoneuroimmunologyatthe InstituteofPsychiatry,PsychologyandNeuroscience(IoPPN),King’s CollegeLondon.Herresearchinterestfocusesontheroleof inflammationandstressonbrainneurogenicalterations,particularly inthecontextofneuropsychiatricandneurodegenerativedisorders, andontheabilityofpsychotropic,anti-inflammatory,and nutrition-basedtreatmentstopreventsuchalterations.Shehasbeen amemberoftheMedicalResearchCouncil(MRC)Immunopsychiatry Consortium,theAMBROSIACERA-NET/MRCConsortium,andthe EuropeanCollegeofNeuropsychopharmacology(ECNP) Immuno-NeuropsychiatryNetworkCoreGroup.Shehasreceived variousawards,includingthePsychoneuroimmunologyAwardfrom thePsychoneuroimmunologyResearchSociety(PNIRs)andthe PreclinicalPsychopharmacologyAwardfromtheBritishAssociation forPsychopharmacology(BAP).AsofApril2024,DrBorsinihas publishedover50papers,withacurrentH-indexof25,andhasbeen therecipientofbothnationalandinternationalresearchgrantsfrom theNationalInstituteforHealthandCareResearch(NIHR),Wellcome Trust,MRC,EuropeanCommissionandRosetreesTrust.Sheispartof theEditorialBoardofseveraljournals,including Brain,Behavior,and, Immunity, FrontiersinNeuroscience,and FrontiersinPsychiatry.She isalsotheprogrammeleaderforthenewMScinPsychologyand NeuroscienceofMind-BodyInterfacelaunchingthisSeptember2024 attheIoPPN.DrBorsiniispassionateaboutpublicengagement.To discussherresearchortopicsbroadlyrelatedtomentalhealth,she hasmademultiplemediaappearancesinnewspapers,including The SundayTimes, TheGuardian,and TheIndependent,andradioandTV programmes,suchas BBCRadio4Today, BBCRadio4AllintheMind, and BBCOneHealth:TruthorScare.DrBorsinigraciouslyanswered theGenomicPressInterview,providingourreaderswithreflections onherpersonalandprofessionaljourney.

Part1:AlessandraBorsini–LifeandCareer

Couldyougiveusaglimpseintoyourpersonalhistory,emphasizing thepivotalmomentsthatfirstkindledyourpassionforscience?

Ihavealwaysfoundthepossibilityofbecomingonedayaresearcher andneuroscientistfascinating.Ihaveastrongsenseofcuriosity,which ledmetomovefrommylittletowninItalytoLondonandtoapplyfor whatatthattimewasconsideredaverynovelBSccourseinPsychologyandNeuroscience.Studyingtheneuroscienceofthebrainandconductinglaboratoryexperimentsalreadyduringmydegree,aswellas beingimmersedinsuchaninternationalacademicandresearchenvironment,allcontributedtoincreasingmypassionforacareerinneuroscience research.

Wewouldliketoknowmoreaboutyourcareertrajectoryleadingupto yourcurrentrole.Whatdefiningmomentschanneledyoutowardthis opportunity?

Afterfinishingmyundergraduatedegree,Ihavehadaverycontinuouscareerpath.IhadtheopportunitytomeetCarmineM.ParianteattheIoPPN, King’sCollegeLondon,andtodoaPhDunderhissupervision.Sincethen, Ihavehadthegreatfortunetohavehimasmymentorandfriend.Assoon asIfinishedmyPhD,IwasawardedaFellowshipfromtheNIHR,whichallowedmetocontinuemyacademiccareerattheIoPPN.Iwasluckytofind afantasticcommunityoffriendsandscientists,soIdecidedtocontinue myresearchthereevenaftermyFellowshipended.EventhoughIamnow aLecturerinPsychoneuroimmunologyattheIoPPN,andhavebeenatthe Instituteformanyyears,IfeellikeIamstillatthebeginningofmyjourney.

Pleasesharewithuswhatinitiallypiquedyourinterestinyour favouriteresearchorprofessionalfocusarea.

Ihavealwaysbeenfascinatedbyinflammation–itscomplexity,abilityto change,adapt,andinteractwithmultiplesystems,andaffectsimultaneouslyboththebrainandthebody.Atthesametime,myparallelinterestin theintricatecomplexityofspecificbrainprocesses,suchasneurogenesis

Received:18April2024.Accepted:20April2024. Publishedonline:24April2024.

Figure1. AlessandraBorsini,PhD,King’sCollegeLondon,UK.

andneuroplasticity,broughtmeclosertotheresearchIamdoingatthe moment–understandingtheneuro-immunologicalmechanismsunderlyingmentalhealthdisorders.Whilepsycho-neuro-immunologyhasalways beenmymainresearchinterestandfocus,overtheyears,Ihavehadthe opportunitytoconnectwithneuroscientistsworkinginthefieldofnutritionalpsychiatry,andIimmediatelyfeltcaptivatedbyhowdiet/nutrition canregulateourimmuneresponseandultimatelyaffectourmental health.

Whatimpactdoyouhopetoachieveinyourfieldbyfocusingon specificresearchtopics?

Idohopemyresearchwillbeabletoprovidenovelinsightsintotheneuroinflammatorymechanismsunderlyingmentalhealthdisordersand,as aconsequence,tocontributetothedevelopmentofnovelandmorepersonalizedtherapeuticapproachesforpatientswithmentalhealthdisorderswithsub-chroniclevelsofinflammation,whoarenotrespondingto currentantidepressanttreatments.

Pleasetellusmoreaboutyourcurrentscholarlyfocalpointswithin yourchosenfieldofscience.

Currently,myteamofresearchersandIarefocusingonseveralprojects. ForourNIHR-fundedstudy,wearegainingmechanisticinsightsonhow long-COVID-19affectsthebrainviaexposinghumanbraincellsdirectly tobloodfromthesepatients–thisisindeedafollow-upstudyfroma previousRosetreesTrust-fundedprojectwherewetestedhowperipheral inflammationinacuteCOVID-19patientswithneurocognitivesymptoms wasaffectingbrainneurogenesis.Inparallel,forourEuropean-funded project,EarlyCause,wehavedevelopedmultipleinvitromodelsofearly lifestress(ELS)usingcellsfromthebrainandthebodyinordertoinvestigatecausativemechanismslinkingELStothedevelopmentofpsychocardio-metabolicmulti-morbidities.Finally,weareinthelaststageof theSymprovestudy,aprojectfundedbyParkinson’sUK,whichaimsto uncovertheneurobiologicalmechanismsunderlyingtheeffectoforal Symprove(aprobiotic)forthemanagementofnon-motorsymptoms,includingdepressionandanxiety,inpeoplewithParkinson’s.Papersfrom thesestudiesshouldcomeoutsoon.

Whathabitsandvaluesdidyoudevelopduringyouracademicstudies orsubsequentpostdoctoralexperiencesthatyouupholdwithinyour researchenvironment?

Overtheyears,Ihavebeeninvolvedinmanynewprojectsandsupervisionroles.ThetwohabitsIhavedevelopedmostareworkinghardand planningahead.Therearetimeswhenmultipledeadlinesareapproaching,andorganizingtasksinadvancehasallowedmetoperformatmy bestwithoutexperiencinganxietyorfeelingpressure.Scienceisfun,and Ivaluecelebratingeverysuccess,nomatterhowbigorsmallitis–this issomethingIlearnedovertheyearsworkingwithCarminePariante.Ido thesamewiththepeoplewhoareworkingwithme.

Inclusion,forme,isafundamentalaspectofscience.Igenuinelybelieve thereshouldbenosignofcultural,social,orethnicbarrierswithinour scientificcommunity.Asawomanandamother,Ialsocondemnanyform ofpregnancyormaternitydiscrimination.

Whatdoyoumostenjoyinyourcapacityasanacademicorresearch risingstar?

Thefreedomtodevelopandinvestigateyourownscientifichypothesis, theexcitementofcreatingnewcollaborationseveryday,andtheprivilege toworkwithamazingpeopleandscientists.

Outsideprofessionalconfines,howdoyouprefertoallocateyour leisuremoments,orconversely,inwhatmannerwouldyouenvision spendingthesemomentsgivenachoice?

Ilovespendingtimeandplayingwithmydaughter;itgivesmemuch joy–Ialsorecentlyrealizedthatitinvolvesmuchphysicalactivity,preciselywhatIneedformymentalhealth.Icomefromasmalltownnearthe seainItaly,soitisinevitablenottomentionthatIamconstantlysearchingforasunnybeach,hotweather,andbluesky,sowheneverIcan,Ifly backtoItalytoremindmyselfofthosescenarios.

Part2:AlessandraBorsini–SelectedquestionsfromtheProust Questionnaire1

Whatisyourideaofperfecthappiness? Beingsurroundedbymyfamily.

Whatisyourgreatestfear? Nottobesurroundedbymyfamilyindifficulttimes.

Whichlivingpersondoyoumostadmire? Notaspecificperson,butanyonewhomanagedtofindabalanceinlife.

Whatisyourgreatestextravagance? Myinterestinaviationandkaraoke.

Whatareyoumostproudof? Beingamumandaresearcher.

Whatisyourgreatestregret? Iwouldhavelovedtovisitmoreremotedestinations,butthereisstill time.

Whatisthequalityyoumostadmireinpeople? Resilience.

Whatisthetraityoumostdislikeinpeople? Arrogance.

Whatdoyouconsiderthemostoverratedvirtue? Perhapsconfidence.

Whatisyourfavouriteoccupation(oractivity)? IlovewalkingthroughthestreetsofcentralLondon.

Wherewouldyoumostliketolive? Inasunnyandhotplace,bythesea.

Whatisyourmosttreasuredpossession? Mymemoriesofthetimespentwithmygrandmother.

1 Inthelatenineteenthcentury,variousquestionnaireswereapopulardiversion designedtodiscovernewthingsaboutoldfriends.Whatisnowknownasthe35questionProustQuestionnairebecamefamousafterMarcelProust’sanswersto thesequestionswerefoundandpublishedposthumously.Proustansweredthequestionstwice,atages14and20.In2003,Proust’shandwrittenanswerswereauctioned offfor$130,000.Multipleotherhistoricalandcontemporaryfigureshaveanswered theProustQuestionnaire,includingamongothersKarlMarx,OscarWilde,ArthurConanDoyle,FernandoPessoa,StéphaneMallarmé,PaulCézanne,VladimirNabokov, KazuoIshiguro,CatherineDeneuve,SophiaLoren,GinaLollobrigida,GloriaSteinem, Pelé,Valentino,YokoOno,EltonJohn,MartinScorsese,PedroAlmodóvar,Richard Branson,JimmyCarter,DavidChang,SpikeLee,HughJackman,andZendaya.The ProustQuestionnaireisoftenusedtointerviewcelebrities:theideaisthatbyansweringthesequestions,anindividualwillrevealhisorhertruenature.WehavecondensedtheProustQuestionnairebyreducingthenumberofquestionsandslightly rewordingsome.Thesecuratedquestionsprovideinsightsintotheindividual’sinner world,rangingfromnotionsofhappinessandfeartoaspirationsandinspirations.

Whenandwherewereyouhappiest?Andwhywereyouso happythen?

Nowisthehappiesttimeofmylife,asIamawife,mum,andanactive scientist.

Whatisyourcurrentstateofmind? Ifeelserene.

Whatisyourmostmarkedcharacteristic? Iamareliableperson,bothinpersonalandprofessionalrelationships.

Amongyourtalentscourses,whichone(s)give(s)youa competitiveedge?

Iamverypersistentanddonotgiveupeasily.

Whatdoyouconsideryourgreatestachievement?

IhavedevelopedandledanentirelynewMSccourseinPsychologyand NeuroscienceofMind-BodyInterface,whichlaunchesthisSeptember 2024.Forfurtherinformationonthisexcitingnewprogramme,clickon this link

Ifyoucouldchangeonethingaboutyourself,whatwoulditbe? Ioftenasktoomuchofmyself.

Whatdoyoumostvalueinyourfriends? Honesty.

Whoareyourfavouritewriters?

PatrickMcGraph,DorisLessing,PauloCoelho.

Whoareyourheroesoffiction? SherlockHolmes.

Whoareyourheroesinreallife? Menandwomenwhoarecommittedtotheirfamiliesandtheircommunity

Whataphorismormottobestencapsulatesyourlifephilosophy? Perasperaadastra.

AlessandraBorsini1

1 InstituteofPsychiatry,Psychology&Neuroscience,King’sCollegeLondon, LondonSE59RT,UK e-mail: alessandra.borsini@kcl.ac.uk

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OpenAccess. ThisarticleislicensedundertheCreativeCommons Attribution-NonCommercial-NoDerivatives4.0InternationalLicense (CCBY-NC-ND4.0).Thelicensemandates:(1)Attribution:Creditmustbegiventothe originalwork,withalinktothelicenseandnotificationofanychanges.Theacknowledgmentshouldnotimplylicensorendorsement.(2)NonCommercial:Thematerial cannotbeusedforcommercialpurposes.(3)NoDerivatives:Modifiedversionsofthe workcannotbedistributed.(4)Noadditionallegalortechnologicalrestrictionsmay beappliedbeyondthosestipulatedinthelicense.Publicdomainmaterialsorthose coveredbystatutoryexceptionsareexemptfromtheseterms.Thislicensedoesnot coverallpotentialrights,suchaspublicityorprivacyrights,whichmayrestrictmaterialuse.Third-partycontentinthisarticlefallsunderthearticle’sCreativeCommonslicenseunlessotherwisestated.Ifuseexceedsthelicensescopeorstatutory regulation,permissionmustbeobtainedfromthecopyrightholder.Forcomplete licensedetails,visit https://creativecommons.org/licenses/by-nc-nd/4.0/.The licenseisprovidedwithoutwarranties.

INNOVATORS&IDEAS:RESEARCHLEADER

UdoDannlowski:Brainstructureandfunctioninthelong-termcourseof mentaldisorders

©TheAuthor(s),underexclusivelicensetoGenomicPress2024

BrainMedicine March2025;1(2):11–13;doi: https://doi.org/10.61373/bm024k.0019

Keywords: Neuroimaging,psychiatry,majordepression,disease trajectories

UdoDannlowskiisapsychiatrist,psychologist,andtranslational neuroimagingresearcherwhoseworkintersectsclinicalpsychiatry, genetics,datascience,andsystemsneuroscience.Hisacademic endeavorsaredrivenbyacommitmenttounravelingthecomplex biologicalandgeneticmechanismsunderlyinglong-termdisease trajectoriesofaffectivedisorders,includingdepressionandanxiety. Dannlowski’suseofbrainimagingtechnologies,suchasmultimodal MRI,toexplorethestructuralandfunctionalanomaliesinpatients withthesedisordersinlongitudinalcohortsoverseveralyearsof follow-upwithmachinelearningtechniqueshassignificantly advancedourunderstandingofbrainmechanismsinmental disorders.Dannlowskiisrecognizedforcontributingtopsychiatryand neuroscience,substantiallyimpactingtheoreticalunderstandingand clinicalpractice.Since2019,hehasbeenheadingtheInstitutefor TranslationalPsychiatryinMünster,Germany,togetherwiththe clinicalSectionforTransitionPsychiatryattheDepartmentforMental Health.WeareprivilegedtopresenttheGenomicPressinterviewwith ProfessorDannlowski,whohasofferedtoshareinsightsfromhis esteemedcareerandpersonalexperiencesforourreaders’benefit.

Part1:UdoDannlowski–LifeandCareer

Couldyougiveusaglimpseintoyourpersonalhistory,emphasizing thepivotalmomentsthatfirstkindledyourpassionforscience?

WhenIwasaskedasakidwhatIwantedtobewhenIgrewup,theanswer alwaysincluded“scientist”tosomedegree–startingwith“caveexplorer,” “dinosaurscientist,"orarcheologist.ThoughIwasafirst-generationacademic,therewasneveraquestionofwhetherIwantedtojoinauniversity,andIstruggledtochoosemysubjectarea.Withinterestsin computerscience,psychology,literature,medicine,andbiology,Istudied bothmedicineandpsychologyandstartedneuropsychologicalstudiesin depressionasamedicalstudent.Combiningresearchandclinicalduties provedtobethemostsustaininginterestsoIbecameaclinicalscientist, nowheadingaresearchinstituteaswellasaclinicalsection.

Wewouldliketoknowmoreaboutyourcareertrajectoryleadingupto yourmostrelevantleadershiprole.Whatdefiningmoments channeledyoutowardthatleadershipresponsibility?

Beforebecomingaresearchgroupleader,Ihadcloseandtrustfulrelationshipswithmysupervisors,whoeventuallybecamefriends.Isawthem strugglingwithseveralparallel,partlyunrelated,andheavilyunderfinancedprojects–anddecidedthatIwantedtodoitdifferently.Instead ofconductingmultiplesmallerstudies,Icombinedneuroimagingandgeneticswithanepidemiologicalscopeinonelargecohortwithlongfollowupperiods.Whilethiswasriskyatanearlycareerstageinadynamicacademicsetting,itwasthebirthoftheMünsterNeuroimagingCohort,which isstillrunning15yearslater.

Received:14March2024.Accepted:15March2024. Publishedonline:20March2024.

Pleasesharewithuswhatinitiallypiquedyourinterestinyour favoriteresearchorprofessionalfocusarea.

Neuroimagingisahighlyinterdisciplinaryareathatoffersaplayground forpracticallyallmyresearchinterests.Functionalmagneticresonance imaging(fMRI)allowedmetoseethebrainatwork,testingpsychological constructsandtraits.Asapsychiatrist,multimodalimagingwaspromisingforprovidingclinicalcorrelatesofdisordersaswellasbiomarkers orpredictorsfortreatmentresponse.Asadatascientist,IfoundhighdimensionalneuroimagingdatatobeanEldoradoforapplyingamultitudeofanalyticstrategies,includingmachinelearningtechniques.

Whatimpactdoyouhopetoachieveinyourfieldbyfocusingon specificresearchtopics?

Tacklingthetranslationalroadblockbyaddressingthelong-termperspectiveofpatientsusingwithin-subjectsdesignsinlargelongitudinal cohorts.Developingstrategiestouncoverbio-psycho-socialdatasignaturesforunderstanding,predicting,andultimatelypreventingrelapses inthelong-termcourseofaffectivedisorders.

Figure1. UdoDannlowski,MD,PhD,InstituteforTranslationalPsychiatry, UniversityofMünster,Germany.

Pleasetellusmoreaboutyourcurrentscholarlyfocalpointswithin yourchosenfieldofscience.

Onefocalpointinvestigatestheneurobiologicaldeterminantsoflongtermdiseasetrajectoriesinmajordepressionusingmachinelearningbasedpredictivemodeling.Highlyrelated,asecondfocalpointisthe associationofgeneticandenvironmentalriskfactorsformentaldisorderswithbrainstructureandfunction.

Whathabitsandvaluesdidyoudevelopduringyouracademicstudies orsubsequentpostdoctoralexperiencesthatyouupholdwithinyour researchenvironment?

Trust,collegiality,appreciation,andsharingofdataandresourceswere thedeterminantsofsuccessfulandfruitfulcollaborations.Thesearenecessaryforconductinglong-termresearchprogramssuchaslarge-scale longitudinalneuroimagingcohorts.Thesevaluesleadtolasting,trustful relationshipsinsideandoutsidethelabwithmentors,facultycolleagues, andtraineesalike.

AtGenomicPress,weprioritizefosteringresearchendeavorsbased solelyontheirinherentmerit,uninfluencedbygeographyorthe researchers’personalordemographictraits.Arethereparticular culturalfacetswithinthescientificcommunitywarrant transformativescrutiny,oristhereacausewithinsciencethatdeeply stirsyourpassions?

Scienceisnourishedbydiversity—bothasaresearchareaandinterms ofthepeopleconductingtheresearch.Diversityneedstoberepresented muchmoreasaresearchtargetandbyresearchersonthefacultylevel.

Whatdoyoumostenjoyinyourcapacityasanacademicorresearch leader?

Imostenjoytheopportunitytofosteracultureofcuriosity,innovation, andcontinuouslearning.Leadingateamofbright,motivatedindividuals towardsdiscoveringnewknowledgeanddevelopingnovelsolutionsto complexproblemsisincrediblyrewarding.Thechancetomentorand guideemergingscholarsandresearchers,watchingthemgrowandsucceed,isaprivilege.Furthermore,thecollaborativeaspectofacademia— buildinginterdisciplinarypartnershipsandnetworks—enrichesthe researchexperience,leadingtomorecomprehensiveandimpactfuloutcomes.Thisrolenotonlyallowsmetocontributetoadvancingmyfield butalsotoplayapartinshapingthefutureofresearchandeducation.

Outsideprofessionalconfines,howdoyouprefertoallocateyour leisuremoments,orconversely,inwhatmannerwouldyouenvision spendingthesemomentsgivenachoice?

Iliketospendtimewithmyfamilyandinnatureonaboat,inthewoods, oronahikingtrail.

Part2:UdoDannlowski–SelectedquestionsfromtheProust Questionnaire1

Whatisyourideaofperfecthappiness?

Mydailyhourofreadingbookswithmy14-year-olddaughter–andplayingDungeonsandDragonswithher.

1 Inthelatenineteenthcentury,variousquestionnaireswereapopulardiversion designedtodiscovernewthingsaboutoldfriends.Whatisnowknownasthe35questionProustQuestionnairebecamefamousafterMarcelProust’sanswersto thesequestionswerefoundandpublishedposthumously.Proustansweredthequestionstwice,atages14and20.Multipleotherhistoricalandcontemporaryfigures haveansweredtheProustQuestionnaire,suchasOscarWilde,KarlMarx,ArthurConanDoyle,StéphaneMallarmé,PaulCézanne,MartinBoucher,HughJackman,David Bowie,andZendaya.TheProustQuestionnaireisoftenusedtointerviewcelebrities: theideaisthatbyansweringthesequestions,anindividualwillrevealhisorher truenature.WehavecondensedtheProustQuestionnairebyreducingthenumber ofquestionsandslightlyrewordingsome.Thesecuratedquestionsprovideinsights intotheindividual’sinnerworld,rangingfromnotionsofhappinessandfeartoaspirationsandinspirations.

Whatisyourgreatestfear? Thedeclineofsanityworldwideandtheabuseofpowerbyafewpersons atthewrongplace.

Whichlivingpersondoyoumostadmire? TherearetoomanypersonsIwouldliketonameherewithoutonesingle personstandingout.

Whatisyourgreatestextravagance? Keepinganold,used,cheapcaraliveformanyyears,whichisbasicallyan ugly,scruffy,anduninspiredwreck.

Whatareyoumostproudof? Mytwodaughters.

Whatisyourgreatestregret? Despitenotbeinga“dinosaurscientist”?Probablytrustingapersonwith adarktriad.

Whatisthequalityyoumostadmireinpeople? Beingabletolaughaboutoneself.

Whatdoyouconsiderthemostoverratedvirtue? Truevirtuescanneverbeoverrated.

Whatisyourfavoriteoccupation(oractivity)?

Exceptforspendingtimewithmykids,theshortboatridestoasundowner atthenearbyriversidebeergarden,andpickingmushroomsinfall.

Wherewouldyoumostliketolive?

Germanyisanexcellentplacetolive.SouthAsiaduringwinter,however, offersevenmoretemptingplacestostay.

Whatisyourmosttreasuredpossession?

Ahousewithariverjettyandkingfishersbreedingnearby.

Whenandwherewereyouhappiest?Andwhyweresohappythen? TheyearsoftravellingAsiatogetherwiththepersonwhowassobraveto marrymelater.

Whatisyourmostmarkedcharacteristic?

Probablyasomewhatidiosyncratichumorandnottakingmyselftoo seriously.

Amongyourtalents,whichone(s)give(s)youacompetitiveedge? Iwouldnotconsidermyselfcompetitive,andnospecifictalentstands out.Mygoalisprobablytoattractexceptionalpeopleandsupporttheir development.

Whatdoyouconsideryourgreatestachievement?

Havingthisincrediblegroupofbrilliantpeoplearoundandhopefully beinglikedbyatleastafewofthem.

Ifyoucouldchangeonethingaboutyourself,whatwoulditbe? Myimpatience,particularlywithnon-academicadministrativecolleagues.

Whatdoyoumostvalueinyourfriends?

Theirexistence.Andtheirrelentlesspatiencewithme.

Whoareyourfavoritewriters?

Thislistmightexceedthewordlimit,startingwithFranzKafka,Hermann Hesse,AstridLindgren,Janosch,DouglasCoupland,StanislavLem,John Steinbeck,FyodorDostoevsky,MaxTegmark,YuvalHarari,MichelHouellebecq,VirginiaWoolf,HarukiMurakami,GabrielGarcíaMárquez,Albert Camus,DouglasAdams,…

Whoareyourheroesoffiction?

Land-surveyorK.,PippiLongstockingandRonjatherobber’sdaughter, Siddhartha,HAL9000,Marvintherobot,HarryHaller.

Whoareyourheroesinreallife?

Mygrandma,thestrongestandwisestpersoneverwalkingthisplanet.

Whataphorismormottobestencapsulatesyourlifephilosophy?

Odietamo.Quareidfaciam,fortasserequiris.Nescio,sedfierisentioet excrucior.(Catullus85)

UdoDannlowski1

1 InstituteforTranslationalPsychiatry,UniversityofMünster, 48149Münster,Germany e-mail: dannlow@uni-muenster.de

Publisher’snote: GenomicPressmaintainsapositionofimpartialityandneutralityregardingterritorialassertionsrepresentedinpublishedmaterialsandaffilia-

tionsofinstitutionalnature.Assuch,wewillusetheaffiliationsprovidedbytheauthors,withouteditingthem.Suchusesimplyreflectswhattheauthorssubmitted tousanditdoesnotindicatethatGenomicPresssupportsanytypeofterritorial assertions.

INNOVATORS&IDEAS:RESEARCHLEADER

VickiL.Clifton:Stress,sex,andtheplacenta:itsroleinfetalandchilddevelopment

©GenomicPress,2024.The“GenomicPressInterview”frameworkisprotectedundercopyright.Individualresponsesarepublishedunderexclusive andpermanentlicensetoGenomicPress.

BrainMedicine March2025;1(2):14–17;doi: https://doi.org/10.61373/bm024k.0097

Keywords: Pregnancy,placenta,fetus,stress,anxiety,depression

ProfessorVickiClifton,PhD,GAICD,DipManag,DipCounselling, FRSM,isaMaterResearchInstitute-UniversityofQueenslandAmplify Fellowspecializinginobstetricsresearchthroughclinicaltrialsand basicbiology.With327publications,h-Index:61,andover14,000 citations,herresearchfocusesonstressandmaternalasthmaduring pregnancy,examiningtheireffectsonmaternalhealth,placental function,fetalgrowth,andchildhealth.Sheisnotablyrecognizedfor herworkonsex-specificplacentalfunctionandstressresponses influencingfetalgrowthandpregnancyoutcomes.ProfessorClifton hasledherinstitution’sasthmaandpregnancyresearchprogram, establishingmulti-disciplinary,end-user-engagedresearchprograms inAustraliaandoverseas.Herinnovativeresearchhasadvancedour understandingoffactorsaffectingasthmaduringpregnancy,leading tonewmodelsofcareandimprovedfetaloutcomes.Herworkhas influencednationalandinternationalasthmamanagement guidelines,identifiedsex-specificmechanismsaffecting maternal-fetalhealth,andexpandedthefrontiersofexisting knowledgeonfetal-neonatalphysiology.Throughpreclinicalstudies andclinicalpartnerships,shehasrapidlytranslatedfindingsinto practiceguidelinesandconsumerinformation.Shecurrentlyleadsthe QueenslandFamilyCohortstudy,astate-widelongitudinalstudy linkingparentalandchildhealthoutcomestobiologicalmechanisms. AFellowoftheRoyalSocietyofMedicine,shepioneeredwomen’s leadershipasthefirstfemalePresidentoftheEndocrineSocietyof AustraliaandthefirstfemaleEditorof Placenta (Elsevier).Asan NHMRCResearchFellow(2000–2023),shehassecuredover $25millionincategory1grants.WeareprivilegedtohaveProfessor Cliftonshareherpersonalandprofessionalinsightswithourreaders inthisGenomicPressInterview.

Part1:ProfessorVickiClifton–LifeandCareer Couldyougiveusaglimpseintoyourpersonalhistory,emphasizing thepivotalmomentsthatfirstkindledyourpassionforscience? Iwasgreatlyinfluencedbymyparents,grandparents,andgreat-uncle, whotaughtmeaboutagriculture,marinelife,geology,paleontology, plantsforfoodandmedicine,andabitofchemistrywhileworkinginmy mum’shairdressingsalonandunderstandingwhyhairendedupcurlywith aperm.Sciencewasallaroundme,anditseemednaturaltofocusona sciencedegree.IattendedtheUniversityofNewcastleandwasfortunate tohavelecturersandmentorswhorecognizedmypotentialandguided meintopostgraduatestudy.Atthesametimeasstartingmypostgraduateresearchdegrees,Ihad3babies,withoneofmysonsdyinginmidgestation.Thisdevastatingexperienceledtothequestion,“Whatwent wrong?”andeventuallyledtostudyingtheplacenta.IjoinedtheMothers’andBabiesResearchCentreattheUniversityofNewcastleandstarted myPhDexaminingplacentalcirculationanditsregulationbystresshormones.FollowingmyPhD,myfamilyandIwerekeenonanadventure,

Received:20October2024.Accepted:22October2024. Publishedonline:29October2024.

VickiL.CliftonPhD,GAICD,DipManag,DipCounselling,FRSM,Mater ResearchInstitute-UniversityofQueensland,Australia.

soIacceptedapostdoctoralfellowshipwithProfJohnChallisatthe UniversityofToronto.Thiswasmyfirstintroductiontofetalphysiology andstimulatedmycuriosityforunderstandingthemechanismsthatregulateplacentalfunctionandfetalgrowthandsurvival.

Wewouldliketoknowmoreaboutyourcareertrajectoryleadingupto yourmostrelevantleadershiprole.Whatdefiningmoments channeledyoutowardthatleadershipresponsibility?

AfterlivinginCanadaformypostdoctoralfellowshipfortwoyears(1995–97),IreturnedtotheUniversityofNewcastle,Australia,whereIstarted

Figure1.

toexaminetheroleofmaternalasthmaandstressanditseffectonthe placentaandfetus(1998–2007).Iformedsomekeycollaborationsand establishedthefirstcontrolledasthmaandpregnancybirthcohort.However,duringthistime,myfirsthusbanddied,andafterseveralyearsof grieving,supportingmychildren,andfeelinglost,IremarriedanddecidedIneededafreshstart.IwasDeputyDirectorattheMother’sand BabiesResearchCentre,andIhadnoforeseeableopportunitytobepromotedfurtherandgainfurtherleadershipexperience,soIstartedtolook fornewpositionsatotherinstitutions.ImettheDirectoroftheRobinson ResearchInstituteinAdelaide,whoinvitedmetotheUniversityofAdelaidetoseewhatIthoughtofthecityanddiscussnewleadershipopportunities.MypartnerandIfellinlovewithAdelaideanddecidedtomove. IwasappointedDirectorofClinicalResearchattheLyellMcEwinHospital inNorthernAdelaideasthehospitaltransitionedtoatertiary-levelteachinghospital(2008-2015).Itwasagreatexperiencedevelopingastrategy forintroducingresearchtothehospitalandthenengagingcliniciansin researchactivity.

AftersevenyearsinAdelaide,IwasinvitedtoBrisbanetogiveatalk attheMaterResearchInstitute.MaterhasthebiggestmaternityhospitalandneonatalintensivecareunitinAustralia,andIwasveryimpressed withitspotentialforcontinuingmyresearch.Iwasofferedapositionas ProgramLeaderofMothers,Babies,andWomen’sHealthatMater,andalthoughIwasnotconsideringamove,theofferwastoogoodtoignorein termsofwhatIcouldachieve,andthechallengewasintriguing.Thisexcitingnewadventurewouldallowmetoestablishalargebirthcohortinthe stateandincreasemycapacitytocollaboratewithfantasticresearchers acrossseveralUniversitiesandInstitutions.

Ifollowmyintuitiononwhentomakeachangeinmycareer,andasa result,Ihaveenjoyedtheexperienceofmovingtonewjobsandexploring newplaces.IamstillinBrisbaneandlovemyroleattheMaterResearch Institute.ManyofmylatestleadershiprolesincludeBoardDirectorand SecretaryofWomen’sHealthandEqualityQueensland.Iwantedtocontributetoimprovingthelivesofvulnerablewomen,anddonatingmytime toanot-for-profitorganizationhasbeenamoretangiblewaytomakea differenceinthelivesofwomen.Thisrolehasalsoopenedupmanyother greatopportunities,includingbeingapartoftheadvisorypanelthatdevelopedtheQueenslandGovernment’sWomen’sandGirlsHealthStrategy.Atthisstageinmycareer,Icontinuetofocusonmyresearchand workonmyfavoriteorgan,theplacenta!

Pleasesharewithuswhatinitiallypiquedyourinterestinyour favoriteresearchorprofessionalfocusarea

Istartedworkinginasthmaandpregnancyresearchduetomyown livedexperience.Iamanasthmatic,andIhadseveresymptomsduring pregnancywhichresultedinadverseoutcomesformybabies(1989–91). Ifoundthattheclinicalcareformyasthma,specificallyduringpregnancy,waslacking.Aliteraturesearchidentifiedthattherewasverylittleresearchinthefield.Iwasfortunatetobeco-locatedwithObstetricsandRespiratoryMedicineattheJohnHunterHospitalinNewcastleandstartedtodiscusspotentialprojectswithProfessorPeterGibsonandProfessorWarrickGiles.Thisledtotheestablishmentofthefirst controlledprospectivebirthcohortofpregnantwomenwithandwithoutasthma(1999–2007).Sincethen,theresearchinthisfieldhasexpandedexponentiallywiththeestablishmentofseveraldifferentbirth cohorts,randomizedcontrolledtrials,andepidemiologicalstudiesthat havetranslatedintosignificantimprovementsinclinicalpractice.The workhasmorphedintoexaminingtheeffectofstressontheplacenta andfetus,whichhasledtoagreaterfocusonmaternalmentalhealthin pregnancy.

Whatimpactdoyouhopetoachieveinyourfieldbyfocusing onspecificresearchtopics?

Basedontheevidencefrommyresearch,maleandfemalefetusesare physiologicallydifferent,whichispartlyconferredbytheplacenta’s sex-specificfunction.Presently,wedonotconsiderthesexofthefetusin Obstetrics.Iwouldliketoseesex-specificmedicineforpregnancycompli-

cations,forthecareofpretermneonates,andforthecareofnewborns. Ourworkalsosuggeststhatmaternalphysiologyinpregnancyvariesdependingonthesexofthefetus,andIhopetheevidenceweprovidecould translateintoclinicaldecisionsaroundinterventionsforpregnantwomen basedonthesexofthefetus.

Pleasetellusmoreaboutyourcurrentscholarlyfocalpointswithin yourchosenfieldofscience Currently,wearefocusedonhowtheplacentamayinfluencematernal stress,anxiety,anddepression.Wehavediscoveredthattheplacentahas 13differentisoformsoftheglucocorticoidreceptor,withoneisoform expressedinthepresenceofmaternalstress,anxiety,anddepression thatactivatesaninflammatoryresponseintheplacentainthepresence ofhighcortisolconcentrations.Mostglucocorticoidreceptorsinhibitinflammation,sothisnewfindingissurprising.Thisworkmayexplainwhy highlevelsofstressandhighinflammationcancoincide.Increasedinflammationinwomenwithanxietyanddepressioncanactdirectlyonnumerouspartsofthebraintoexacerbatesymptoms,andwehypothesize theplacentahasaroleincontributingtotheriseininflammationwith pregnancyand,inturn,influencingmum’sbrain.Weareworkingonthe mechanismsrightnow;maybethisworkwillimpactthemanagementof perinatalmentalhealthsomewhereinthefuture.

Whathabitsandvaluesdidyoudevelopduringyouracademicstudies orsubsequentpostdoctoralexperiencesthatyouupholdwithinyour researchenvironment?

Sayyesasmuchasyoucan.Alwaysstayuptodatewiththeliterature, investtimeweeklyinsupportingyourteamandstudents,stayconnected withyourwidernetwork,andcommunicateclearly.Don’tbeafraidtoask forwhatyouneedortakeariskonanidea,andperseverewhenyoufail. Furtheryoureducation.

AboriginalandTorresStraitIslanderpeopleofAustraliadeserveequalopportunityinallaspectsofsociety,includingscience.Greaterinvestment inculturallyappropriateschooleducationforAboriginalandTorresStrait IslanderchildrenthatleadsthemtoculturallyappropriateUniversityeducationandacademiccareersisessentialforchangingtheoutcomesfor thisimportantpopulation.Iamespeciallypassionateaboutimprovingthe livesofAboriginalandTorresStraitIslanderwomenandseeingthemempoweredthrougheducation.

Whatdoyoumostenjoyinyourcapacityasanacademicor researchleader?

Ilovethewholejob,buttherearethreeaspectsofbeinganacademicthat Iparticularlyenjoy.Firstofall,thedata!Itisaprivilegetothinkabouta problem,formulateahypothesis,andtestit.Second,workingwithdifferentpeoplelocally,nationally,andinternationallywhohavedifferentareas ofexpertiseandthinkdifferentlyfromme.Third,andmostimportantly, beingabletomentorandsupervisestudents.

Outsideprofessionalconfines,howdoyouprefertoallocateyour leisuremoments,orconversely,inwhatmannerwouldyouenvision spendingthesemomentsgivenachoice?

Ihaveanamazinghusband,acircleofclosefriends,andabeautifulfamily, andmostofmyfreetimeisspentwiththem.IfIhadnothingelsegoing on,IwouldprobablysnorkelontheGreatBarrierReefeveryday.Iregret notbeingamarinebiologistsomedays.MaybeIwilldoanotherPhDin marinebiologywhenIretire!

Figure2. VickiCliftonandherpartnersnorkelingontheGreatBarrierReefnear Cairns.Shereflectedonherfirstreefexperience:“Wewereonanorganized tour,anditwasasillytouristpicture.However,itmakesmesmilewheneverI lookatitbecauseitwasanamazingday.”

Part2:ProfessorVickiClifton–SelectedquestionsfromtheProust Questionnaire1

Whatisyourideaofperfecthappiness? Ahealthyfamilyislivingtheirbestlife.

Whatisyourgreatestfear? Climatechange.

Whichlivingpersondoyoumostadmire? Manypeople.SenatorLindaBurney,JaneGoodall,andGretaThunberg.

Whatisyourgreatestextravagance? Longholidays.

Whatareyoumostproudof? Myfamily.

Whatisyourgreatestregret?

NotspeakingupwhenIknewsomethingwaswrongandnotfollowingmy intuitionwhenIknewitwasright.

Whatisthequalityyoumostadmireinpeople? Fearlessness.

1 Inthelatenineteenthcentury,variousquestionnaireswereapopulardiversion designedtodiscovernewthingsaboutoldfriends.Whatisnowknownasthe35questionProustQuestionnairebecamefamousafterMarcelProust’sanswersto thesequestionswerefoundandpublishedposthumously.Proustansweredthequestionstwice,atages14and20.In2003,Proust’shandwrittenanswerswereauctioned offfor$130,000.Multipleotherhistoricalandcontemporaryfigureshaveanswered theProustQuestionnaire,includingamongothersKarlMarx,OscarWilde,Arthur ConanDoyle,FernandoPessoa,StéphaneMallarmé,PaulCézanne,VladimirNabokov, KazuoIshiguro,CatherineDeneuve,SophiaLoren,GinaLollobrigida,GloriaSteinem, Pelé,Valentino,YokoOno,EltonJohn,MartinScorsese,PedroAlmodóvar,Richard Branson,JimmyCarter,DavidChang,SpikeLee,HughJackman,andZendaya.The ProustQuestionnaireisoftenusedtointerviewcelebrities:theideaisthatbyansweringthesequestions,anindividualwillrevealhisorhertruenature.WehavecondensedtheProustQuestionnairebyreducingthenumberofquestionsandslightly rewordingsome.Thesecuratedquestionsprovideinsightsintotheindividual’sinner world,rangingfromnotionsofhappinessandfeartoaspirationsandinspirations.

Whatisthetraityoumostdislikeinpeople? Ignorance.

Whatdoyouconsiderthemostoverratedvirtue? Cleanliness:Idespisehouseworkandthriveincreativeclutter.

Whatisyourfavoriteoccupation(oractivity)? Snorkeling.

Wherewouldyoumostliketolive? Ialreadylivethere:bytheoceaninAustralia.

Whatisyourmosttreasuredpossession? AcedarbedsidecabinetcarvedbymyGreatUnclePeterformyGreat AuntyCisswhentheywereengagedabout110yearsago.Theirloveand respectforeachotherwasinspirational.

Whenandwherewereyouhappiest?Andwhywereyousohappythen? IdidnotrealizeitwasmyhappiestdayuntilIlookedbackandfounditwas neverlikethatagain.Myclosestfamilyandfriends,whomIlovedearly, werealltogetheratmysecondwedding.Itwasagreatcelebrationbythe ocean,withthesunshiningandtheconversation,laughter,food,andwine flowingfreely.Sincethen,Ihavelostmanyofmyfamilymemberstoillness,accidents,andaging,sothatdaywillneverberecaptured.

Whatisyourcurrentstateofmind? Contentbutmotivated.

Whatisyourmostmarkedcharacteristic? Loyalty.

Amongyourtalents,whichone(s)give(s)youacompetitiveedge? Creativityandperseverance.

Whatdoyouconsideryourgreatestachievement? Translatingmyresearchintoatangibleoutcomeforwomen’shealth. Ifyoucouldchangeonethingaboutyourself,whatwoulditbe? Doubtinmyability.

Whatdoyoumostvalueinyourfriends? Loyalty.

Whoareyourfavoritewriters? WilliamKotzwinkleandAnitaDiamant.

Whoareyourheroesoffiction? AylainClanoftheCaveBearbyJeanAuels.

Whoareyourheroesinreallife? CaptainPaulWatsonandJulianAssange.

Whataphorismormottobestencapsulatesyourlifephilosophy? Carpediem.2

VickiL.Clifton1

1 MaterResearchInstitute,UniversityofQueensland,MaterMothersHospital, SouthBrisbane,Queensland4101,Australia e-mail: vicki.clifton@mater.uq.edu.au

Publisher’snote: GenomicPressmaintainsapositionofimpartialityandneutrality regardingterritorialassertionsrepresentedinpublishedmaterialsandaffiliations ofinstitutionalnature.Assuch,wewillusetheaffiliationsprovidedbytheauthors, withouteditingthem.Suchusesimplyreflectswhattheauthorssubmittedtousand itdoesnotindicatethatGenomicPresssupportsanytypeofterritorialassertions.

2 Latinphrasemeaning“seizetheday”–acalltomakethemostofthepresentmomentratherthanwaitingfortomorrow.

OpenAccess. The“GenomicPressInterview”frameworkiscopyrightedtoGenomicPress.Theinterviewee’sresponsesarelicensed toGenomicPressundertheCreativeCommonsAttribution-NonCommercialNoDerivatives4.0InternationalLicense(CCBY-NC-ND4.0).Thelicensemandates: (1)Attribution:Creditmustbegiventotheoriginalwork,withalinktothelicenseandnotificationofanychanges.Theacknowledgmentshouldnotimplylicensorendorsement.(2)NonCommercial:Thematerialcannotbeusedforcommercial purposes.(3)NoDerivatives:Modifiedversionsoftheworkcannotbedistributed. (4)Noadditionallegalortechnologicalrestrictionsmaybeappliedbeyondthose stipulatedinthelicense.Publicdomainmaterialsorthosecoveredbystatutory exceptionsareexemptfromtheseterms.Thislicensedoesnotcoverallpotential rights,suchaspublicityorprivacyrights,whichmayrestrictmaterialuse.Thirdpartycontentinthisarticlefallsunderthearticle’sCreativeCommonslicenseunless otherwisestated.Ifuseexceedsthelicensescopeorstatutoryregulation,permissionmustbeobtainedfromthecopyrightholder.Forcompletelicensedetails,visit https://creativecommons.org/licenses/by-nc-nd/4.0/.Thelicenseisprovidedwithoutwarranties.

INNOVATORS&IDEAS:RESEARCHLEADER

EuripedesC.Miguel:Riskfactorsforobsessive-compulsiveandothermentalhealth disordersandtheirtreatmentandpublicpolicyimplications

©TheAuthor(s),2024.ThisarticleisunderexclusiveandpermanentlicensetoGenomicPress

BrainMedicine March2025;1(2):18–21;doi: https://doi.org/10.61373/bm024k.0061

Keywords: OCD,DevelopmentalPsychiatry,DigitalMentalHealth, ImplementationScience

EuripedesConstantinoMiguelisafull,tenuredProfessorandHeadof theDepartmentofPsychiatryattheFacultyofMedicine,Universityof SãoPaulo(FMUSP),andanAdjunctAssociateProfessoratYale UniversitySchoolofMedicine.HegraduatedfromFMUSPand completedhisPsychiatryResidencyandPhDattheInstituteof PsychiatryattheUniversityofSãoPaulo.Afterapostdoctoral fellowshipatMassachusettsGeneralHospital,HarvardMedical School,ProfessorMiguelreturnedtoBrazilin1994topioneerthe Obsessive-CompulsiveSpectrumDisordersProgram.Heleadsthe NationalInstituteforDevelopmentalPsychiatry www.inpd.org.br, focusingonearlyidentificationandinterventionofmentalhealth disorders.Since2023,hehasledtheNationalCenterforScienceand InnovationinMentalHealth(CISM) www.cism.org.br,enhancing mentalhealtheducationandresearchthroughinnovativesolutions andpublic-privatepartnerships.ThisGenomicPressInterview featuresProfessorMiguel’scandidreflectionsonhisprofessional achievementsandlife’sjourney.

Part1:EuripedesC.Miguel–LifeandCareer

Couldyougiveusaglimpseintoyourpersonalhistory,emphasizing thepivotalmomentsthatfirstkindledyourpassionforscience?

IknewIwantedtobecomeaphysicianfromaveryearlyage.Myfather,a psychiatrist,servedasarolemodelforme.Itwascommonformyfatherto bringsomeofhispatients,whoweresometimesdepressiveorpsychotic, toourranch.Thisprovidedmewithauniqueopportunitytoobservetheir recoveryastheylivedwithus.IdidwhatIcouldtohelpandwasstruckby howrewardingtheseexperiencesweretomyfatherandme.Thus,mydecisiontobecomeadoctorwasstronglyassociatedwiththisfulfillingfeelingofhelpingpatients.Later,IenrolledintheFacultyofMedicineatthe UniversityofSãoPaulo(FMUSP),thetopmedicalschoolinBrazil.There, Iengagedinseveralacademicactivities,includingservingasPresident ofthestudentsportsclub(AssociaçãoAtléticaAcadêmicaOswaldoCruz). TheexperienceofrepresentingstudentstotheDeanandleadinginfindingwaystopursuecommongoalswasverysignificantforme,fostering asolidattachmenttomymedicalschool.Aftercompletingmyresidency inPsychiatry,IwassureIwantedtobecomeafutureleaderatFMUSP. Thisambitionmeantbecomingafullprofessor,whichrequiredpursuinganacademiccareer,includingobtainingaPhD,postdoctoraltraining abroad,anddevelopingmyresearchskills.Teachingbecamemypassion duringthistime,especiallyasIrecognizedthatteachingisthebestway tolearn.Inturn,Irealizedthatconductingresearchwasthebestwayto developcriticalthinking,whichallowedmetopreparebetterlectures.In thisway,researchbecameameanstoachievemygoals.Duringthisprocess,Ialsodiscoveredthatconductinghigh-qualityresearchandgaining

Received:27July2024.Accepted:30July2024. Publishedonline:5August2024.

deSãoPaulo,Brazil

deepknowledgeinaspecificareaalongsidecolleagueswasveryrewardingandgreatlyenjoyed.

Wewouldliketoknowmoreaboutyourcareertrajectoryleading uptoyourmostrelevantleadershiprole.Whatdefiningmoments channeledyoutowardthatleadershipresponsibility?

WhenIfinishedmyPhD,IwastheChiefoftheConsultationPsychiatric ServiceatourInstituteofPsychiatry.IchosetodomypostdoctoraltrainingatMassachusettsGeneralHospitalprimarilybecauseithasoneof thearea’smostrenowneddepartments.However,uponmyarrival,Irealizedthattheirfocuswasmuchmoreonteachingandclinicalcarethan onresearch,whichwastheprimarypurposeofmyscholarship.During thisperiod,IhadtheopportunitytoparticipateintheOCDClinicledby MichaelJenike.AlthoughOCDwasnotanareaofinterestformeatthat time,Isawthisasthebestopportunityavailable.Tobegininanarea whereIhadnopriorbackground,IstartedastudygroupwithScottRauch andLeeBaer(bothfromtheOCDClinic),KatherinePhillips,andBarbara Coffey,whowasatMcLeanHospitalnearby.Withtheirhelp,Ideveloped

Figure1. EuripedesC.Miguel,MD,PhD,FaculdadedeMedicina,Universidade

aprojectfocusedontheclinicalphenomenologyofOCDandTourette Syndrome.Duringtheproject’sdevelopment,IlearnedthattheChild StudyCenteratYalewasthemostproductiveinstitutioninTouretteSyndrome,withJamesLeckmanbeingoneoftheleadingfiguresinthisfield. IvisitedYaletopresentmyprojecttohimandhiscolleagues(David PaulsandDonaldCohen),andtheysoonbecamepartofmyproject,providingthemethodologicalrefinementIneeded.Severalpapersresulted fromthisfruitfulpartnership,andwehavecontinuedourcollaborations tothisday.BackinBrazil,IhelpedcreateacompetitiveOCDResearch groupthatwasoneofthemostproductiveintheworldformanyyears. In2009,apositionforFullProfessoratFMUSPwasannounced,andIsubmittedmyapplication,alongwithseveralothercolleagues.TheopportunitywasinChildandAdolescentPsychiatry,althoughIwasanadult psychiatrist.Therefore,mystrategywastoproposeaninnovativeproject focusedonidentifyingindividualsatriskforpsychiatricdisordersand interventionstomitigateorpreventsymptomexpression.Afewmonths beforetheopenselectionprocess,Brazil’stwomainresearchfoundations (CNPqandFAPESP)launchedasignificantgrantopportunity.Iapplied forthatgrantwithmycolleaguesLuizRohdeandJairMari(withwhom Ihavebeencollaboratingformorethan25years)andsuccessfullycreatedtheNationalInstituteforDevelopmentalPsychiatryforChildrenand Adolescents www.inpd.org.br,focusingontheearlyidentificationandinterventionofmentalhealthdisordersinindividualsatrisk.ThisgrantprovidedthecredentialsIneededtobecomeafull,tenuredProfessorofChild andAdolescentPsychiatryattheDepartmentofPsychiatryatFMUSP–whereIhavebeenconsistentlyelectedChair(orVice-Chair)ofthedepartmentforthepast15years.Therefore,Ibelievethatthedefiningmoments thatmadeallthispossibleinvolvedmakingthemostofthesituationsI encounteredbyadaptingmyskillsetstomatchavailableopportunities, choosingtherightpeopletoworkwith,andfosteringtheserelationships forlife.

Pleasesharewithuswhatinitiallypiquedyourinterestinyour favoriteresearchorprofessionalfocusarea.

Whatpiquedmyinterestweretheopportunitiesthataroseduringmycareerthatallowedmetodelivercaretothoseinneedinawaythatmade sensewithinthelargergoalofservingmyinstitutionasaleader.

Whatimpactdoyouhopetoachieveinyourfieldbyfocusingon specificresearchtopics?

Toprovidenewevidence-basedtreatmentsthatwillmakeadifference inthelivesofpatientswithOCDandtheirfamilies,andtoimplementa fewtestedinterventionsinmentalhealthcaredeliverythatcanbetransformedintopublicpolicies.

Pleasetellusmoreaboutyourcurrentscholarlyfocalpointswithin yourchosenfieldofscience.

IcontinuetoinvestintheareawhereIhavepublishedthemost,whichinvolvesObsessive-CompulsiveDisorder(OCD).Myworkismainlyfocused onclinicalphenotypes,theirunderlyingneurobiologicalsignatures,and howthisknowledgecanbetransformedintotreatmentsthatprovide somereliefforindividualswithOCDandtheirfamilies.Morerecently, Ihaveredirectedmyfocustotheearlyidentificationandintervention ofmentalhealthdisordersinindividualsatriskforsuchdisorders.In 2023,wecreatedtheNationalCenterforScienceandInnovationinMentalHealth(CISM)(www.cism.org.br).Throughthisgrant,whichreceives publicandprivatefunding,weaimtoidentifymodifiableriskandprotectivefactorsinacohortstudyinvolvingindividualsatriskformental healthdisorders.Afascinatingpartofthisprojectisthedevelopmentof scalabledigitalmentalhealthsolutionsbasedontheseriskfactorsthat wearetestinginpragmaticclinicaltrialstopromoteimprovedmental health.Additionally,otherinterventionsarebeingtestedinindividuals whohavealreadybeendiagnosedbutdonothaveaccesstotreatment. Oncetheireffectivenessisdemonstrated,theseinterventionswillbe implementedintwoseparatecitiesinBrazil,providingevidenceforthe

creationofpublicpolicieswiththepotentialtotransformthelivesofpeoplewithmentalhealthdisordersandtheirfamilies.

Whathabitsandvaluesdidyoudevelopduringyouracademicstudies orsubsequentpostdoctoralexperiencesthatyouupholdwithinyour researchenvironment?

Leadershipisbuiltnotthroughauthoritarianismbutbyaddressingthe needsofeachteammemberandfulfillingagreed-uponcommitments. Thisapproachrecognizesthatknowledgeisuniversalandshouldbe shared,which,inturn,producesateamthatgrowstogether,leadingto greatersuccess.

Morethanaspecificcause,whatcaptivatesmearevalues,suchastheidea ofseeking,inthemosthonestwaypossible,atruththatisonlyprovisional butoffersnewmodelsthathelpusmovebeyondcurrentlimitations–even ifthisprovisionaltruthultimatelyprovestobeanillusion.

Whatdoyoumostenjoyinyourcapacityasanacademicor researchleader?

Ifindbeingabletobringpeopletogetheraroundcommongoals,develop thebestineachofthem,andactaccordingtopreviouslymadeagreementskeepspeopleworkingtogetherforlongperiods.Inshort,toinspire anatmosphereoftrust.

Outsideprofessionalconfines,howdoyouprefertoallocateyour leisuremoments,orconversely,inwhatmannerwouldyouenvision spendingthesemomentsgivenachoice?

Mymother,MariaLydia,is93yearsold.Myfatherpassedaway15years ago.Ihavefourchildren,whoarenowadults.Threeofthemaremarried (Helena,Alice,andAndré),tomytwosons-in-law(ArthurandLuli)and mydaughter-in-law(Luciana),respectively.Gustavo,myyoungestson,is 17yearsold.Ihavefourgrandchildren(Tomás,Noah,Dudu,andLaila), withonemoregrandsonexpectedbytheendof2024.Thereisnothing Ienjoymorethanspendingtimewithallofthem,ifpossible,alongwith mywife,MariaLúcia.Ialsoenjoyspendingtimewithmyclosefriends. Individually,mymainhobbyisequestrianism,andIloveparticipatingin horsejumpingcompetitions.

Figure2. Amomentofjoywithmyentirefamilyin2024.

Part2:EuripedesC.Miguel–SelectedquestionsfromtheProust Questionnaire1

Whatisyourideaofperfecthappiness?

Idonotbelieveinperfecthappiness.Forme,happinessconsistsofinstants.TheseinstantsofhappinessoccurmorefrequentlywhenIamclose toandinteractingwithsignificantpeopleinmylife.

Whatisyourgreatestfear?

Makingwrongchoicesandlosingsignificanttimeinmylife,especially nowthatIdonothavemuchleft.

Whichlivingpersondoyoumostadmire? Therearesomany:Icannotchoosejustone.

Whatisyourgreatestextravagance? Practicingequestrianism.

Whatareyoumostproudof? ThefamilyandfriendsIhavebuiltovermylife.

Whatisyourgreatestregret?

Ihaveseveral.Icannotnamethegreatest,butIhopeIhavelearnedfrom eachone.

Whatisthequalityyoumostadmireinpeople? Transparencyandgenerosity.

Whatisthetraityoumostdislikeinpeople? Dishonestyorinsincerity.

Whatdoyouconsiderthemostoverratedvirtue? Gratitude.

Whatisyourfavoriteoccupation(oractivity)? Beingadoctorcaringforpatients.

Wherewouldyoumostliketolive? Inmycurrenthome.

Whatisyourmosttreasuredpossession? Myfamily.

Whenandwherewereyouhappiest?Andwhywereyousohappythen? IamhappiestwhenIamgatheredaroundabigtablewithmywife,mychildren,theirsignificantothers,andmygrandchildren–justhangingaround. Thesemomentsoftogethernessandthejoyofbeingsurroundedbymy lovedonesbringmeimmensefulfillment.

Whatisyourcurrentstateofmind? Unsettled,inaconstantsearchforwisdom.

Whatisyourmostmarkedcharacteristic?

Energetic,determined,andresilient.

Amongyourtalents,whichone(s)give(s)youacompetitiveedge? Iamgoodatbringingpeopletogethertoworktowardscommongoals overextendedperiods,ensuringthatagreementsandcommitmentsare fulfilled.

Whatdoyouconsideryourgreatestachievement?

ThatIhaveafamilythatchosestobewithmewhentheydonothaveto be.

Ifyoucouldchangeonethingaboutyourself,whatwoulditbe? Iwanttobemorepresentandavailable,particularlytosignificantpeople inmylife.

Whatdoyoumostvalueinyourfriends?

Genuinewarmthandacceptance,allowingmetotrulybemyself.

Whoareyourfavoritewriters?

Idonothaveafavoritewriter.ThismaybebecauseIdonotconsidermyselfanintellectual.EverythingIreadisassociatedwithpracticalapplication,includingmyresearchwork.Thus,Ireadextensivelyontopicsrelated tomyprofession.Ienjoyednovelsandsuspensebooksinthepast,but nowIseekoutbooksthatofferwisdom,oftenrecommendedbypeopleI admire.

Whoareyourheroesoffiction?

Ihaveaprofoundadmirationforheroes,bothrealandfictional.WhenI wasyounger,Ioftenimaginedmyselfasahero.AsIgotolder,theprospect ofaheroicdeathorgainingprestigeattheexpenseofdoingsomething detrimentaltomyselfbecamelessappealingtome.So,Itransformedthis admirationintoadesiretotakeonleadershiprolesguidedbytheprinciple ofleadingtoserve.ThisideawaslikelyinstilledinmebytheJesuitsduring mytimeatColégioSãoLuiz.

Whoareyourheroesinreallife?

Mynumerousmentors.Amongthem,Ihighlightmyfather,whoseexampleinspiredmetobecomeapsychiatrist;duringmymedicalstudies,Paulo VazdeArruda,whoexemplifiedalovingattitudeintherelationshipbetweenaprofessorandastudentandwhoseinfluencehadatransgenerationaleffectonme;ValentimGentilFilho,myrolemodelasaphysician, demonstratingmethodologicalrigorinresearchandcareforpublicresponsibilitiesinleadershiproles;andJamesLeckman,whoisanexampleofgenerosityinsharingknowledgeandpursuingprojectswithsocial relevance.

Whataphorismormottobestencapsulatesyourlifephilosophy?

Thepoem‘Dreams’byLangstonHughesbestencapsulatesmylifephilosophy:

Holdfasttodreams

Forifdreamsdie

Lifeisabroken-wingedbird

Thatcannotfly.

Holdfasttodreams

Forwhendreamsgo

Lifeisabarrenfield

Frozenwithsnow.

Hughes,aleadingvoiceoftheHarlemRenaissance,capturedprofound truthsinaccessiblelanguage.Thispoemremindsusthatouraspirations givelifemeaningandpropelusforward.Throughoutmycareer,Ihave oftenreturnedtotheselineswhenfacingchallenges,findinginthemthe strengthtopersevere.

EuripedesC.Miguel1

1 FaculdadedeMedicina,UniversidadedeSãoPaulo,05469-030SãoPaulo, SãoPaulo,Brazil

e-mail: ecmiguel@usp.br

changes.Theacknowledgmentshouldnotimplylicensorendorsement.(2)NonCommercial:Thematerialcannotbeusedforcommercialpurposes.(3)NoDerivatives: Modifiedversionsoftheworkcannotbedistributed.(4)Noadditionallegalortechnologicalrestrictionsmaybeappliedbeyondthosestipulatedinthelicense.Public domainmaterialsorthosecoveredbystatutoryexceptionsareexemptfromthese terms.Thislicensedoesnotcoverallpotentialrights,suchaspublicityorprivacy rights,whichmayrestrictmaterialuse.Third-partycontentinthisarticlefallsunderthearticle’sCreativeCommonslicenseunlessotherwisestated.Ifuseexceeds thelicensescopeorstatutoryregulation,permissionmustbeobtainedfromthe copyrightholder.Forcompletelicensedetails,visit https://creativecommons.org/ licenses/by-nc-nd/4.0/.Thelicenseisprovidedwithoutwarranties.

INNOVATORS&IDEAS:RESEARCHLEADER

AnnamariaCattaneo:Threemainquestions:Stress,mental,andphysicalhealth:Is thegutmicrobiomethekey?Whicharethebiologicalmechanismsdrivingperinatal depression,andhowdotheyaffectthementalandphysicalhealthoftheoffspring? Pharmacologicalandnon-pharmacologicalinterventionsinreducingtheriskof developingmooddisordersorinimprovingsymptomatology:Isinflammationthe keydriver?

©TheAuthor(s),2024.ThisarticleisunderexclusiveandpermanentlicensetoGenomicPress

BrainMedicine March2025;1(2):22–25;doi: https://doi.org/10.61373/bm024k.0079

Keywords: Stress,inflammation,gutmicrobiome,interventions, biomarkers,mooddisorders

AnnamariaCattaneoisanAssociateProfessorattheUniversityof Milan,DepartmentofPharmacologicalandBiomolecularSciences, andtheHeadoftheLaboratoryofBiologicalPsychiatryattheIRCCS FatebenefratelliInstituteinBrescia,wheresheisalsoDeputy ScientificDirector.Sheiscurrentlyassociateeditorof Brain, Behavior,&Immunity—Health,anofficialjournalofthe PsychoneuroimmunologyResearchSociety.Shededicatesher researchtounderstandingthecomplexinterplaybetweenearlylife adversitiesandthedevelopmentofmentalhealthdisorders.Herwork focusesonthebiologicalmechanisms,suchasneuroplasticity, inflammation,gutmicrobiome,andepigenetics,thatconnectearly lifeexperiencestomentalhealthvulnerabilitieslaterinlife. Recently,DrCattaneohasexpandedherresearchtoexplorethe liver-brainaxisanditsroleinthedevelopmentofcomorbidities betweenmentalandphysicaldisorders.Additionally,sheisactively involvedinidentifyingperipheralbiomarkersassociatedwiththerisk ofdevelopingmooddisordersandtreatmentresponse.Asignificant focusofhercurrentworkisonperinataldepression,aimingto uncoverthebiological,social,andenvironmentalfactorsthatshape theriskfordepressionduringpregnancyanditsimpactonoffspring outcomes.AstheCoordinatorofthe HappyMumsProject,aHorizon Europeinitiative,sheleadseffortstoimproveourunderstanding ofthebiologicalmechanismsunderlyingthedevelopmentof depressivesymptomsinpregnancyandtheefficacyofinterventions. DrCattaneo’spassionforherworkextendsbeyondthelaboratory,as sheactivelyengagesindisseminationactivitiestoraiseawareness aboutmentalhealthissuesamongthegeneralpopulation.Through eventslikethe HappyRun intheMonzaParkand LucieOmbre / LightsandShadows,shebringstogetherscience,art,andcommunity topromotementalwell-being.Inthis"GenomicPressInterview," AnnamariaCattaneokindlysharesinsightsintoherlifeand impressivecareer,providingourreaderswithaglimpseintothe drivingforcebehindherground-breakingresearchandtireless effortstoadvanceourunderstandingofmentalhealth.

Part1:AnnamariaCattaneo–LifeandCareer Couldyougiveusaglimpseintoyourpersonalhistory,emphasizing thepivotalmomentsthatfirstkindledyourpassionforscience? Fromayoungage,Ihavebeendeeplydrawntoscientificinquiry.Thispassionhasshapedmyacademicjourney,guidingmetowarddisciplineslike molecularbiologyandpharmacology.

Received:28August2024.Accepted:20September2024. Publishedonline:3October2024.

Figure1. AnnamariaCattaneo,PhD,UniversityofMilanandIRCCSCentroSan GiovannidiDio–Fatebenefratelli,Italy.

Growingup,Iwasalwayscuriousabouthowthingsworked.However,it wasonlyinhighschoolthatItrulyrealizedthedepthofmyinterest.Ihad abiologyteacherwhobroughtthesubjecttolife,explainingcomplexconceptsinawaythatmadethemfascinatingandaccessible.Istartedtodevelopaninterestinthefieldofmedicine.However,intheway,Iwantedto knowmoreaboutthecausesofunderlyingpathologiesandwaystotreat themsuccessfully.Inthatperiod,Ialsolostafamilymemberbecauseof anillness(cancer),andthiseventstrengthenedmydeterminationtoexploreanddiscovertheoriginsofcertainmedicalconditionsandtoseek waystopreventortreatthem.Iunderstoodthepowerofsciencetonot onlyanswerquestionsbutalsotoasknewones.Thisrealizationdrove metopursueacareerinresearch,whereIcanexploretheunknownand

contributetoexpandingourunderstandingoftheworld.Theseexperiences,combinedwithadeep-seatedcuriosityandadrivetomakeameaningfulimpact,havefuelledmypassionforscienceeversince.Theysetme onapaththathasbeenbothchallengingandincrediblyfulfilling,andthey continuetoinspiremeinmyworktoday.

Wewouldliketoknowmoreaboutyourcareertrajectoryleadingupto yourmostrelevantleadershiprole.Whatdefiningmoments channelledyoutowardthatleadershipresponsibility?

AlthoughIinitiallyfocusedoncancerresearchduringmystudiesatthe University,mycareerpathshiftedafteraone-yearresearchtraineeship inalaboratoryspecializinginpreclinicalmentaldisordersstudies.This experiencesparkedanewdirectioninmyresearchinterests.Also,immediatelyaftermydegreeinpharmacy,IhadtheopportunitytopursueaPhD inmoleculargeneticsandapplyittomedicalsciencesatapsychiatricinstitute,enablingmetocontinuefocusingonmentaldisorders.ConductingmyPhDresearchatapsychiatrichospitalprofoundlyimpactedmycareertrajectory,asitdeepenedmyunderstandingofthecriticalrolethat scienceandresearchplayinadvancingthementalhealthfield.Thisexperiencenotonlyintensifiedmypassionforthefieldbutalsoallowed metodevelopcriticalaspectsofmyresearchindependently.Duringmy PhD,Ihonedessentialskillssuchasgrantwritingandstudentsupervision,whichhavebeeninstrumentalinmycareer.Anotherimportantmomentwasin2013,whenIsecuredmyfirstgrant—anERANETNeuron grant—whichnotonlyfundedmyownsalarybutalsosupportedthefirst tworesearcherswhojoinedmyteam.Thismarkedthebirthandgrowth ofmylab,whichnowincludes21researchers,rangingfromundergraduatestudentstoPhDcandidatesandpostdoctoralfellows,andmorethan 15grant-fundedprojects.

Pleasesharewithuswhatinitiallypiquedyourinterestinyour favouriteresearchorprofessionalfocusarea. Duringmycareer,Ihavealwaysbeeninterestedinthelinkbetweenadverseexperiencesinearlylife—suchaschildhoodandadolescence—and theonsetofmentalillnessesinadulthood.Thebirthofmythreechildren hassignificantlyenrichedmylifeandsharpenedmyscientificfocuson theprofoundbiologicalchangesinwomenduringsensitiveperiodssuch aspregnancyandpost-partum.Differentlinesofresearchhighlightthe crucialimpactoftheperinatalperiodonlong-termdevelopmentaloutcomesinchildren.Thishasdeepenedmyscientificinterestinunderstandinghowstressandotheradverseexposuresduringtheperinatalperiod mightinfluencetheimmediatehealthofmothersandtheirchildrenand thepotentialtransgenerationaleffects.Furthermore,giventhesignificantroleoftheenvironmentinshapingbothindividualvulnerabilityand resilience,Iamparticularlyinterestedininvestigatingpostnatalfactors thatmayserveasmoderatorsandprotectorsagainstrisksestablishedin uterothatcanarisefrommaternalmentalillnessorhigh-stressexposure duringpregnancy.Thesepostnatalprotectivefactorscouldbeessential inpotentiatingresilience,andindeed,myresearchfocusesonhowthese postnatalinfluencescanpotentiallymitigateorbuffertheadverseeffects ofprenatalstressors,ultimatelypromotinghealthierdevelopmental outcomes.

Myresearchnowseekstoelucidatethecomplexbiologicalmechanismsthatmediatetheseimpacts,includinghormonal,inflammatory,and epigeneticchanges,toinformmoreeffectiveinterventionsandpreventivestrategies.

Whatimpactdoyouhopetoachieveinyourfieldbyfocusingon specificresearchtopics?

TheseveralprojectsI’mfocusingonallshareacommongoal:toimprove thewell-beingofindividualswithmentaldisordersorthosewhoareat highriskofdevelopingthesepathologies.Muchofmyresearchfocuseson identifyingbiomarkersinbloodorsaliva,whichcanbepivotalinenhancingclinicalpracticesforprevention,diagnosis,andtreatment.Recently, I’veexpandedmyworktoincorporateAItools,aimingformoredirectand non-invasiveimpactsonpublichealth.Forinstance,theprojectsfocused

onperinatalpsychiatryincludeanappdesignedtoremotelygatherdifferentdatafrommothers,monitorandenhancelifestylechoicestopromote mentalwell-beingduringpregnancy,andcontinuouslyassesstheeffectivenessoftreatments.

Pleasetellusmoreaboutyourcurrentscholarlyfocalpointswithin yourchosenfieldofscience?

Mymainscientificinterestliesinexploringtherolesofinflammation, stress,and,morerecently,thegutmicrobiome.Abetterunderstandingof thealterationsinthesebiologicalprocessesthatcanbeobservedinpatientssufferingfrombothmentalandphysicalillnessesispivotalforthe developmentofpersonalizedinterventions.Forinstance,it’scommonto findthatpatientswithdepressionhaveundergonestressfulevents,exhibitheightenedcentralandperipheralinflammation,andexperienceintestinaldysbiosis.Additionally,someofthesepatientsdonotrespondto conventionaldrugtreatments.Thisevidencedrivesmycuriositytounderstandhowthesefundamentalmechanismsareinterconnectedandhow theyinfluenceresponsestopharmacologicalinterventions.Mygoal,as Ihavementioned,ispatientcare:bydelvingdeeperintothesemechanisms,Ihopetocontributetooptimizingtherapeuticapproaches,potentiallyreducingtheneedforpatientstoenduremultiple,oftenunsuccessful,treatmenttrials.

Whathabitsandvaluesdidyoudevelopduringyouracademicstudies orsubsequentpostdoctoralexperiencesthatyouupholdwithinyour researchenvironment?

Duringmystudiesandpostdoctoralexperiences,Ilearnedtheimportance ofmaintainingrigorousscientificmethods,ensuringthatallexperiments aremeticulouslydesignedandexecutedpreciselyandaccurately.Now, asalableader,Iprioritizeupholdingthesestandards,notonlyformyselfbutalsofortheresearchersImentor.Thisdisciplineisfundamental topublishingreliablepapersandensuringthatourresultscanbereproduciblebyothers,aboveourselves,whichiscrucialforadvancingscientific knowledge.

Iamalsodedicatedtoconductingallworkwithtransparencyand honesty,ensuringthateveryresultisreportedaccurately.Upholding theseethicalstandardsisessentialformaintainingthecredibilityofour research.

Additionally,Ihavealsolearnedtheimportanceofcuriosity,collaboration,andperseverance,valuesthatItrytodisseminatetopeoplein mylab.Byregularlyengagingwithhigh-qualityresearchpublications,we canfeedourintellectualcuriosityandexpandourknowledge,allowing ustodevelopnewideasandapproaches.Researchcannotbedonebya singleresearcher/individual:interactingwithothersisessentialtorefiningourworkandmakingourprojectsmorecompetitive.Theexchange ofideasoftenleadstobreakthroughsthatwouldonlybepossible.Perseveranceisequallycrucial.Consistent,hardwork—approachedwithdeterminationratherthansuperficiality—isthekeytoproducinghigh-quality researchthatleadstoimpactfulpublications.Ialsolearnedtheimportanceofmentorship.Therefore,Iactivelyworktosupportthegrowthof youngerresearcherslikemymentorssupportedme.Iprioritizefostering alearningenvironmentwhereeveryonefeelsempoweredtosucceed.

AtGenomicPress,weprioritizefosteringresearchendeavoursbased solelyontheirinherentmerit,uninfluencedbygeographyorthe researchers’personalordemographictraits.Arethereparticular culturalfacetswithinthescientificcommunitythatwarrant transformativescrutiny,oristhereacausewithinsciencethatdeeply stirsyourpassions?

IfeelperfectlyalignedwiththeprioritiesadoptedbyGenomicPress.

Whatdoyoumostenjoyinyourcapacityasaresearchleader?

Iamincrediblyfortunatetobeascientist.WhatImostenjoyasanacademicandresearcheristheopportunitytoexploreunchartedscientific territoriesandcontributeknowledgethatcanhaveatangibleimpact onpatients’lives.Itakegreatsatisfactionindevelopingprojectsand

designinginterventionstoimprovepatients’well-beingandqualityof life,abovetheirsymptoms,andininspiringthenextgenerationof researchers.

Outsideprofessionalconfines,howdoyouprefertoallocateyour leisuremoments,orconversely,inwhatmannerwouldyouenvision spendingthesemomentsgivenachoice?

Ilovespendingtimewithmyfamilyandtraveling.Ourhomesettingencouragesoutdooractivitiesinnature,suchaswalkingorhavingpicnics inthenearbymountains.Iplantripstoenjoyqualitytimetogether,ideallybytheseasidewheneverpossible.Ialsoorganizespecialoutingswith justoneofmychildren,allowingmetofocusoneachofthemindividually. Forexample,whenItravelforconferencesabroad,Isometimesbringmy daughtertohavesomeone-on-onetimetogether.Lastyear,Ialsotook mysecondchild,whowaseightyearsold,withmetoTurinbecauseIhad atalkthere.Duringmyfreetime,wevisitedtheJuventusstadium,hopingIcouldpersuadehimtoswitchallegiancetomyfavouriteteam.Unfortunately,myeffortsfailed—heremainsasteadfastInterfan.Weeven stoppedbytheJuventusshoptobuyajersey,butwhenthestaffasked whichnametoputonit,heboldlyrequestedthenameofanInterplayer. Itrulywantedtodisappearrightthere—onthespot.

Part2:AnnamariaCattaneo–Selectedquestionsfromthe ProustQuestionnaire1

Whatisyourideaofperfecthappiness?

Myideaofhappinessisconnectedtosmall,simplemoments—thosebrief, individualexperiencesoreventsduringtheday,suchasatextmessage, ahug,asmile,comingbackhomeafteratoughworkingday,orevenan emailsayingthatasubmittedpaperhasbeenacceptedforpublication orasymposiumacceptedforaconference.Tome,happinessalsomeans peacefulnessandtheabsenceofworries.

Whatisyourgreatestfear?

Astrivialasitmaysound,mygreatestfearisdeath.Deathfeelsinsurmountable,unlikeotherchallengeswemayface,whichcanoftenbeovercome,tolerated,orresolved.

Whichlivingpersondoyoumostadmire?

It’sapersonveryclosetomewho,despitehehadtofacedifficultexperiences,healwaysfindsawaytosmileandtostaypositive.Whennegative thingshappentome,healwaysencouragesmeandobligemetofocuson positiveaspectsIhave.

Whatisyourgreatestextravagance?

Balancingacareerasascientistwithraisingthreeyoungchildren.

Whatareyoumostproudof?

ThepassionandenthusiasmIputintoeverythingIdo:Iamamomofthree youngkidsandascientistmanagingalabwithmorethan20researchers.

Figure2. Dr.AnnamariaCattaneoenjoyingasunnydaybythesea,herpreferredlivingenvironment.TheimagecapturesDr.Cattaneosmilingwarmly whilewearingawovensunhat,embodyingthecalmingandinspirational atmosphereshedescribesasheridealsetting.Theclearblueskyandglimpse ofcolourfulfoliageinthebackgroundhintattheseasidelocationshefinds soappealingforitssoothingwaves,refreshingbreezes,andinvigorating sunlight.

Whatisyourgreatestregret?

Ihaveyettobeabletorenovatemyparents’house,whichiswhereIwould lovetomovewithmyfamily.

Whatisthequalityyoumostadmireinpeople? Respect,honesty,andtransparency.

Whatisthetraityoumostdislikeinpeople? Selfishness.

Whatdoyouconsiderthemostoverratedvirtue? Modesty.

Whatisyourfavouriteoccupation(oractivity)?

Scientificdisseminationiscertainlyoneofmyfavouriteactivitiesinthe workingenvironment,whetheritisdoneinthemostclassicwayor throughmoreoriginal,pleasurable,andentertainmentactivities.The ideais,therefore,toreachnotonlythescientificcommunitybutalso youngpeopleandpeopleingeneral.

Wherewouldyoumostliketolive?

Acitybytheseaismypreference.Thesoundofthewaves,theseabreeze, andthesunlightcreateacalmingatmosphereandserveasasourceof inspiration(Figure2).

Whatisyourmosttreasuredpossession?

It’satravelsouvenir,specificallyabagwovenfrompalmleavesIbrought backfrommytriptoTanzania.

Whenandwherewereyouhappiest?Andwhyweresohappythen?

Thebirthofmychildrenisoneofthemostjoyfulmomentsofmylife,becausethisfilledmewithloveandgratitude.Ithasforeverchangedthe wayIviewtheworldandpeoplearoundme.

Whatisyourcurrentstateofmind? Mostlypositive.

Whatisyourmostmarkedcharacteristic?

Mymostdistinctivetraitisperseveranceandtheabilitytobounceback.

Amongyourtalents,whichone(s)give(s)youacompetitiveedge?

Atalentthatsetsmeapartismyemotionalintelligence.Myabilitytounderstandandregulatebothmyownemotionsandthoseofothersenables metonavigatecomplexinterpersonaldynamics,fosterstrongrelationships,andleadteamseffectively,evenindifficultcircumstances.

Whatdoyouconsideryourgreatestachievement?

Asignificantachievementinmycareerhasbeenmyprogressoverthe years.In2013,Isecuredmyfirstgrant—anERANETNeurongrant—which fundedmysalaryandsupportedthefirsttworesearcherswhojoinedmy team.Today,mylabhasgrowntoinclude21researchers,includingPhD students.Thisgrowthisatestamenttoyearsofperseverance,dedication, andhardwork,aswellasthesupportmyfamilyreceived.Icouldneverbe ascientistinmycareerand,atthesametime,raisethreekidswithoutthe supportfrommyfamily.

Ifyoucouldchangeonethingaboutyourself,whatwoulditbe?

IfIcouldchangeonethingaboutmyself,itwouldbetostrikeabetterbalancebetweendirectnessanddiplomacy.WhileIvaluehonestyandtransparency,Irecognizethatsometimesamorenuancedapproachisneeded tocommunicateeffectivelyandmaintainharmoniousrelationships.

Whatdoyoumostvalueinyourfriends?

Inmyfriends,Iappreciatetrust,honesty,andempathy.

Whoareyourfavouritewriters?

Honestly,Ihavenothadmuchtimetoreadbookslately.Afewyearsago, whenIhadmorefreetime,IreadseveralbooksbyBambarenandKing Albon.

Whoareyourheroesoffiction?

MyfavouriteheroisCatwoman,acomplexandintriguingcharacterknown foragility,cunning,strength,andindependence.Asamasterthiefwitha robustmoralcode,sheoftenstraddlesthelinebetweenheroandanti-

hero.Herfelineeleganceandoriginalitymakeheraformidablepresence, whileherdepthanddualityrevealalayeredpersonalitythatchallenges conventionalnotionsofgoodandevil.

Whoareyourheroesinreallife?

JaneGoodall:Arenownedprimatologistandconservationist,Jane Goodall’spioneeringstudiesonchimpanzeesrevolutionizedourunderstandingofanimalbehaviour.Herlifelongdedicationtowildlifeconservationandhumanitarianworkhasmadeheraleadingenvironmentaland animalrightsadvocate.

Whataphorismormottobestencapsulatesyourlifephilosophy?

HereIwouldliketociteasongfromoneofmyfavouriteItaliansingers, VascoRossiwhichsays: “Iwantarecklesslife;Iwantalifelikeinthe movies;Iwantalifewhereit’snevertoolate;Oneofthosewhereyounever sleep;Iwantalife;You’llseewhatalifeitwillbe,uh."

AnnamariaCattaneo1

1 DepartmentofPharmacologicalandBiomolecularSciences, UniversityofMilan,20133Milan,Italy e-mail: annamaria.cattaneo@unimi.it

Publisher’snote: GenomicPressmaintainsapositionofimpartialityandneutrality regardingterritorialassertionsrepresentedinpublishedmaterialsandaffiliations ofinstitutionalnature.Assuch,wewillusetheaffiliationsprovidedbytheauthors, withouteditingthem.Suchusesimplyreflectswhattheauthorssubmittedtousand itdoesnotindicatethatGenomicPresssupportsanytypeofterritorialassertions.

INNOVATORS&IDEAS:RESEARCHLEADER

CelsoArango:Thefutureofpsychiatryinevitablydependsonprimaryprevention

©TheAuthor(s),2024.ThisarticleisunderexclusiveandpermanentlicensetoGenomicPress

BrainMedicine March2025;1(2):26–28;doi: https://doi.org/10.61373/bm024k.0091

Keywords: Prevention,childandadolescentpsychiatry,riskfactors, resilience,neurodevelopmentaldisorders

Dr.CelsoArangostandsasapreeminentauthorityinpsychiatry, wieldingconsiderableinfluencethroughhismultifacetedroles.As DirectoroftheInstituteofPsychiatryandMentalHealthatHospital GeneralUniversitarioGregorioMarañónandProfessorofPsychiatry attheUniversidadComplutensedeMadrid,hespearheadsSpain’s advancementsinmentalhealthresearchandtreatment.Dr.Arango’s expertiseresonatesglobally,reflectedinhisvisitingprofessorships atrenownedinstitutions,includingtheUniversityofCalifornia,San Francisco,theUniversityofMaryland,andKing’sCollegeLondon.His commitmenttointernationalcollaboration,evidencedby partnershipswithover100institutionsworldwide,significantly propelstheglobalpsychiatriccommunityforward.Dr.Arango’s exceptionalcontributionshavegarneredprestigiousaccolades, notablyhiselectionastheyoungestmemberoftheRoyalNational AcademyofMedicineinSpainandhisrecentinductionintothe NationalAcademyofMedicineintheUnitedStates.Atthecoreofhis researcheffortsliesadedicatedfocusonearly-onsetpsychosisand neurodevelopmentaldisordersinyoungindividuals,workthatnot onlyadvancesscientificunderstandingbutalsoofferstangiblehope forimprovedtreatmentoutcomes.Dr.Arango’suniqueblendof clinicalexpertise,researchacumen,andacademicleadership positionshimatthevanguardofinnovationinmentalhealthcare, potentiallyrevolutionizingourapproachtounderstandingand treatingpsychiatricdisordersacrossthelifespan.Inthisexclusive GenomicPressInterview,Dr.Arangosharesinsightsonhislifeand career,offeringourreadersaglimpseintothemindofoneof psychiatry’smostinfluentialfigures.

Part1:CelsoArango–LifeandCareer

Couldyougiveusaglimpseintoyourpersonalhistory,emphasizing thepivotalmomentsthatfirstkindledyourpassionforscience?

WhenIwasachild,Irememberhelpingmyfather,whowasapsychiatrist, byplacingtherequiredstampsonhisprescriptions.Ialsolistenedtohis fascinatingandcuriousstoriesaboutclinicalcasesheattendedworldwide.Ihavealwaysbeenobsessedwiththetruthandhaveneverliked peoplewhoexpecttheiropinionstobeacceptedwithoutdatatoback themup.

Wewouldliketoknowmoreaboutyourcareertrajectoryleadingupto yourmostrelevantleadershiprole.Whatdefiningmoments channeledyoutowardthatleadershipresponsibility?

Ihavealwaysbeenrestlessanddrivenbythesearchfornewchallenges andopportunities.AlthoughIwasborninPalmadeMallorca,Istudied medicineinOviedo,innorthernSpain,wheremyfather’sfamilyisoriginallyfrom,aswellasinManchester,intheUnitedKingdom.Aftercompletingmyresidencyinpsychiatry,Ipursuedafellowshipinschizophrenia researchattheUniversityofMaryland.There,Imetmymentor,Professor WilliamCarpenter,whohasguidedmeeversince.

Received:1October2024.Accepted:3October2024. Publishedonline:10October2024.

UponmyreturntoSpain,Ibeganmyworkwiththefirmbeliefthat strengthliesinunity,modesty,andcollaboration.IbecamethefirstscientificdirectoroftheSpanishNetworkedCenterforMentalHealthResearch(CIBERSAM),and,togetherwithotheroutstandingpsychiatrists inSpain,suchasEduardVieta,IhelpedensurethatSpanishpsychiatry collaboratedacrossanetworkwithmanyotherscientificdisciplines.I currentlyrunwhatislikelythelargestdepartmentofpsychiatryinthe country,withover350staffmembers.

Pleasesharewithuswhatinitiallypiquedyourinterestinyour favoriteresearchorprofessionalfocusarea

Myresearchhasevolved,likelyreflectingmybeliefthatresearchshould bedynamicandinformedbyitsresults.Iinitiallyfocusedonschizophrenia

Figure1. CelsoArango,MD,PhD,HospitalGregorioMarañón,UCM,CIBERSAM, Madrid.Spain.

Figure2. CelsoArangoparticipatingintheLanzaroteInternationalHalf MarathonontheIslandofLanzarote,CanaryIslands,Spain.Amidsttheiconic palmtreesoftheisland,Dr.Arangoiscapturedinfullstride,flashingabright smileandathumbs-uptoonlookers.Hisenthusiasticengagementinthischallengingeventreflectstheenergyanddeterminationhebringstohispioneeringworkinpsychiatry.Thevibrantislandsettingprovidesastrikingcontrast toDr.Arango’susualclinicalenvironment,highlightinghisabilitytobalance rigorousprofessionalpursuitswithanactivelifestyle.

andfirstpsychoticepisodes,primarilyinchildandadolescentpopulations.Ithenbecameinterestedinsecondarypreventionofpsychosis, followedbyresearchintoprodromalstagesandriskfactorsforpsychosis.Currently,Iamfocusedonprimarypreventionofmentaldisorders,exploringuniversal,selective,andindicatedprimaryprevention strategies.

Whatimpactdoyouhopetoachieveinyourfieldbyfocusingon specificresearchtopics?

Ihavecometounderstandthattherearenospecificriskorresiliencefactorsforparticulardisordersandthattheincreaseintheincidenceand prevalenceofmentaldisorderscanonlybeaddressed,asinmanyother areasofmedicine,throughprimaryprevention.

Pleasetellusmoreaboutyourcurrentscholarlyfocalpointswithin yourchosenfieldofscience

Weneedtolearntoworkwithbasicresearcherstounderstandthemechanismsthroughwhichriskfactorsshapebrainfunctionandgeneexpression,andwithmanyotherspecialtiesanddisciplinestoeffectively preventmentaldisordersbyminimizingriskfactorsandenhancingresilience.Wemustcollaboratewithobstetricians,neonatologists,pediatricians,educators,employers,policymakers,sociologists,andothers.

Whathabitsandvaluesdidyoudevelopduringyouracademicstudies orsubsequentpostdoctoralexperiencesthatyouupholdwithinyour researchenvironment?

Igreatlyappreciateflexibility,originality,anddisruptivethinkingthat questionswidelyacceptedbeliefs.Valuessuchashonesty,humility,and punctualityarealwaystopprioritiesforme.Ilovebeingsurroundedby peoplewhoknowmorethanIdoandhavingtheopportunitytolearn somethingnewdaily.

Unfortunately,theSpanishsystemhastraditionallybeeninfluencedby nepotismandestablishedconnectionsratherthanmeritocracy.Itisanunjustsystemthatprioritizesone’slastnameandpersonalconnectionsover individualmerit.Thissystemhasharmedgenerationsofyoungtalentwho havehadtoemigrateorgiveupontheirdreams.

Whatdoyoumostenjoyinyourcapacityasanacademicor researchleader?

Igreatlyenjoyteachingpsychiatrytofifth-yearmedicalstudentsand watchingasyoungresearchersIhavetrainednowleadtheirinvestigations.

Outsideprofessionalconfines,howdoyouprefertoallocateyour leisuremoments,orconversely,inwhatmannerwouldyouenvision spendingthesemomentsgivenachoice?

Ienjoyplayingsports,especiallyrunning,asithelpsmerelievemuch stress.Ialsoloveparticipatinginmychildren’sactivities,suchassoccer andpaddletennis.Wetrytotakeafamilytripeveryyear,andIenjoyour summerbreakinViveiro,avillageinnorthernGaliciawherewehavea familyhome.Timeseemstopassmuchmoreslowlythere.

Part2:CelsoArango–SelectedquestionsfromtheProust Questionnaire1

Whatisyourideaofperfecthappiness?

Idonotbelieveinperfecthappiness;itspursuitcanonlyleadtofrustrationanddissatisfaction.

Whatisyourgreatestfear?

Iworrythatmychild’sneeds,assomeonewithsevereintellectualdisabilities,willnotbemetwhenIamnolongerinthisworld.

Onabroaderlevel,mygreatestfearishowpopulism,post-truththinking,andextreme,reductionistpositions,whichevenaffectpsychiatry, havebeengaininggroundinrecenttimes.

Whichlivingpersondoyoumostadmire?

Onaprofessionallevel,mymentor,WilliamCarpenter,hasbeeninstrumental,whileonapersonallevel,mywifeandchildrenhavebeenmy greatestsupport.Additionally,figureslikeRamónyCajalandGregorio Marañóninspiremebeyondthepersonalrealm.

Whatisyourgreatestextravagance?

Iamnotsureifitisconsideredanextravagancethesedays,butIamabig fanofmyfootballteam,AtléticodeMadrid,andIfeelquiteupsetwhen theydonotplaywell.

Whatareyoumostproudof?

IfeelveryproudoftherecognitionIreceivefromgratefulpatientsfor whatIhavebeenabletodoforthem.

Whatisyourgreatestregret?

Nothavingbeenclosertomyfatherinhislastyears.

Whatisthequalityyoumostadmireinpeople? Intelligence,compassion,andsincerity.

Whatisthetraityoumostdislikeinpeople? Lackofintegrity.

Whatdoyouconsiderthemostoverratedvirtue?

Theonesthatshouldneverbeconsideredvirtues:powerandmoney.

Whatisyourfavoriteoccupation(oractivity)?

IgreatlyenjoymyclinicalworkandthefeelingthatIamhelpingmypatientsandtheirfamilies.Ialsotrulyenjoypromotingphilanthropyfor childpsychiatry,whichhasgivenmetheopportunitytomeetwonderful peoplelikeAliciaKoplowitz.Ialsolovesingingwithmymusicianfriends!

Wherewouldyoumostliketolive?

InSpain.IwillalwaysliveinSpaineventhoughImayworkabroadtemporarily.

Whatisyourmosttreasuredpossession?

Theloveofmyfamilyandthefriendshipofmyfriends.

Whenandwherewereyouhappiest?Andwhyweresohappythen?

Iwasveryhappyduringmyuniversitystudies,inatimethatfeltfreerfrom responsibilitiesandworries,surroundedbypeoplewithwhomIformed deepfriendshipsthatpersisttothisday.

Whatisyourcurrentstateofmind?

Moreatpeacethanever,withnewchallengesthatexciteme,andfocusing moreonwhatIgenuinelybelieveisworthwhile.

Whatisyourmostmarkedcharacteristic?

Iamquitereliableandtrytobefairtothosearoundme.

Amongyourtalents,whichone(s)give(s)youacompetitiveedge?

Togrowinthefaceofadversityandnevergiveuponanything.Tobea dreamerwhofightsfiercelyfortheirdreams.

Whatdoyouconsideryourgreatestachievement?

Tofightagainstnepotisminmycountryandstrivetoensurethatmany differentpeoplecollaboratetowardcommongoals.Additionally,thecreationofthespecialtyofchildandadolescentpsychiatryinSpainafter meetingwithnineconsecutivehealthministers!

Ifyoucouldchangeonethingaboutyourself,whatwoulditbe?

Probablyspendingmoretimewithmychildrenwhentheywereyoung.

Whatdoyoumostvalueinyourfriends?

ThattheyshowupwhenIneedthemthemost.

Whoareyourfavoritewriters?

GabrielGarcíaMárquez,MaggieO‘FarrellandPhilipRoth.

Whoareyourheroesoffiction?

Morethanheroes,oneofthethingsIenjoythemostiswatchingthefilms oftheMarxBrothers.

Whoareyourheroesinreallife?

Volunteerswhoinvesttheirtimeinhelpingthoseinneed,andindividualswholeavebehindallmaterialpossessionstoassistthosetheydonot know.

Whataphorismormottobestencapsulatesyourlifephilosophy?

Surroundyourselfwithpeoplewhoarebetterthanyou.

CelsoArango1

1 InstituteofPsychiatryandMentalHealth,HospitalGeneralUniversitario GregorioMarañón,andUniversidadComplutensedeMadrid28009.Madrid,Spain e-mail: carango@hggm.es

Publisher’snote: GenomicPressmaintainsapositionofimpartialityandneutrality regardingterritorialassertionsrepresentedinpublishedmaterialsandaffiliations ofinstitutionalnature.Assuch,wewillusetheaffiliationsprovidedbytheauthors, withouteditingthem.Suchusesimplyreflectswhattheauthorssubmittedtousand itdoesnotindicatethatGenomicPresssupportsanytypeofterritorialassertions.

INNOVATORS&IDEAS:ACADEMICLEADER

NancyJaneRothwell:Braininflammationandthepathtoleadership

©GenomicPress,2025.The“GenomicPressInterview”frameworkisprotectedundercopyright.Individualresponsesarepublishedunderexclusive andpermanentlicensetoGenomicPress.

BrainMedicine March2025;1(2):29–31;doi: https://doi.org/10.61373/bm025k.0002

Keywords: Obesity,braininflammation,stroke,leadership,science careers,academicinnovation

Breakingbarriersinboththelabandtheboardroom,DameNancy RothwellhasshapedmodernBritishscienceinwaysfewothershave. BeginningherresearchjourneyattheUniversityofLondon,shemade apivotalmovetotheUniversityofManchesterin1987–adecision thatwouldforgeanextraordinarypartnershipspanningoverthree decades.Duringherearlycareer,shefollowedherscientificcuriosity intotheintricateworldoffatcellswithgroundbreakingresearchthat crackedopenourunderstandingofhowthebodyregulatesitsweight throughthermogenesisandbrownfatmetabolism,providingcrucial insightsintoobesityandcachexia.Then,inaboldpivotthatwould definethenextphaseofhercareeratManchester,sheturnedher attentiontothebrain’sinflammatoryresponseinstrokeandother neurologicalconditions,conductingpioneeringresearchthatbridged thegapbetweenbasicbiologyandclinicalapplications.Herscientific brillianceearnedherFellowshipintheRoyalSociety,markingher placeamongBritain’smostelitescientists.Herdeepconnectionwith Manchesterdeepenedfurtherwhen,withoutplanningit,shefound herselfmakinghistoryin2010astheUniversity’sfirstfemale PresidentandVice-Chancellor,steeringoneofBritain’slargest universitiesthroughfourteenyearsofgrowthandtransformation until2024.Herleadershipstyle,markedbythesamecuriosityand determinationthatdroveherresearch,helpedpositionManchesteras aglobalpowerhouseinhighereducation.Now,astheUniversity’s CampaignandExternalRelationsAmbassador,shesitsdownwith GenomicPresstosharewhatshehaslearnedaboutscience, leadershipandwhysometimesthebestdiscoveriescomefromtaking theroadlesstravelled–offeringreadersarareglimpseintothemind ofsomeonewhohasexcelledatbothgroundbreakingresearchand institutionalleadershipwhilehelpingbuildManchesterintoa world-leadingcentreofacademicexcellence.

Part1:NancyRothwell–LifeandCareer

Couldyougiveusaglimpseintoyourpersonalhistory,emphasizing thepivotalmomentsthatfirstkindledyourpassionforscience?

Myinterestinsciencewasfirstsparkedattheageofabout6bymyfather, abiologyteacherwhokeptlotsofspecimensinjarsatourhouse.WhenI was9,Imissedabout18monthsofschoolduetoillness.Then,Istarted toreadsomeofhissciencebooksandbegantodraw.

Infact,IdroppedbiologywhenIwas14becauseIfoundtheplant sciencepartboring(sorry,botanists)andinsteadtookMaths,Physics, Chemistry,andArtforAlevels.Myfirstcareerchoicewasart,butmykind teachersaidIwasn’tgoodenoughtomakeadecentlivingasanartist.My secondchoicewasMaths,butIdecidedthiscouldbeunsociable(sorry, mathematicians).Ultimately,IstudiedPhysiologyatQueenElizabethCollege(nowpartofKings),UniversityofLondon.

Received:29December2024.Accepted:8January2025. Publishedonline:28January2025.

IhadnocareerplansatalluntilIundertookafinal-yearresearch projectonfatmetabolism.Iwasquicklyhookedonresearch,andIundertookaPhDinthermogenesisandbodyweightregulation.ThiswasfollowedbyalongcareerinresearchinLondonand,from1987,inManchester.

ApivotalmomentwassecuringfundingfromtheRoyalSocietyfora 10-yearUniversityResearchfellowship,whichgavemethefreedomto pursueanyresearch,moveinstitutionsafewyearslatertoManchester, andchangefields.

Wewouldliketoknowmoreaboutyourcareertrajectoryleadingupto yourmostrelevantleadershiprole.Whatdefiningmoments channelledyoutowardthatleadershipresponsibility?

Ihaveneverhadanyplanstotakeonanyleadershiproles,thoughalong thewayofmyresearch,Ididhappentotakeonsomerolessuchasheadof thedivisionofNeuroscienceinManchester,thenVice-DeanforResearch fortheSchoolofBiologicalSciencesandseveralexternalrolesonnational bodiessuchastheMRC,RoyalSociety,CancerResearchUKandfornine yearsasanon-executivedirectorofAstraZeneca.

Allthatchangedin2004whentheVictoriaUniversityofManchester andUMISTmergedandanewPresidentandVice-Chancellor,AlanGilbert, arrivedfromMelbourneandaskedmetobeVice-PresidentforResearch fortheUniversity.IwasreluctantsinceIthenheldanMRCResearchChair andhadanextensiveandthrivingresearchgroup.Iwaspersuadedand thoroughlyenjoyedit.In2008I(againreluctantly)becameDeputyPresidentandVice-ChancelloroftheUniversity.Overthenexttwoyears,Alan’s healthdeclined,andIhadtostepinincreasingly.In2010Iwasagain

Figure1. NancyJaneRothwell,BSc,PhD,DSc,UniversityofManchester,UK.

persuadedtoapplyfortheroleofPresidentandVice-Chancellor,which Iservedasfor14yearsuntil2024.

Pleasesharewithuswhatinitiallypiquedyourinterestinyour preferredareaofresearchorprofessionalfocus.

Thefirstpartofmyresearchcareerwasinthermogenesisandmetabolism,aninterestpiquedbyaresearchprojectasanundergraduatewith ProfessorMikeStock,wholatersupervisedmycareer.

AfurtherpivotalmomentoccurredafterImovedtoManchester,where Iinvestigatedtheimpactofinfection,injury,anddiseaseonmetabolism andbodytemperature.Weusedarodentstrokemodeltotestthehypothesisthatthecytokineinterleukin-I(IL-1)causedhypermetabolismand fever,whicharecommonafterbraindamage.Ourhypothesisprovedcorrect,butwehadtodoonelast’controlexperiment’tocheckthattheIL-1 antagonist(IL-1Ra)didnotaffecttheextentofdamagecausedbystroke. Tooursurprise,thedamagewasgreatlyreducedbyIL-1Ra.Fromthatmomenton,Ichosetoleavethefieldofmetabolismandresearchneuroimmunologyandbraininflammation.

Whatwerethekeyimpactareasofyourresearchtopics?

Inthefirstpartofmycareer,Idemonstratedthatoverfeedingrodents ledtoanincreaseindiet-inducedthermogenesisandactivationofbrown fat,whichisverysimilartotheeffectofthecold.Hence,someanimals remainedleandespiteanincreaseinenergyintake,whileothersimilar strainsbecameobese.

Later,themainimpactsshowedthataninflammatorymoleculecontributedtobraindamage,whichwasnotknownthen.Asaresult,we understoodsomeofthemechanismsofthatdamageanditsclinical implications.

Couldyoutellusmoreaboutyourmostrelevantfocalpointswithin yourchosenfieldofscience?

Afocalpointinunderstandingenergybalanceandbodyweightregulation istherecognitionthatinvoluntaryenergyexpenditureandenergyintake contributetooverallenergybalance.

Inneuroimmunology,therewasagrowingrecognitionoftheimportanceoftheimmunesystemandinflammationinbraindiseases.

Whathabitsandvaluesdidyoudevelopduringyouracademicstudies orsubsequentpostdoctoralexperiences,thatyouhavemaintained throughoutyourlife?

Honesty,integrityandopenness.Justoccasionallybeingopenmeansthat youwillbe’scooped,’butonmanymoreoccasions,itwillhelpinvaluable stepsforward,insights,andnewcollaboratorsandfriends.

Thescientificcommunitystilllacksdiversity.GenderbalancehasimprovedsinceIwastraining,atleastinbiology,butthediversityof ethnicity,background,andgeographyisstillpoor.

Whathaveyoumostenjoyedinyourcapacityasacademicorresearch leader?

Undoubtedly,trainingyoungscientistsandclinicianscientists.Ihave supervisedover50PhDstudents,severalofwhomarenowresearch leadersandprofessors.Everyfewyears,wemeetupforafantastic reunion.

Outsideprofessionalconfines,howdoyouprefertoallocateyour leisuremoments,orconversely,inwhatmannerwouldyouenvision spendingthesemomentsgivenachoice?

SpendingtimeatourhouseinSwedensurroundedbyforestsandlakes.I havealsodevelopedapassionforgardeninginthelastfewyears.

Figure2. AstrikingnewlandmarkonManchester’scampus,theNancyRothwellBuildingcutsanimposingfigureagainstthecity’sskyline.Whatbegan asanambitiousengineeringhubhasbecomeafittingtributetooneofthe University’smostinfluentialleaders.Namedin2024tohonorDameNancy’s remarkable14-yeartenureasVice-Chancellor,thisseven-storypowerhouseis nowhometothousandsofbuddingengineersandscientists.Thebuilding’s sleekblackexterior,capturedinthetopimage,contrastswiththeintimate glimpsebelowofitsdedicationplaqueandtimecapsule–athoughtfultouch thatlinksthebuilding’scutting-edgefacilitieswiththerichhistoryofinnovationatManchester.

Part2:NancyRothwell–SelectedquestionsfromtheProust Questionnaire1

Whatisyourideaofperfecthappiness?

Beingwithfriendsandfamilyandhavingarewardingjobwhereyoufeel youcanmakeadifference.

Whatisyourgreatestfear?

Idonotreallyhaveagreatestfear,butperhapshavingahighlydebilitatingdiseasesuchasthegreatscientistProfessorSirColinBlakemore suffered.

Whichlivingpersondoyoumostadmire?

SirDavidAttenboroughwasanamazingsciencecommunicatorbutalsoa lovelyandhumbleperson.Hecametovisitmeduringrehearsalsforthe RoyalInstitutionlecturesthatIdeliveredfortheBBC.Hebroughtmehis bookandconfidedthattheRIlectureswerethehardestthinghehadever done.

Whatisyourgreatestextravagance? Fastcars.

Whatareyoumostproudof? Trainingsomanygreatscientists.

Whatisyourgreatestregret?

Beingtooriskaverseduringtheearlierpartofmycareer.Asmycolleague ProfessorSirAndreGeim(NobellaureateinPhysics2010)said‘Ifyoufollowthetroddenpath,youmayfindthatallthegrasshasbeeneaten’.

Whatisthequalityyoumostadmireinpeople? Honestyandkindness.

Whatisthetraityoumostdislikeinpeople? Dishonestyandmeanness.

Whatdoyouconsiderthemostoverratedvirtue?

Intellect.Toolittlescientificemphasisisplacedoninsight,imagination, andintuitiveleaps.

Whatisyourfavouriteoccupation(oractivity)? Discoveringnewknowledge.

Wherewouldyoumostliketolive?

WhereIlivenow-UKandSweden,splitbetweencityandcountryside.

Whatisyourmosttreasuredpossession?

Istruggledwiththisone,butmaybeitwasmymother’sweddingring, whichhasbeenpasseddownthroughgenerations.

Whenandwherewereyouhappiest?Andwhyweresohappythen?

WhenIwasinalabcoatearlyinmycareerbecauseIwasdiscoveringthings formyselfratherthanjustsupervisingthem,andwhenIwasonaboatin alakeinSwedenbecauseitwassoquietandpeaceful.

Whatisyourcurrentstateofmind? Calmbutusuallybusy.

Whatisyourmostmarkedcharacteristic? Mymothersaidbeingorganized,butmypartner(ofover50years)would sayoptimism.

Amongyourtalents,whichone(s)give(s)youacompetitiveedge? Perseveranceandoptimism.

Whatdoyouconsideryourgreatestachievement?

BeingelectedaFellowoftheRoyalSociety.

Ifyoucouldchangeonethingaboutyourself,whatwoulditbe? Bemorefocused,butIlikevariety.

Whatdoyoumostvalueinyourfriends? Loyalty.

Whoareyourfavouritewriters?

SirPeterMedawar,ArthurConanDoyle,and,alongtimeago,EnidBlyton.

Whoareyourheroesoffiction? IcouldnotanswerthisonebecauseitchangesdependingonwhatIread.

Whoareyourheroesinreallife?

SirDavidAttenborough,DameBridgetOgilvie,SirPeterMedawar.

Whataphorismormottobestencapsulatesyourlifephilosophy? Doasyouwouldbedoneby.

Manchester,England,UnitedKingdom 29December2024

NancyRothwell1 1 UniversityofManchester,OxfordRoad,Manchester,M139PL,UK e-mail: Nancy.rothwell@manchester.ac.uk

Publisher’snote: GenomicPressmaintainsapositionofimpartialityandneutrality regardingterritorialassertionsrepresentedinpublishedmaterialsandaffiliations ofinstitutionalnature.Assuch,wewillusetheaffiliationsprovidedbytheauthors, withouteditingthem.Suchusesimplyreflectswhattheauthorssubmittedtousand itdoesnotindicatethatGenomicPresssupportsanytypeofterritorialassertions.

BrainMedicine

PERSPECTIVE

Sterolbiosynthesisdisruptionbycommonprescriptionmedications:critical implicationsforneuraldevelopmentandbrainhealth

ŽeljkaKorade1 ,andKárolyMirnics2

Sterolbiosynthesisisessentialforcellularfunction,producingnotonlycholesterolbutalsocriticalbioactivemoleculesthatregulatecell signaling,growth,andmembranefunction.Inthebrain,cholesterolmetabolismoperatesindependentlybehindtheblood–brainbarrier, maintainingitsownhomeostaticbalance.Anemergingconcerninclinicalpharmacologyisthediscoverythatmanycommonprescriptiondrugs unintentionallyinterferewithpost-lanosterolsterolsynthesispathways.Whileacuteeffectsofthesemedicationsaredocumented,their long-termconsequencesforbraindevelopmentandfunctionremainunclear.Studiesusingcellculturesandmousemodelsindicateheightened riskduringpregnancy,wheredrug-inducedsteroldisruptionmayinteractwithgeneticfactorsfrombothmotherandfetus,particularlywhen multiplemedicationsareprescribed.Thissignificantresearchgaphasimportantimplicationsforclinicalpractice.Ourreviewconsolidates currentevidenceabouthowprescriptionmedicationsaffectpost-lanosterolbiosynthesisandoutlinescriticalareasrequiringurgent investigation.

BrainMedicine March2025;1(2):32–37;doi: https://doi.org/10.61373/bm025p.0011

Keywords: DHCR7,prenataldevelopment,prescriptionmedicationsideeffects,Smith-Lemli-Opitzsyndrome(SLOS),sterolbiosynthesis

Introduction:BrainSterolBiosynthesisisCriticalforNormalBrain DevelopmentandFunction

Cholesterolisessentialforallmammaliancells,especiallybraincells(1). Thehumanbrainaccountsforapproximately2%oftotalbodyweight, yetitcontainsabout25%ofcholesterolandcholesterolderivativesof thehumanbody(2–4).Thebody’sandthecentralnervoussystem(CNS) cholesterolpoolsareseparatedbytheblood–brainbarrier(BBB),each relyingindependentlyonitsintrinsiccholesterolbiosynthesis(5).Brain sterolbiosynthesisstartsduringintrauterinedevelopmentandcontinuesthroughoutthepatient’slifetime(5, 6).Inanunesterifiedform,brain cholesterolispredominantlyfoundinthemyelinsheathsandplasma membranesofthevariousbraincells(2, 6).

Synapseanddendriteformationandaxonalguidancearebothsteroldependentprocesses,andthesterolbiosynthesispathwaygenerates dozensofbioactivemoleculescriticalfornormalbrainfunction(7–11).

Preservedcholesterolhomeostasisisalsonecessaryforregularfunctioningoftheadultbrain:inaging,highbraincholesterolhasbeen connectedtobettermemoryfunction,whilelowcholesterolisassociated withanincreasedriskfordepression(12–14).Inaddition,disturbances incholesterolbiosynthesisand/ormetabolismhavebeenreportedin Huntington’sdiseaseandAlzheimer’sdisease(15–17).Lowcholesterol concentrationsmaypredisposeanindividualtoaggression,impulsivity, andviolence(18–20).

CholesterolBiosynthesisisaComplexBiochemicalProcess

Cholesterolissynthesizedfromacetyl-CoAinalongcascadeoftwo finalparallelchainsofenzymaticeventscalledtheKandutsch-Russelland Blochpathways(Figure1)(21).Conversionofthefinalsterolprecursor, 7-dehydrocholesterol(7-DHC),tocholesterolismediatedbyDHCR7in theKandutsch-Russellpathway(22).IntheBlochpathway,DHCR7isnecessaryforthereductionof7-dehydrodesmosterol(7-DHD)todesmosterol(DES)(23).Thus,disruptionofDHCR7functionpreventsnormal

cholesterolproductionthroughbothpost-lanosterolbiosyntheticpathwaysandresultsinelevationof7-DHCand7-DHDandreductionincholesterolanddesmosterollevels(24).

7-DHCand7-DHC–DerivedOxysterolshaveStrongBiologicalEffects Reducedcholesterolproductionisdetrimentaltothebrain,butthearisingpathophysiologyismorecomplex(25).Ascholesterolprecursors 7-DHC,8-DHC,and7-DHDaccumulate(24, 26, 27),anewchallenge emerges:7-DHCisthemostoxidizablelipidknowntodate,withapropagationrateconstantof2,160(thisis200timesmorethancholesterol and10timesmorethanarachidonicacid)(28, 29).Asaresult,7-DHC spontaneouslyoxidizes,generatinghighlyreactive7-DHC–derivedoxysterols(30),impairingcellviability,differentiation,andgrowth(31, 32). Themostinvestigated7-DHC–derivedoxysterol,DHCEO,interfereswith neuronalmorphology,neuriteoutgrowth,andfasciculation(31, 33).Furthermore,7-DHC–derivedoxysterolsaresimultaneouslymarkersofoxidativestress(34)andbiologicallyactivemoleculesthatmodifyimmunefunction(33, 35).7-DHDand8-DHC,whilemuchlessstudied,are alsolikelytogeneratetheirownoxysterols,astheyhaveacomparable peroxidationrateto7-DHC(29).

PathogenicVariantsinSterolBiosynthesisGenesResultin DevelopmentalDisabilities

Whileacompletelackofcholesterolbiosynthesisisincompatiblewith life,partialcholesterolproductionduetopathogenicvariantsinpostlanosterolgenesresultsincomplexdevelopmentaldisabilities(36). Mutationsinpost-lanosterolbiosynthesisareassociatedwithSmithLemli-Opitzsyndrome(SLOS)(mutationsinDHCR7)(25),desmosterolosis(mutationsinDHCR24)(37, 38),chondrodysplasiapunctata1 [mutationsinemopamilbindingprotein(EBP)](39, 40),andlathosterolosis(mutationsinSC5D)(41).Allthesesyndromesaffectbrainand craniofacialdevelopmentandleadtointellectualanddevelopmental disabilities(36, 42).

1 DepartmentsofPediatrics,BiochemistryandMolecularBiologyandChildHealthResearchInstitute,UniversityofNebraskaMedicalCenter,Omaha, NE68198-5450, USA; 2 Munroe-MeyerInstituteforGeneticsandRehabilitation,DepartmentsofPsychiatry,BiochemistryandMolecularBiology,andChildHealthResearchInstitute,UniversityofNebraskaMedicalCenter,Omaha,NE68198-5450,USA

CorrespondingAuthor: KárolyMirnics,MD,PhD;ProfessorofPsychiatry,Biochemistry&MolecularBiology,Pharmacology&ExperimentalNeuroscience,Munroe-Meyer InstituteforGeneticsandRehabilitation,UniversityofNebraskaMedicalCenter,985450NebraskaMedicalCenter,Omaha,NE68198-5450.Phone:402-559-5702; E-mail: karoly.mirnics@unmc.edu

Received:25November2024.Revised:4January2025and10February2025.Accepted:11February2025. Publishedonline:25February2025.

Figure1. Commonlyusedprescriptionmedicationshaveapost-lanosterol biosynthesisinhibitingeffect.PathogenicvariantsintheDHCR7generesult inSLOSwithahallmarksterolinhibitionsignature.Thisprofileencompasses theaccumulationof7-DHCand7-DHDandthereductionofdesmosteroland cholesterollevels.Manycommonlyusedprescriptionmedicationsgiverise tosimilarbiochemicalsignaturesandcanbeconsideredsterolbiosynthesis inhibitors.Thepost-lanosterolpathwayisgreatlysimplifiedforreadability.

DHCR7InhibitorsDuringPregnancyareConsideredTeratogens

BolandandTatonettipublishedasystematicliteraturereviewin2016, whichrevealedthatfirst-trimesterexposuretoDHCR7inhibitorsmetthe criteriaforteratogenicity.Asaresult,theysuggestedthatDHCR7activityshouldbeconsideredduringdrugdevelopmentandprenataltoxicity assessment(43).

ManyPrescriptionMedicationshaveSterolBiosynthesisInhibiting SideEffects

Whilecholesterolandpost-lanosterolintermediatesdonotcrossthe BBB,manyprescriptionmedicationsdosoeasily(44).Thesemedications, designedforunrelatedprimaryindications,caninterferewithdevelopmentalbrainsterolbiosynthesis(45–51).Somemedicinesmightdirectly inhibitkeyenzymesinvolvedinsterolbiosynthesis,whileotherscouldinterferewithbiosynthesisbyalteringgeneexpression,affectingtheavailabilityofsubstrates,ordisruptingregulatorypathways(51).Regardless ofthespecificmechanismsinvolved,theconsequencesofdisruptedsterol homeostasiscanimpactnormalbrainfunctionineithercase.

Todate,over30prescriptionmedicationshavebeendescribedashavingpost-lanosterolbiosynthesisinhibitingsideeffects(52, 53).Aripiprazole,cariprazine,trazodone,andhaloperidolhavebeenthemostextensivelystudiedregardingtheireffectsonsterolbiosynthesis(46, 48, 54, 55).Whiletheydonothaveahighdegreeofstructuralsimilarityor mechanismofaction(exceptaripiprazoleandcariprazine),theysharea commonbiochemicalsignatureandareallCNS-targetingmedications. TheyareallDCHR7inhibitorsduringdevelopmentwithachemicalsignaturethatincludeselevationof7-DHC,8-DHC,and7-DHDanddecreased desmosterolandcholesterol(52).Thesefindingshavealsobeenvalidated across invitro systems(52, 53, 56),rodentexperimentsandtissuetypes (45, 46, 48, 49),andanalysesofbloodsamplesfrompsychiatricpatients andwomenofreproductiveage(47, 54).

Single-AlleleDHCR7PathogenicVariantsRepresenta LatentVulnerability

Rodenttransgenicmodelsandinvitrohumanfibroblastculturessuggest thattheDHCR7genotypemattersregardingthemagnitudeofsterolinhibition(54).Pathogenicvariantsofthe DHCR7 gene,presentinapproximately1%–3%ofthehumanpopulation(57, 58),mightnotbesufficient toproduceadiseasebutrepresentalatentvulnerability.Morethan200

likelypathogenicvariantsofDHCR7havebeenidentifiedtodate(59, 60). Whiletheexactpathogenicvariantsmightvaryinfrequencyacrossdifferentpopulations,theoverallfrequencyofvulnerabilityappearstobecomparableacrosssexandethnicgroups,withperhapstheexceptionofEast AsianandKoreanpopulations(0.5%–1%)(61).DHCR7± individualshave increasedbaseline7-DHClevels.Whentheirhumanfibroblastsareexposedtomedicationswithsterol-inhibitingsideeffects,thesterolbiosynthesisdisruptionreachesamagnitudeclosetothatseeninpatientswith SLOS(50, 54).RodenttransgenicfindingsonDhcr7± micealsoconfirmed thesefindings,providingadditionalinsightsintothepotentialunderlying pathophysiology.Namely,amaternalexposuremodelrevealedthatboth maternalandoffspringDhcr7± heterozygosityconferredvulnerability: Dhcr7± pupsborntoDhcr7± mothersshowedthehigheststerolbiosynthesisdisruptioninreposetoaripiprazole,trazodone,andcariprazine(45, 46, 48).Thus,itappearsthat,atleastinexperimentalsystems,genetic vulnerabilityandchemicalinhibitionsynergize,withyetunknownconsequencesonhumanhealth.Themechanismbywhichthisgene–medication interactionoccursremainsunknown,andthismightbedifferentforthe variouscompoundsthatcaninhibitsterolbiosynthesis.Namely,whilethe pathogenicgeneticvariantwillreducetheavailabilityoftheDHCR7enzyme,themedicationscaneitherdirectlyinhibitthesameenzyme,inhibit anotherupstreamenzymeinthepost-lanosterolbiosynthesispathway,or interferewithgenesbelongingtonetworksresponsibleforsterolenzyme biosynthesis,degradation,orturnover.Ultimately,elevated7-DHCandrelatedoxysterollevelshavesubstantialbiologicalactivities,includinginhibitingHedgehogresponse(62, 63),akeydriverofnormalbraindevelopment.Similarly,thep75neurotrophinreceptorexpressiondependson thecholesterolbiosynthesismachinery(64).

SterolBiosynthesisInhibitingPolypharmacyEffectsare SynergisticorSummative Weliveintheageofpolypharmacy,anationwideandworldwidechallenge (65–67).PolypharmacyisincreasinglycommonintheUnitedStatesand contributestothesubstantialburdenofdrug-relatedmorbidity.Quinn andShahcountedtheincidenceofmultidrugcombinationsobservedin 4billionpatient-monthsofoutpatientprescriptiondrugclaimsfrom 2007–2014intheTruvenHealthMarketScanDatabases(65).Theyfound thatamongpatientstakinganyprescriptiondrug,halfwereexposedto twoormoredrugs,while5%wereexposedtoeightormore.Notably,CNS polypharmacyisparticularlycommonlyseeninthetreatmentofmental illness(68).

IfgeneticDhcr7± vulnerabilityandchemicalinhibitionofsterol biosynthesissynergize,couldtwoormoremedicationswithsterolinhibitingsideeffectshaveasimilar,synergistic,orsummativeeffect? Invitro,rodent,andhumanbiomaterialstudiessuggestthismightbe thecase(69, 70).NeuronalandastrocyticculturestreatedwithARI+TRZ showedanadditiveeffect,increasingthe7-DHC/CHOLratioby15-to20foldovervehicle-treatedcultures.Inaddition,adultmicetreatedwith ARI+TRZpolypharmacyaffectedmultipleorgansystemsofthebody, leadingtodecreasedproliferationandreductionofneuralprogenitor cellsinthehippocampiofmaleadultmiceanddecreasedexpressionof microglialmarkerIBA1inthebrain(69, 70).Furthermore,inastudyof pregnantwomentakingprescriptionmedications,itwasreportedthat womentakingmorethanonemedicationwith7-DHC–elevatingsideeffectshadthehighest7-DHClevelsintheirblood,suggestingasynergistic orsummativeeffectofpolypharmacy(47).

Thisraisesthequestionofwhenandwherewillthepolypharmacyeffectssummateorsynergize.Thedrugsthatshowsynergyhavedifferent mechanismsofaction,mostcommonlymediatedthroughaspecificreceptor.Ifatleastonemedication’sinhibitionofpost-lanosterolenzymes isreceptor-based(andnotdirectchemicalinhibition),theoverlapping receptordistributionwilldefinethesiteofmostsubstantialsynergy.In thecaseofnonoverlappingreceptordistribution,synergyorsummations wouldnotbeobserved;instead,itwouldaffectabroadertissuedistributionwhereeitheroneofthereceptorsisexpressed.Thiscouldgive risetoaverydifferentphenotypeandsuggestthateachcombinationof polypharmacycouldhavedifferentultimateconsequences.Shouldthis bethecase,thiswouldbefurthercomplicatedbythedevelopmental

ThereareLikelytobeMultipleDevelopmentalVulnerabilityPeriods toPost-LanosterolInhibition

Thevastmajorityofpost-lanosterolinhibitiondataobtainedtodatehas focusedonintrauterinedevelopmentandmaternalintakeofmedications duringpregnancy.However,manyinfantsmightbepotentiallytreated with(knownoryetunknown)medicationsthatcouldinhibitsterolbiosynthesis.Earlypostnataldevelopmentisalsolikelytobeacriticalvulnerabilitywindow(71)asthisisaperiodofprogressivemyelinationand developmentofglialcells,bothhighlysterol-dependentprocesses.Furthermore,pubertyisaperiodofrapidlychanginghormonalhomeostasis,synapticpruning,andcontinuedmyelination,allstronglyinfluenced bysterolbiosynthesis(72, 73).Thisisalsoaperiodwherephysiciansare morelikelytoprescribemedicationswithsterol-inhibitingsideeffects. Theoverallandspecificmedicationeffectscausingpartialsterolinhibitionarealmostentirelyunknowninthesepostnatalvulnerabilityperiods. Yet,thedetrimentaleffectsofpost-lanosterolinhibitionwouldnotresult indysmorphologiesseenduringfetaldevelopmentbutcouldhavefunctionalconsequences.Namely,interferencewithmyelinationandsynapticpruning,bothsterolbiosynthesis-dependentprocesses,couldresult inchangesinfunctionalconnectivity.Suchdisruptionswouldultimately resultinlearningdifficulties,emotionaldisturbances,developmental delay,languageacquisitionchallenges,orbehavioralalterations.

DifferentialEffectsof DHCR7 InhibitioninTissueandCellTypes Whilerepresentingonly2%ofbodyweight,thebraincontains25%ofthe body’scholesterolandsterolderivatives.However,brainsterolbiosynthesisisnothomogenousacrossbrainregions.Forexample,cholesterolin theponsandcerebellumis ∼2.5timeshigherthanintheneocortex(74). Furthermore, insitu hybridizationforpost-lanosterolbiosynthesisenzymesrevealsmarkedlydifferentexpressionlevelsacrosscelltypes,with veryhighexpressionintheprincipalneuronsofthehippocampus(64)and serotoninergiccells.Thislaterisalsounderscoredbyafunctionalvulnerabilityof Dhcr7± mice,revealinganincreasedhead-twitchresponse tothe5-HT2Aagonist1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)(75).Thesefindingshaveseveralpotentiallysignificantimplications.First,thebrainislikelythemostsensitiveorgantodevelopmentalsterolinhibition.Second,itislikelythatbrainregionsthathavethe highestenzymeexpressionandsterolproductionarethemostlikelyaffectedbysterolinhibition.Third,asdevelopmentalsterolaccumulation proceedsdifferentlyacrossthedifferentbrainregions,thesamesterolinhibitingmedication,givenatothertimes,mightaffectdifferentbrain structures.Fourth,high7-DHClevelsarelikelytoaffectthevariousbrain celltypesdifferently,perhapsregulatedbytheirneurochemicalcontent. Finally,whendiscussingtheeffectsofpost-lanosterolbiosynthesisdisruption,onemustconsiderthatsterolsmightbesynthesizedinonecell orregion.Still,theyarealsoactivelytraffickedtoallpartsofthebrainand interchangedbetweenglialandneuronalcells(76).

ThereisStillaSignificantAmountofCriticalKnowledgeMissing

Whilethereisplentyofevidencesuggestingacautionaryapproachwhen usingmedicationswithsterol-inhibitingsideeffectsduringpregnancy, therearesignificantgapsinourcurrentdata.

1.Wehavelimitedknowledgeofhowthesemedicationsinterferewith developmentalsterolbiosynthesis.Themechanismmightbedirect inhibitionoftheenzyme(s)orreceptor-mediated,andsuchinformationwouldbeessentialtoobtain.

2.WhileweunderstandthatDHCR7singleallelepathogenicvariants mightpotentiatetheeffectsofsterolinhibitingeffects,suchsynergy hasnotyetbeeninvestigatedforsinglecopypathogenicallelesin genesencodingotherpost-lanosterolenzymes(e.g.,DHCR14orEBP).

3.Wedonotunderstandtheeffectsofelevated8-DHCand7-DHDand theiroxysterols.Basedontheirchemicalstructureandproperties,

theyareverylikelytobeabundantandbiologicallyactive,butnosuch informationisavailabletodate(29).

4.Theexacttimewindowofapotentialdevelopmentalvulnerabilityremainsunknown,asisthedoseanddurationofmedicationsthatcould causepotentialharm.

bm.genomicpress.com timingofreceptorexpressionvs.thetimingofpolypharmacy.Thus,the samecombinationofsterol-inhibitingpolypharmacycoulddifferentlyaffectdifferentorgans,regions,orcelltypesbasedontheirdose,timingof polypharmacy,receptorexpressionpattern,mechanismofaction,developmentalstage,genotype,andmanyotherfactors.

5.Wedonotknowwhetherthereisacriticalthresholdorconcentrationof7-DHC(oroxysterols)thatbecomesharmfultothedeveloping baby’sbrainorothertissue(31).

6.Canco-morbiditiesalsosynergizewithmedication-inducedinhibitionofsterolbiosynthesis,likepolypharmacyandDhcr7genotype? Diabetes,pre-eclampsia,metabolicconditions,andlifestylefactors couldtheoreticallymakethedevelopmentaloutcomesofsterolinhibitionmuchworse.

7.Weareexposedtohundredsofchemicalsthroughoutourdailylives, andsomeofthemhavesterolinhibitionproperties(51, 53, 77, 78).Dothesechemicalspredisposetodevelopmentaldisabilities,in particular,iftheyarecombinedwiththealreadyidentifiedsterolinhibitinggeneticfactorsorprescriptionmedications?

8.Commonlyusedmedicationscanpotentiallyinhibitotherenzymesin thepost-lanosterolbiosynthesispathway(51).Forexample,amiodaronealterscholesterolbiosynthesisthroughtheinhibitionofEBP anddehydrocholesterolreductase24(DHCR24),bothofthempostlanosterolenzymes(79).Yet,thisisagreatlyunderstudiedarea.

9.ArecentlyidentifiedFetalFentanylsyndrome(FFS)(80)arisingin newbornsborntomotherswithnonprescriptionfentanylusehasa remarkablephenotypicandbiochemicalsimilaritytoSLOS.ThissuggeststhatFFSpartiallyarisesfromsterolinhibition(81).Furthermore,arecentreviewfoundthat10of12case-controland7of 18cohortstudiesdocumentedstatisticallysignificantpositiveassociationsbetweenmaternalopioiduseduringpregnancyandcongenitalmalformations(82).Arethesedysmorphologiesaresultof sterolbiosynthesisinhibition,oraretheyarisingthroughanunrelatedmechanism(83)?

10.Aretheredeleteriousconsequencesoflong-termuseofmedications withsterol-inhibitingsideeffectsforadults?Lowcholesterollevels appeartobeassociatedwithanincreasedriskfordepression(84, 85, 13, 12).Furthermore,arecentstudyevaluatinginteractionsbetween antipsychoticsandmedicationsusedinthetreatmentofcardiovasculardiseasereportedthehighestnumberofinteractionsamongbetablockersandantipsychotics(66).Remarkably,thecombinationsthat reportedthemostcommonadverseoutcomesincludedthemedicationsthathavebeenpreviouslyidentifiedashaving7-DHC–elevating sideeffects–includingmetoprololandnebivolol(49).

PotentialClinicalImplicationsandRecommendationsforPoliciesand FutureResearch

Basedontheabove-presentedcautionaryfindings,webelievethatinclinicalpractice,severalapproachesarewarranted:

Pregnantmotherswith DHC7± genotypeshouldnotbeutilizingmedicationswith7-DHC–elevatingsideeffects.Thereareusuallysafealternativestothesemedications,sothisapproachshouldrarelyinterfere withthebestpatienttreatment. Werecommendgenetictestingofpregnantwomenwhomustutilize medicationswithsterol-inhibitingsideeffects.Ifprenataltestingis alsoperformed,itisimperativetogaininsightintothe DCHR7 status oftheunbornchild.Thisisespeciallyimportantwhentheunbornchild andmothercarrysingle-allele DCHR7± pathogenicvariants,asthese babiesmightbethemostvulnerabletopost-lanosterolbiosynthesis disruptions. PatientswithSLOSshouldneverreceivemedicationswith7-DHC–elevatingsideeffects. CliniciansshouldbeeducatedaboutthepotentialdangerofmedicationswithDCHR7-inhibitingsideeffectsforthedevelopingbrain. Duringpregnancy(andpotentiallyduringothervulnerabilityperiods), theyshouldavoidprescribingpolypharmacythatshowspotentialsynergisticinteractiononthepost-lanosterolbiosyntheticpathways.It israrelyappreciatedthat7-DHC–elevatingmedicationsmighttarget

differentorgansystems(e.g.,psychotropicandcardiacmedications–trazodone + metoprolol),yettheirunwantedeffectsmightconverge onthesamebiochemicalpathway.

Nationalregulatoryorganizationsshouldpaycloseattentiontoall theabove-listedfindingsanddeveloporreviseknowledge-basedguidelinesforutilizingsuchmediations.Furthermore,pharmaceuticalcompaniesshouldroutinelyassessnewlydeveloped(andperhapsalready approved)medicationsfortheireffectsondevelopmentalsterolbiosynthesis.Inaddition,nationalfundingagenciesshouldinvestinresearchto finddefinitiveanswerstotheseessentialpublichealthquestions.With therapidemergenceofnewtechnologiessuchas insitu metabolomics andlipidomics(74, 86),bioinformatics,newmodelsystems[including inducedpluripotentstemcells(iPSCs)(87)andhumanizedmice],and novel,high-resolutionimagingtechnologies,weshouldbeabletogain amoredefinitiveinsightintherisk-rewardequationforeachmedication anddevelopasafe,personalizedtreatmentplanforourpatients.

Conclusions

Unintendedsterolinhibitionbymanyprescriptionmedicationsiswell documented,anditisapotentialcauseforconcernwhenusedduring pregnancy.Nevertheless,itshouldbeacknowledgedthatmanyofthe findingspresentedaboveareobtainedusinginvitroandtransgenicrodentmodels.Whilethepost-lanosterolbiosyntheticpathwayishighly conservedbetweenrodentsandhumans,itisuncertainwhichofthose findingstranslatetothehumanpopulation.Foreachindividual,themagnitudeofsteroldisruption(andpotentialconsequencesfortheunborn child)willlikelydependonlifestyle,dosage,potentialpolypharmacy, geneticmakeup,andotherpossiblefactors.Nevertheless,theabovepresenteddataadvisescautionandaconservativeapproachintheuse ofmedicationswithsterol-inhibitingsideeffectsduringpregnancy.

FundingSources

R01MH110636(K.M.),R56HD111119-01A1.ResearchwaspartlysupportedbytheChildHealthResearchInstitute(CHRI),UNMC,Omaha,NE.

AuthorContributions

K.M.andZ.K.obtainedmanyofthepresentedresults,discussedthefindings,andwrotethemanuscripttogether.Bothauthorshavereadandapprovedthemanuscript.Theauthorstakefullresponsibilityforalldata, figures,andtextandapprovethecontentandsubmissionofthestudy. Norelatedworkisunderconsiderationelsewhere.Correspondingauthor: Prof.Mirnicsforallaspectsofthepresentedwork.

AuthorDisclosures

Theauthorshaveconfirmedthatnoconflictofinterestexists.

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CD2APinAlzheimer’sdisease:Keymechanismsandtherapeuticpotential

YongWang1 ,andYun-wuZhang1

Alzheimer’sdiseaseaffectsmillionsworldwideasoneofthemostdevastatingneurodegenerativeconditions,characterizedbytwodistinct pathologicalfeatures:amyloidplaques(composedofclustered β -amyloidpeptides)andneurofibrillarytangles(madeofhyperphosphorylated Tauprotein).Thesehallmarkchangestriggeracascadeofevents,includingprogressivesynapticdysfunction,inflammation,andthe breakdownoftheprotectiveblood–brainbarrier.Recentbreakthroughresearchthroughgenome-wideassociationstudieshasidentified CD2-associatedprotein(CD2AP)asasignificantriskfactorindevelopingAlzheimer’sdisease,withthiscrucialadaptorproteinemergingasa keyplayerinseveraldiseasemechanismsduetoitsfundamentalroleincellulartransportandcytoskeletalarchitecture.Growingevidence revealsthatCD2APinfluencesmultipleaspectsofAlzheimer’sdiseasepathogenesis,from β -amyloidmetabolismanddepositionto Tau-mediatedneurotoxicity,synapticintegrity,blood–brainbarrierfunction,andmicroglialactivationstates.UnderstandingCD2AP’s physiologicalandpathologicalrolesinthenervoussystem,particularlyitscelltype-specificfunctions,iscrucialfordevelopingeffective therapeuticstrategiesthattargetCD2APlevelsforAlzheimer’spreventionandtreatment,requiringacomprehensiveunderstandingofCD2AP biologyinneuronalcells.

BrainMedicine March2025;1(2):38–45;doi: https://doi.org/10.61373/bm025i.0026

Keywords: Alzheimer’sdisease, β -amyloid,blood–brainbarrier,CD2-associatedprotein,microglia,neuroinflammation,synapse,Tau

Alzheimer’sdisease(AD)isaneurodegenerativediseasecharacterized byimpairmentsincognitivefunctions,especiallyinlearningandmemory.Theprimarypathologicalfeaturesobservedinthebraintissuesof deceasedpatientswithADincludeextracellularamyloidplaquescomposedof β -amyloid(Aβ )peptidesandintracellularneurofibrillarytangles(NFTs)formedbyhyperphosphorylatedTauproteins(1).Duetoan agingsocietyworldwide,thenumberandproportionofpeoplewithADor otherdementiasareexpectedtogrowinthecomingyears.In2019,some 55millionpeoplewereestimatedtohavedementiaacrosstheworld, afigurepredictedtoincreaseto139millionby2050,accordingtothe WHO.TheannualcostofdementiawasestimatedtobeUS$1.3trillionin2019,withthisfigureexpectedtomorethandoubleby2030to $2.8trillion(2).

ADcanbeclassifiedintoearly-onsetAlzheimer’sdisease(EOAD)and late-onsetAlzheimer’sdisease(LOAD)basedontheageofonset(before orafter65yearsold),withEOADaccountingfor5%–10%oftheincidence (3).StudiesindicatethatEOADisoftenlinkedtofamilialgeneticmutations,particularlyinthegenesencoding β -amyloidprecursorprotein (APP),presenilin-1(PS1),andpresenilin-2(PS2)(4, 5).Incontrast,the majorityofLOADcasesaretypicallysporadicandassociatedwithmultiplefactors,includingenvironmentalinfluences.Sincetheidentificationin1993oftheApolipoproteinE(APOE) ε 4alleleasasignificantgeneticriskfactorforLOAD(6, 7),genome-wideassociationstudies(GWAS) haveuncoveredadditionalgenesrelatedtoLOAD,suchas TREM2, BIN1, MS4A4, CD33, and CD2AP (8–10). CD2AP encodesCD2-associatedprotein (CD2AP),alsoreferredtoasCasligandwithmultipleSH3domains(CMS) (8–11).Inthisarticle,weprovideaconcisereviewonthelatestresearch advancementsconcerningthefunctionalroleofCD2APinAD.

CD2APIntroduction

Thehuman CD2AP geneislocatedonchromosome6andcomprises18exons(Figure1A).Itencodesaproteinconsistingof639aminoacidswith amolecularweightofapproximately71kDa.Themouse Cd2ap geneis locatedonchromosome17andcontains18exons,encodingaproteinof 637aminoacids.TheCD2APproteinisascaffoldproteinthatwasinitially

identifiedduetoitsinteractionwiththetransmembraneproteinCD2in Tcells.ThisinteractionfacilitatesCD2clusteringandstabilizesthe connectionbetweenTcellsandantigen-presentingcells,leadingtoits namingin1998(12).

CD2APisprimarilycomposedofthreeconsecutiveSH3domainsnear theN-terminus,aproline-richregioninthemiddle,andacoiled-coildomainattheC-terminus[Figure1A,withthethree-dimensionalstructureofCD2APderivedfromAlphaFold3(13, 14)].TheSH3domainsof CD2APspecificallyrecognizetargetproteinsequencescomposedofextendedpolyprolinetypeIIhelices.TheyareessentialforCD2APinteractionwithvariouscellularcomponents,includingcytoskeletalregulators, multiplesignalingmolecules,andapoptosisregulatoryfactors(15–17). Thecentralproline-richregionofCD2APmediatesligand-dependentinteractionswithactin-bindingproteins,facilitatingtheirrecruitmentto endocyticCD2AP-Cbl-epidermalgrowthfactorreceptorcomplexes(18). TheC-terminalcoiled-coildomainofCD2APisindispensableforitsactinbindingcapability,asthisregioncontainsaconservedsequenceofapproximately20residues,knownastheCARMILpeptidethatspecifically interactswithactin-cappingprotein(CP).ThisinteractionenablesCPto bindtothebarbedendsofactinfilaments,therebycappingthefilamentsandregulatingactinmonomeradditionandloss.Furthermore,the C-terminalregionofCD2APcontainsspecificbindingsitesformembrane proteinssuchasnephrinandpodocin,highlightingitsmultifunctional roleincellularprocesses(19–23).

CD2APisexpressedthroughoutthebody,withrelativelyhighlevels inthestomach,duodenum,colon,andkidneys.CD2APisparticularlyenrichedinpodocytesoftheglomeruli(24).Inglomerularcells,CD2APplays acrucialrolebyinteractingwithproteinssuchasnephrinandpodocin attheslitdiaphragm,anchoringtheseproteinstotheactincytoskeleton.Thisinteractionisessentialformaintainingthefunctionofpodocytes andtheslitdiaphragmduringtheglomerularfiltrationprocess(25, 26). CD2APisindispensablefornormalglomerularfunction.Micewithacompleteknockoutofthe Cd2ap geneexhibitprogressiveglomerulardysfunctionduetothelossofpodocytefootprocessintegrityandtypicallydieof renalfailurewithin6to7weeksafterbirth(27).

1 FujianProvincialKeyLaboratoryofNeurodegenerativeDiseaseandAgingResearch,InstituteofNeuroscience,SchoolofMedicine,XiamenUniversity,Xiamen,Fujian 361102,China

CorrespondingAuthor: Yun-wuZhang,FujianProvincialKeyLaboratoryofNeurodegenerativeDiseaseandAgingResearch,InstituteofNeuroscience,SchoolofMedicine, XiamenUniversity,Xiamen,Fujian361102,China.E-mail: yunzhang@xmu.edu.cn Received:5February2025.Revised:25February2025.Accepted:28February2025. Publishedonline:18March2025.

Figure1. TheschemeofCD2AP.(A)Human CD2AP geneandCD2APprotein.The CD2AP geneislocatedonchromosome6p12.3andhas18exons.TheCD2AP proteincontainsthreeSH3domains,aproline-richdomainandacoil-coildomain.Thethree-dimensionalstructureofCD2APisderivedfromAlphaFold3.SNPs associatedwithADarelisted.(B)ComparisonofCD2APsequencesofdifferentspeciesaroundK633(highlightedbyaredbox).

CD2APalsoparticipatesintumorgrowthbutshowsdiverseeffectsin differentcancers.Forexample,CD2APwasfoundtodisplayaspecificexpressionpatterninhumanurogenitalorgansbutwithdistinctexpression patternsinseveraltypesofkidneytumors(28).Anotherstudyrevealeda reductionofCD2APexpressioninrenalclearcellcarcinoma(ccRCC)and anassociationoflowerCD2APexpressionlevelwithworsepatientprognosis,implicatingthatCD2APmaybeaprognosticbiomarkerforccRCC (29).Inaddition,CD2APwasfoundtoformascaffoldproteincomplexwith TKS4forregulatingthemigrationandepithelial-mesenchymaltransition pathwaysofHCT116coloncancercells(30).Furthermore,CD2APcould promotecelladhesionandinfluencecytoskeletalassemblybyinteractingwiththeproteinCAPZA1,therebyregulatingthemetastasisofgastric cancercells(31).Recently,wealsorevealedthatCD2APwasupregulatedinglioblastoma,inwhichCD2APcouldenhancetheNF-κ Bsignaling byinteractingwithTRIM5,therebypromotingthemalignantbehaviorof glioblastoma(32).

SincetheidentificationoftheassociationbetweenCD2APandAD,the functionofCD2APinthebrainhasbeenattractingmoreandmoreattention.ThemRNAdatafromtheAllenBrainAtlassuggestthatalthough CD2APmaybeexpressedatlowlevelsinneurons,itisrelativelyenriched inhighlyplasticbrainregionssuchasthehippocampus,cortex,andcerebellum(33, 34).Inaddition,highexpressionofCD2APwasobservedin dendriticendosomesofprimaryculturedmouseneurons(34).Sinceneuronssharemorphologicalsimilaritieswithpodocytes,asbothpossess abundantactin-richprojectionsandhavecommonactinregulatorssuch assynaptopodinandcortactin(35),CD2APmightplayasignificantrolein neuronsasitdoesinpodocytes.Indeed,theabsenceofCD2APinneurons wasshowntocausesynapticdamage(36–38).Moreover,werecentlydiscoveredthatCD2APwasexpressedathigherlevelsinmicrogliacompared toneuronsinmiceandthatCD2APcouldregulatemicroglialactivationin responsetoAβ toxicity(39).ThesefindingsindicatethatCD2APalsoplays acriticalroleinthecentralnervoussystem.

RelationshipBetweenCD2APandAD CD2AP Single-NucleotidePolymorphismsAreAssociatedwithAD In2011,Naj etal. andHollingworth etal. independentlyconducted genome-wideassociationstudies(GWAS)usinglargesamplesand consistentlyidentifiedthatthesingle-nucleotidepolymorphism(SNP) rs9349407in CD2AP intron1significantlyassociatedwithLOAD(8, 9). Subsequentreplicativestudiesreportedcontroversialresultsonthe associationbetweenrs9349407andAD,withbothpositive(40–42) andnegative(43–46)correlationssuggested.However,mostnegative studiesusedrelativelysmallsamplesizes.Anotherworkstudyingdeceasedindividualswhounderwentcompleteneuropathologicalevaluationsfoundthatthers9349407locuswasrelatedtoneuriticplaque pathology(47).

TheworkbyHollingworth etal. furtheridentifiedthattheSNP rs9296559in CD2AP intron1wasalsoassociatedwithLOAD(9),andthis associationwasconfirmedinthesouthernHanChinesepopulation(42). OtherstudiesidentifiedadditionalSNPsinthe CD2AP genetoassociate withAD,suchasrs10948363in CD2AP intron2(48, 49)andrs116754410 in CD2AP exon18(50),ofwhichthelatterresultsinamissensemutation (K633R)inCD2AP.TheaminoacidK633islocatedinthecoiled-coildomainofCD2AP,andonerecentstudyfoundthatCD2APK633Roverexpressioninneuronscouldincreasespinedensityandvolume.Incontrast,its overexpressionfailedtorescueimpairedspinedensityinCD2AP-deficient neurons(37).Herein,wealsoevaluatedtheconservationofK633and founditconservedfromhumanstozebrafish(Figure1B),furtherimplicatingtheimportanceofK633forCD2APfunction;thisrequiresfurther investigation.Moreover,TheSNPrs9473117locatedupstreamof CD2AP wasreportedtobeassociatedwithEOAD(51).

CD2APExpressionAlterationinAD Itwasreportedthat CD2AP expressiondecreasedinperipheralbloodlymphocytesinpatientswithLOAD(42).However,werecentlynoticedthatin oneproteomicstudywithlargedatasets(52),CD2APproteinlevelswere significantlyincreasedinthebrainofpatientswithADcomparedtocontrolsubjectsandasymptomaticpatientswithAD(39).Wealsofoundthat CD2APlevelssignificantlyincreasedinthehippocampusofthe5xFADAD modelmiceatpathologicalstagesbutnotatpre-pathologicalstages, andsuchanincreaseprobablyoccurredspecificallyinmicroglia(39).Our findingsimplicatethatCD2APalterationsinADoccurafterpathologicalchanges.Consistentwithourresults,anearlierstudyalsoreported thatCD2APlevelswereincreasedinthebrainoftheAPP/PS1ADmodel mice(53).

AlthoughseveralSNPsaround CD2AP havebeenreportedtobehighly associatedwithAD,onlyafewstudieshaveexploredtheeffectsofsome oftheseSNPson CD2AP expressionsofar.Inastudyanalyzinghuman braingeneexpressiondata,researchersfoundthattheminoralleleof rs9349407wasonlyassociatedwithdecreased CD2AP expressioninthe cerebellarcortex(54).Whilethestudyshowedthatrs9473117associates withEOAD,theminoralleleofrs9473117wasfoundtoassociatewith increased CD2AP expressioninthethalamusandcerebellarcortex(51). Inaddition,Paveškovi ´ c etal. leveragednewpairedsingle-nucleusRNAsequenceandwholegenomesequencingdataandfoundthattherisk variantofrs9473117,togetherwiththoseofrs7767350andrs9369716 thatareinstronglinkagedisequilibriumwithrs9473117,increaseshuman CD2AP mRNAexpressioninbothexcitatoryandinhibitoryneurons, aswellasinmicroglia(36).

CD2APRegulatesAPPTransportandAβ Production OnemajorpathologicalfeatureofADistheformationofamyloidplaques composedofAβ ,whichisderivedfromAPPthroughsequentialcleavages. First,APPiscleavedbythe β -secretase(BACE1)togeneratesolubleextracellularAPP(sAPPβ )andaC-terminalfragment(CTFβ ).APPCTFβ isthen cleavedbythe γ -secretasetoproduceAβ fragmentsof40or42amino acidsinlength,namelyAβ 40andAβ 42(55, 56).ThecleavageofAPPis determinedbythesubcellularlocalizationofAPPanditsinteractionswith BACE1and γ -secretaseduringmembrane,endosome,andlysosometrafficking(57, 58).

CD2APisanactin-associatedadaptorproteinthat,alongwithseveralmembersoftheRabfamily,participatesinthedockingprocessof

vesiclestotargetmembranesandregulatesendosomemorphology(19). SeveralstudieshavesuggestedthatCD2APisinvolvedintheintracellulartransportandcleavageofAPPforAβ production.Furusawa etal foundthatoverexpressionofCD2APatthecellularlevelacceleratedthe transportofAPPfromearlyendosomestolateendosomes,thusinitiating thedegradationprocessofAPPwithoutaffectingitsdegradationrate. Incontrast,knockingdownCD2APincellssignificantlyincreasedintracellularAPPlevels(59).Ubelmann etal. alsoshowedthatCD2APcould keepAPPandBACE1apartinearlyendosomesinneurons:CD2APdeficiencyincreasedthetrappingofAPPatthelimitingmembraneofearly endosomesandthusreduceditssortingfordegradationindendritesso thatAPPandBACE1hadelevatedconvergenceinearlyendosomesfor increasedAβ generation(34).However,Liao etal. reportedthatinthe N2a-APP695cellline,overexpressingAPP,knockingdownCD2APreduced cellmembraneAPPlevelsandAβ releaseandloweredtheAβ 42/Aβ 40ratio.Moreover,theyfoundthatin1-month-oldAPP/PS1micewithcompletelossofCD2AP,theAβ 42/Aβ 40ratiowasdecreased.While,CD2AP haploinsufficiencyhadnoeffectonAβ depositionupto7monthsofage inAPP/PS1mice(60).OnerecentstudyalsoreportedthatinAPP/PS1 micewithneuron-specificCD2APknockout,Aβ levelswerenotaltered at4.5monthsofage(61).Duetotheinconsistencyindifferentstudies,thespecificroleofCD2APinAPPprocessingandAβ requiresfurther in-depthinvestigation. Table1 summarizesreportedstudiesontheeffectsofCD2APonAPPtrafficking/Aβ generationandotherAD-related processes.

CD2APModulatesTau-mediatedNeurotoxicity NeurofibrillarytanglesformedbyhyperphosphorylatedTauproteinrepresentanotherimportantpathologicalfeatureofAD.Inonestudyusing immunohistochemicalassaystoexploretheassociationbetweenCD2AP expressionandADpathologiesinpostmortemhumanbrainsamples, CD2APwasfoundnotassociatedwithAβ depositsinvesselsorparenchymalplaques.Instead,CD2APimmunodetectioninneuronswaspositively associatedwithBraakneurofibrillarystage(62).Furthermore,theADassociated CD2AP SNPrs10948363wasfoundtoassociatewithNFTs (63),theAD-associated CD2AP SNPrs9349407wasfoundtoassociate withanincreaseintotalTauproteinlevelsincerebrospinalfluid,andthe rs9381563variantin CD2AP wascorrelatedwithchangesinphosphorylatedTaulevelsincerebrospinalfluid(64).

CD2APalsoaffectstheneurotoxicitycausedbyTau.InafruitflyAD modelexpressinghumanTau,researchersfoundthatknockdownofthe cindrgene(thehumanhomologof CD2AP)robustlyenhancedTautoxicity (65).Xue etal.alsofoundthatthespecificknockoutofCD2APinneurons inAPP/PS1miceresultedinasignificantincreaseinthephosphorylation levelsofendogenousTauprotein.Incontrast,thetotalTauproteinlevelsremainedunchanged(61).Additionally,thedeficiencyofCD2APled toelevatedP38phosphorylationlevelsinthesemice.TreatmentwithP38 phosphorylationinhibitorsattenuatedtheincreasedphosphorylationof endogenousTauproteincausedbythelossofCD2AP(61).Itisknown thatP38canphosphorylateTau(66, 67).However,althoughsomestudies consistentlyreportedthathighglucoseandTGFβ treatmentsdecreased CD2APwhileincreasedP38phosphorylation(68, 69)andthatCD2APdeficiencyenhancedTGFβ -inducedP38activation(70),theprecisemechanismbywhichCD2APinfluencesP38phosphorylationremainsunclear anddeservesfurtherscrutiny.

CD2APRegulatesSynapticGrowthandDevelopment

Synapsesarethecorestructuresforsignaltransmissionbetweenneurons,andabnormalitiesinsynapticfunctionarecloselylinkedtocognitiveimpairment.IntheearlystagesofAD,synapticdysfunctionappears, althoughthenumberofsynapsesdoesnotsignificantlychangeatthis stage.However,inthemidtolatestagesofAD,thereisasignificantlossof synapsesandneuronaldeath,leadingtoasharpdeclineincognitiveabilities(71–76).Ojelade etal. foundthatthecindrgenewasinvolvedinthe developmentandmaturationofsynapsesduringthegrowthoffruitflies. Mutationsincindrdisruptedthereleaseandrecyclingofsynapticvesicles,impairingsynapticplasticity(38).TheyalsonoticeddecreasedlevelsofsomesynapticproteinsinCD2APknockoutmice(38).Additionally, theyshowedthatcindrinteractedwith14-3-3ζ toregulatetheubiquitin

Table1. CurrentknowledgeonthecontributionofCD2APtovariousAD-relatedprocesses

Studysystem

APPandAβ

FindingsReferences

Cells(HEK293,COS-7,N2a,neurons)CD2APoverexpressionenhancesAPPtransportfromearlyendosomes tolateendosomesandAPPdegradation.CD2APknockdownhas oppositeeffects (59)

Cells(N2a,neurons)CD2APknockdownstallsAPPatthelimitingmembraneofearly endosomes,increasestheencounterofAPPandBACE1,and promotesAβ generation (34)

N2a-APP695cellsCD2APknockdownreducesAβ 40andAβ 42andAβ 42/40ratio,reduces cellsurfacelevelsofAPPbutnottotalAPP (60)

PS1APPmicewithCD2APKONosignificantchangeofAβ 40andAβ 42,butdecreasedAβ 42/40ratio in1-montholdmice (60)

PS1APPmicewithCD2APhaploinsufficiencyNosignificantchangeofAβ 40andAβ 42andAβ plaquesat7months old.OnlydecreasedPBS-solubleAβ 42/40ratioin7-month-old femalemice (60)

APP/PS1micewithneuron-specificCD2APKOAβ notalteredin4.5-month-oldmice.(61)

Tau

FliesexpressinghumanTauCD2APknockdownenhancesTautoxicity(65)

APP/PS1micewithneuron-specificCD2APKOIncreasedsynapticdeficitsandsynapticproteinlossat4.5monthsold(61)

Synapse

NeuronsCD2APknockdownreducesspinedensityandsizeandneuronalactivity(37) NeuronsCD2APknockoutdisruptsneuronalandsynapticmorphology(36)

FliesCD2APdeficiencyimpairssynapsematurationandfunction(38)

CD2APKOmiceDecreasedcertainsynapticproteinsat5monthsold(38)

CD2APheterozygousandhomozygousKOmiceAbnormalpre-synapticreleasewithincreasedpaired-pulsefacilitation at5to8weeksold (36)

CD2APhomozygousKOmicePerturbationofproteinsinvolvedinsynapticfunctionat5weeksold(36) 5xFADmicewithmicroglialCD2AP haploinsufficiency Improvedsynapticdamageat7monthsold(39)

Microglia

CD2AP-deficientmicrogliaReducedphagocytosisability(39) 5xFADmicewithmicroglialCD2AP haploinsufficiency Attenuatedmicrogliosisat7-monthsold(39)

Blood–brainbarrier(BBB)

CD2APKOmicewithCD2APtransgeneexpression inthekidney

Behaviors

CompromisedBBBintegrity(85)

CD2APheterozygousKOmiceSubtleimpairmentsindiscriminationlearningat2.5-monthsold(36) Nestin-CremediatedbrainCD2APKOmiceNoobviouscognitiveandmotorbehaviorchangesat3.5-and 12-monthsold (36)

APP/PS1micewithneuron-specificCD2APKOAcceleratedcognitivedeficitonsetat4.5-monthsold(61) 5xFADmicewithmicroglialCD2AP haploinsufficiency Improvedcognitivebehaviorsat7-monthsold(39)

CD2APKOmicewithCD2APtransgeneexpression inthekidney Normalbehaviors(85)

Abbreviation:KO,knockout.

proteasomesystem,therebyaffectingtheconversionofsynaptophysin andplasmamembranecalciumATPase(PMCA);andtheabsenceofcindr increasedPMCAlevelsanddecreasedcytosoliccalcium(38).Researchby Mirfakhar etal. foundthatCD2APknockdowninneuronsresultedindecreasedspinedensityandsizeanddecreasedneuronalactivity(37).They alsoproposedthatCD2APcontrolstheformationandgrowthofdendritic spinesbyregulatingthebalanceofF-actinpolymerizationanddepolymerization(37).Paveškovic etal.alsoobservedamarkedreductionin thenumberofsynapsesandimpairedsynapticplasticityinthehippocampusofCD2AP-deficientmice(36).Inaddition,CD2APwassuggestedto regulatethelengthandcomplexityofneuronalaxonsandthenumberof filopodiaatgrowthconesthroughcoordinatingnervegrowthfactorsignaling(77).Moreover,werecentlyfoundthatspecificdeletionofCD2AP inmicrogliaattenuatedsynapticdamagein5xFADmiceatpathological stages,thoughthisisattributedtoreducedsynapsephagocytosisby

CD2AP-deficientmicroglia(39).Thesefindingscollectivelysuggestthat CD2APplaysacrucialroleinsynapticdevelopmentinneurons,anditsalterationmaycontributetosynapticdysfunctioninAD.Asummaryofthe regulationofAPP,Tau,andsynapsesinneuronsbyCD2APisillustratedin Figure2

CD2APRegulatesMicroglialActivity

InadditiontoAβ plaquesandTautangles,ADisalsocharacterizedby neuroinflammation.Microgliaareprimaryimmunecellsofthebrainand areactivatedinresponsetotoxicitytoexertprotectivefunctionduring theearlystagesofAD.However,inthelaterstagesofAD,excessively activatedmicrogliacanexacerbatediseaseprogressionbyreleasingtoxic proinflammatoryfactorsandphagocytosingfunctionalsynapses(78–81). CD2APwasinitiallydiscoveredasaligandforCD2inTcells,implicating itssignificantroleinimmunecells(12).WerecentlyfoundthatCD2AP

Figure2. ImpactofCD2APfunctioninneurons.CD2APregulatesAPPtransportfromendosomestolysosomes,Tauphosphorylation,andsynapseformation andmaintenanceinneurons.CD2APdeficiencyresultsinincreasedAPPretentioninendosomesforelevatedAβ generation,increasedTauphosphorylationand accumulation,andreducedsynapsenumbersandsynapticproteinssuchassynaptophysinandPSD95.

deficiencyreducedmicroglialresponsetoAβ andmicroglialphagocytosisability.Notably,weshowedthatincontrasttothedeterioratingeffect ofneuronalknockoutofCD2APinAPP/PS1mice(61),microglialCD2AP deficiencyattenuatedcognitivedefects,synapticdamage,anddiseaseassociatedmicroglia(DAM)in5xFADmiceatpathologicalstages(39).We furthersuggestedthatonepossibilityforsucharescuingeffectwasthat CD2APcouldinteractwiththecriticalmicroglialsurvivalfactor,colony stimulatingfactor1receptor(CSF1R),sothatCD2APdeficiencyamelioratedtheCSF1Rsignaling–mediatedmicroglialactivationanddownstreamexpressionoftheC1qcomplement,whichiscrucialforsynapse phagocytosis,andtheformationofDAMstriggeredbytoxicAβ (Figure3) (39).Theseeminglycontradictorydataregardingtheeffectsofmicroglial CD2APandneuronalCD2APonAβ pathologiesarelikelystemfromdistinctactionmechanismsineachinvestigatedcelltype.However,itisalso possiblethattheyarecausedbydifferentexperimentalmodelsusedin thesestudies.However,sofar,ourunderstandingoftheroleofCD2AP inmicrogliaandothercelltypeslagsbehindthatinneurons.Thereare urgentrequirementsforelucidatingthepathophysiologicalfunctionsof CD2APindifferentcelltypesandparallellycomparingtheircontributions toAD.

CD2APParticipatesintheIntegrityoftheBlood–BrainBarrier Theblood–brainbarrier(BBB)providesaphysicalbarriertoprotectthe brainfromharmfulmaterialsintheperipheralenvironment.ThedisruptionoftheBBBcanleadtotheinfluxofneurotoxicbloodbornedebris,cells,andmicrobialpathogensintothebrain,triggeringinflammatoryresponsesandrelatedimmunereactions,whichmayinitiate variouspathwaysleadingtoneurodegenerativediseasessuchasAD (82–84).MRIstudieshaveshownthattheBBBfunctionisimpairedinpatientswithearlyADandotherneurodegenerativediseases.Analysesof postmortemtissuesofADpatientbraintissuesalsosupportthisconclusion(82).Brainmicrovascularendothelialcells,whichexpresshighlevelsofCD2AP,arekeycomponentsoftheBBB(85).CD2APhomozygous knockoutmicewithCD2APtransgeneexpressioninthekidneyattenuated theirmortalityrate.Suchmiceshowedoverallnormalbehaviors.However,theyhadcompromisedtheintegrityoftheBBBsointraperitoneally administeredpentylenetetrazolincreasinglypenetratedintothebrainto induceseizuresinmuchshorterlatencyperiodsinthesemicethanincon-

trols(85).ThisfindingimplicatesthatabnormalexpressionofCD2APin brainmicrovascularendothelialcells,ifany,mayleadtoBBBdysfunction andfacilitateADprogression.

Conclusion

CD2APisintricatelyinvolvedinintracellularproteintransportanddegradation,vesicletrafficking,cellsignaling,andcytoskeletonremodeling.As ariskfactorforAD,abnormalitiesinCD2APinthenervoussystemmay contributetothepathogenesisofADthroughvariousmechanisms,includinginfluencingthetransportandprocessingofAPPandthusAβ generation,participatinginTau-mediatedneurotoxicity,disruptingsynaptic functionandvesiclerelease,modulatingmicroglialactivation,andcompromisingtheintegrityoftheBBB.However,thespecificmolecularmechanismsbywhichCD2APparticipatesintheseprocesseshaveyettobe fullyelucidated.Moreover,CD2APindifferentneuralcelltypesmayhave contradictoryeffectsonADpathologies.Furtherdetailedresearchinto thepathophysiologicalrolesofCD2APinthenervoussystem,especially invariouscelltypes,willprovidenewinsightsintothepathogenesisof AD.Withacomprehensiveunderstandingoftheexactpathophysiological functionsofCD2APindifferentneuralcells,itisalsopossibletodesign celltype–specificdrugstopromoteCD2APlevelsinthosewhoseCD2AP deficiencyispathogenic(e.g.,neurons)andtoreduceCD2APlevelsin thosewhoseCD2APelevationispathogenic(e.g.,microglia)aspotential therapeuticapproachesforAD.

AuthorContributions

Y.W.wroteadraft.Y.-w.Z.reviewedandrevisedthemanuscript.

Allauthorshavereadandapprovedthemanuscript.Allauthorstake fullresponsibilityforalldata,figures,andtextandapprovethestudy’s contentandsubmission.Norelatedworkisunderconsiderationelsewhere.Allauthorsstatethatallunprocesseddataareavailable,andall figuresaccuratelypresenttheoriginaldata.

Correspondingauthor:ProfessorYwZforanyaspectofthework. Thiscorrespondingauthortakesfullresponsibilityforthesubmission process.

FundingSources

ThisworkwassupportedbygrantsfromtheNationalNaturalScience FoundationofChina(U21A20361and82130039),theLingangLaboratory

Figure3. ImpactofCD2APdeficiencyinmicrogliainAD.MicroglialCD2APlevelsareincreasedinAD,leadingtoelevatedCSF1RsignalingandC1qexpression andcytoskeletonremodelinginmicroglia,resultingintheformationofdisease-associatedmicroglia(DAM)andelevatedmicroglialphagocytosis ofsynapses. CD2APdeficiencyinmicrogliaattenuatedthesechangestoprotectagainstAD.

(LG-GG-202401-ADA030200),StateKeyLaboratoryofVaccinesforInfectiousDiseases,XiangAnBiomedicineLaboratory(2023XAKJ0102054), andtheKeyScientificResearchProjectforHealthandHygieneofFujian Province(2023ZQNZD018).

AuthorDisclosures

Theauthorshaveconfirmedthatnoconflictofinterestexists.

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BrainMedicine

RESEARCHARTICLE

Maternalimmuneactivationimpairshippocampalpyramidalneuronexcitabilityin newbornratoffspring:Implicationsforneurodevelopmentaldisorders

LuciaMoravcikova1 ,RomanMoravcik1 , 2 ,KristinaCsatlosova1 , 3 ,LubicaLacinova1 ,DanielaJezova4 ,andEliyahuDremencov1 , 4

Maternalinfectionduringpregnancyisassociatedwithanincreasedriskofneurodevelopmentaldisorders,includingdepression, schizophrenia,andautismspectrumdisorder.Thehippocampusplaysacriticalroleinthesedisorders,buttheimpactofmaternalimmune activation(MIA)onearlyhippocampalneuronfunctionremainspoorlyunderstood.Weinvestigatedtheeffectsoflipopolysaccharide-induced MIAinpregnantrats(20–80 μg/kgongestationaldays15–19)ontheelectrophysiologicalpropertiesofhippocampalpyramidalneuronsfrom newbornoffspring.Primaryneuronalcultureswerepreparedfromthehippocampiofnewbornratsandmaintainedfor13daysinvitro(DIV13). Whole-cellpatch-clamprecordingsassessedneuronalexcitabilityparametersbetweenDIV4-13.MIAsignificantlyalteredactionpotential characteristicsinoffspringhippocampalneurons,including:(1)increasedlatencytime,thresholdpotential,andrepolarizationpotential;(2) decreasedpeakpotential,ascendanddescendvelocities;and(3)reducedspontaneousandevokedfiringfrequencies.Thesealterations suggestimpairedglutamatergicneurotransmissioninthehippocampusofMIAoffspring,withpotentialsex-specificeffectsobservedfor spontaneousactivity.OurfindingsdemonstratethatMIAsignificantlydecreasestheexcitabilityofhippocampalpyramidalneuronsinnewborn offspring.Thisreducedglutamatergicneurotransmissionmaycontributetothepathophysiologyofneurodevelopmentaldisordersassociated withmaternalinfectionduringpregnancy.Thisstudyprovidesnovelinsightsintoearlyneurophysiologicalchangesfollowingprenatalimmune challengethatmayinformtherapeuticinterventionstargetinghippocampalfunction.

BrainMedicine March2025;1(2):46–52;doi: https://doi.org/10.61373/bm025a.0029

Keywords: Electrophysiology,glutamate,hippocampus,lipopolysaccharide,maternalimmuneactivation,neurodevelopmentaldisorders,neuronalexcitability

Introduction

TherecentCOVID-19pandemicdemonstratedthatourcivilizationismore vulnerabletoacuteinfectiousdiseasesthanitwasthoughtbefore.Since acutecontagiousdiseasesarenotavoidingpregnantwomen,theinvestigationoflong-termconsequencesofmaternalinfectionontheoffspring isstronglyneeded.Ithasbeenreportedthatthechildrenofwomensufferingfromanacuteinfectiousdiseaseduringpregnancywerefoundto haveahigherriskoffuturedevelopmentofdepression(1),schizophrenia(2–6),andautism(7).However,knowledgeofthemechanismsmediatingtheneurodevelopmentaleffectsofmaternalinfectiousillnessis limited.

Anacuteinfectiousillnessincreasesbloodconcentrationsofinflammatoryandanti-inflammatorycytokinesandstresshormones,suchas corticosteroids.Thesefactorscanpasstheplacenta,aswellastheblood–brainbarrier,andaffectembryonalneurodevelopment.Studiesinlaboratoryanimalsinvolvingmaternalimmuneactivation(MIA)withabacterial(lipopolysaccharideorLPS)(8)orviral(polyinosinic:polycytidylic acidorPolyI:C)(9)antigensshowedthattheMIAprimarilyaffected centralserotonergic(5-HT)anddopaminergicpathways,aswellasthe hippocampus.

OurpreviousstudyshowedthattheMIAwithLPSalteredtheratesof thespontaneousfiringactivityofcentral5-HTanddopamine-secreting neuronsinoffspringinasex-dependentway.Theformerwasdecreased inbothsexes,andthelatterincreasedinmalesonly(8).Similareffects ontheexcitabilitypatternofdopaminergicneuronswereobservedafter theMIAwithimmuneactivationbyPolyI:C(9).OffspringofLPS-treated damshadalsolower5-HTanddopaminelevelsinthemedialprefrontal cortex,nucleusaccumbens(10),striatum(11),amygdala(12),andhypothalamus(13).Thedecreaseinbrain5-HTanddopaminelevelswas

Withregardstothehippocampus,MIAdecreasedlocal5-HTand dopaminelevels(14),densitiesofserotonin-1A(5-HT1A )andglucocorticoidreceptors(10, 15),concentrationsofthebrain-derivedneurotrophic factor(BDNF),andimpairedadultneurogenesisinthehippocampus(16). Totheauthors’bestknowledge,theeffectsofMIAontheexcitabilityof hippocampalneuronsinoffspringhavenotyetbeeninvestigated.The knowledgeoftheexcitabilitypatternofhippocampalneuronsundernormalandmaternalstress–inducedconditionsis,however,importantfor understandingthemechanismsofhippocampalneuronalplasticity.The presentstudyis,therefore,aimingtotestthehypothesisthatMIAleads toimpairedfunctioningofhippocampalpyramidalneuronsisolatedfrom thehippocampiofnewbornoffspring.Thenoveltyofthepresentstudy isthatitisthefirsttoassesstheeffectoftheMIAontheexcitabilityof theindividualoffspringhippocampalpyramidalneuronsveryearlyafter birth.

Results

PrenatalLPSDoesNotAlterVrest

MIAbyLPSdidnotaffectVrest ofhippocampalneuronsisolatedfromnewbornoffspring,asmeasuredattheDIV4-13oftheircultivation.AtDIV10, however,astatisticallysignificantinteractionbetweensexandprenatalLPStreatmentwasobserved(F1,63 = 10.40, p = 0.002).PrenatalLPS tendedtoincreaseVrest infemalesanddecreaseitinmales;nevertheless, theTukeypost-hoctestdidnotrevealanybetween-groupdifferences. AtDIV13,statisticallysignificantsexdifferencesinVrest wereobserved (F1,29 = 9.06, p = 0.005);itwashigherinfemalescomparedtothemales, regardlessofprenatalLPStreatment(notshown).

1 InstituteofMolecularPhysiologyandGenetics,CentreofBiosciences,SlovakAcademyofSciences,84005Bratislava,Slovakia; 2 DepartmentofAnimalPhysiologyand Ethology,FacultyofNaturalSciences,ComeniusUniversityinBratislava,84215Bratislava,Slovakia; 3 InstituteofExperimentalPharmacologyandToxicology,Centerfor ExperimentalMedicine,SlovakAcademyofSciences,84005Bratislava,Slovakia; 4 InstituteofExperimentalEndocrinology,BiomedicalResearchCenter,SlovakAcademy ofSciences,84005Bratislava,Slovakia

CorrespondingAuthor: EliyahuDremencov,InstituteofMolecularPhysiologyandGenetics,CenterforBiosciences,SlovakAcademyofSciences,Dúbravskácesta9,84005 Bratislava,Slovakia.E-mail: eliyahu.dremencov@savba.sk

Received:3December2024.Revised:28February2025.Accepted:4March2025. Publishedonline:18March2025. accompaniedbyareduceddensityof5-HTneuronsinthedorsalraphe nucleusanddopamineneuronsinthesubstantianigra(13).

Figure1. EffectofMIAonthemembraneactionpotentialthreshold(B),peak(C),andrepolarization(D)valuespotentialoftheoffspringhippocampalneurons. ∗ p < 0.05, ∗∗ p < 0.01, ∗∗∗ p < 0.001,and ∗∗∗∗ p < 0.0001incomparisonwithcontrols,Tukeypost-hoctest.

PrenatalLPSIncreasesVthr andVrepandDecreasesVpeak PrenatalLPShadastatisticallysignificantincreasingeffectontheVthr as measuredatDIV4(F1,43 = 23.64, p < 0.0001),DIV10(F1,63 = 10.83, p = 0.007),andDIV13(F1,29 = 18.41, p = 0.0002; Figure1A).PrenatalLPS hadalsoastatisticallysignificantlydecreasedVpeak ,asmeasuredatDIV4 (F1,43 = 4.73, p = 0.04)andDIV10(F1,63 = 29.96, p < 0.0001, Figure1B) andincreasedVrep ,asmeasuredatDIV7(F1,53 = 7.87, p = 0.007),DIV10 (F1,63 = 4.67, p = 0.03),andDIV13(F1,29 = 4.44, p = 0.04, Figure1C).At DIV4,Vpeak infemaleswashighercomparedtothemales(F1,43 = 4.94, p = 0.03).AtDIV10,theVpeak differencebetweencontrolandprenatallyLPStreatedratswashigherinfemalescomparedtothemales(F1,43 = 4.21, p = 0.046).Nosexdifferencesandnosex × treatmentinteractionfor theseparameterswereobserved.Thevaluesfromtheindividualneurons/ recordingsareshowninthefigureusingthedots.

PrenatalLPSIncreasesTlat andDecreasesVmax-ascend andVmax-descend PrenatalLPShadastatisticallysignificantincreasingeffectontheTlat ,as measuredatDIV4(F1,43 = 234.70, p < 0.0001)andDIV7(F1,53 = 42.54, p < 0.0001; Figure2A).PrenatalLPSstatisticallysignificantlysuppressed theVmax-ascend ,asmeasuredatDIV4(F1,43 = 74.59, p < 0.0001),DIV7 (F1,53 = 47.23, p < 0.0001),DIV10(F1,63 = 4.98, p = 0.03),andDIV13 (F1,29 = 9.93, p = 0.004; Figure2B),andVmax-descend ,asmeasuredat DIV4(F1,43 = 127.00, p < 0.0001),DIV7(F1,53 = 46.31, p < 0.0001),and DIV13(F1,29 = 6.99, p = 0.01, Figure2C).AtDIV4,Vmax-ascend washigherin

Figure2. EffectoftheMIAonthelatencytime(A)andascend(B)anddescend(C)velocitiesoftheAPsgeneratedbytheoffspringhippocampalneurons.

∗ p < 0.05, ∗∗ p < 0.01, ∗∗∗ p < 0.001,and ∗∗∗∗ p < 0.0001incomparisonwithcontrols,Tukeypost-hoctest.Thenumbersofrecordingsfromindividualneuronsare shownonthebars.

femalescomparedtomales(F1,43 = 4.11, p = 0.049).Nosexdifferences intheactionpotential(AP)thresholdpotentialandlatencytimeandno sex × treatmentinteractionfortheseparameterswereobserved.Thevaluesfromtheindividualneurons/recordingsareshowninthefigureusing thedots.

PrenatalLPSSuppressedtheDepolarizingCurrentPulse–inducedand SpontaneousActivityofHippocampalNeurons

PrenatalLPSsignificantlysuppressedthenumberofAPswithinthe depolarizingcurrentpulse(DCP)-inducedAPseries,asmeasuredat DIV10(F1,63 = 22.06, p < 0.0001)andDIV13(F1,29 = 15.36, p = 0.005; Figure3A).Nosexdifferencesandnosex × treatmentinteractionswere observed,asmeasuredatDIV10-13.Thespontaneousactivitywassig-

nificantlydecreasedaswell,butonlyatDIV13andonlyinmalerats (Figure3B).AsignificanteffectofprenatalLPStreatment(F1,19 = 5.60, p = 0.03)andsignificantsex × treatmentinteraction(F1,19 = 6.38, p = 0.02)wasdetected.Thevaluesfromtheindividualneurons/recordings areshowninthefigureusingthedots.

Discussion

TheresultsofthepresentstudyshowthatmaternalMIAinducedsignificantalterationsinthewaveformoftheAPsgeneratedbyoffspring hippocampalneurons.Thus,theAPsgeneratedbyhippocampalneurons isolatedfromtheoffspringofLPS-treateddamsarecharacterizedby decreasedthreshold,peak,andrepolarizationpotentials,decreasedAP ascendanddescendspeeds,andincreasedlatencytime,comparedtothe

Figure3. EffectoftheMIAontheevoked(A)andspontaneous (B)activityoftheoffspringhippocampalneurons. ∗ p < 0.05, ∗∗ p < 0.01,and ∗∗∗ p < 0.001in comparisonwithcontrols,Tukeypost-hoctest.Thenumbersofrecordingsfromindividualneuronsareshownonthebars.

APsgeneratedbyhippocampalneuronsisolatedfromoffspringofcontrol dams.MIAalsoledtodecreasedDCP-inducedandspontaneousactivityof hippocampalneuronsinoffspring.Thesummaryoftheeffectsofprenatal LPSontheexcitabilityofhippocampalneuronsisshownin Table1

WefoundthattheMIAdidnotaltertherestingmembranepotentialofneuronsisolatedfromthehippocampiofnewbornoffspring,as

Table1. SummaryofthestatisticallysignificanteffectsoftheMIAon theexcitabilityofglutamateneuronisolatesfromtheoffspring hippocampi

DIV4DIV7DIV10DIV13

Restingpotential0001

APthresholdpotential

APlatencytime

APrepolarizationpotential0

Spontaneousactivityn/e00

AP,actionpotential;DIV,day-in-vitro;0,npeffect; ↑,increasingeffect; ↓,decreasingeffect;n/e,notevaluated; 1 ,significantinteractionbetween sexandprenatalLPStreatment; 2 ,significantsexdifference.

measuredduringtheearly(DIV3-7)andlate(DIV10-13)stagesof invitro maturation.Inourpreviousstudy(17),however,wereportedthatmaternalstressledtoanenhancementofVrest oftheneuronsisolatedfrom thehippocampiofnewbornoffspring,asmeasuredatDIV4-10.Thedifferencebetweentheresultsofthepresentandpreviousstudiesmightbe explainedbythenatureofthestresssituationandthetimeofitsapplication.Ourpreviousstudyexaminedtheeffectofpregestationalchronic unpredictablestress.ThepresentstudystudiedtheeffectofstressassociatedwithMIAduringthethirdtrimesterofgestation.

ItwasfoundthatMIAledtotheincreasedthresholdpotentialof APgenerationintheoffspringhippocampalneurons.Asaresult,the APlatencytimewasincreased,andthenumberofAPsobservedduringtheDCPapplicationdecreased.OtherintrinsicAPcharacteristicsaffectedbytheMIAdecreasedascendanddescendspeedsandincreased repolarizationpotentials.Therefore,maternalstresslikelyaltersthe voltage-dependentionchannels’expressionand/oractivityintheAP generation.Indeed,stress-inducedchangesintheexpressionofcertain voltage-dependentionchannels,suchasKv1(18)andKv7(19)voltagedependentpotassiumchannels,werereported.Theexactmechanismmediatingtheeffectofmaternalstressontheexpressionand/oractivityof thevoltage-dependentionchannelsintheoffspringneuronsisnotyet known.However,itislikelytobebasedontheinteractionsbetweenmaternalandembryonalstresshormones(e.g.,corticosteroids),pro-(e.g., interleukins-1and12:IL-1/12,tumornecrosisfactor-alpha:TNF-α ,and interferon-gamma:IFNγ )andanti-inflammatory(e.g.,interleukins-4, 6and10:IL-4/6/10),cytokines,andneurotrophicfactors(e.g.,brainderivedneurotrophicfactor:BDNF)(20–22).

AnotherinterestingfindingofthepresentstudyisthatprenatalLPS decreasedtheaveragepeakvalueoftheAPsgeneratedbyhippocampal neuronsisolatedfromthenewbornoffspring.Thisfindingissimilarto thatofapreviousstudy(23).However,GrigoryanandSegalfoundthat prenatalstresstendedtodecreasetheVpeak potentialofAPsgenerated byoffspringhippocampalneurons,buttheeffectwasnotstatisticallysignificant.Inthepresentstudy,theeffectoftheMIAwassignificant.These differencesmightbeexplainedbythenatureofthestressorsbeingapplied:forcedswimmingandcagedeclinationinGrigoryanandSegal’s versus MIAinthisstudy.

WefoundthatMIAdecreasedthedepolarizationpulse–inducedand spontaneousgenerationoftheAPsinthepyramidalneuronsisolated fromnewbornmalehippocampi.Thefiringactivityoftheneuronsisthe mostfundamentalcharacteristicdeterminingtheneurotransmitterreleasefromthenerveterminals(24).Itis,therefore,likelythattheMIAled todecreasedglutamateneurotransmissionintheoffspringhippocampi andperhapsinotherbrainareasaswell.

Asexplainedinourpreviousstudies,thedepolarizationpulse–induced firingactivityofthecultivatedhippocampalneuronsresultsfromthedirectactivationofthevoltage-dependentsodiumchannels.Itis,therefore, primarilydependentontheintrinsicpropertiesoftheneurons.Thespontaneousactivity,however,dependsonexternalexcitatorysynapticinputs. Itisconsequentlydeterminedbythewholeneuronalnetwork(17, 25). MIA-induceddecreaseintheevokedactivityofthehippocampalneurons isolatedfromtheneonataloffspringbrainmightthusresultfromtheincreasedAPthresholdpotential,whichmay,inturn,becausedbytheabnormalexpressionofsomevoltage-dependention,forexample,potassiumchannels(18, 19).

Asinourpreviousstudies(17, 25),spontaneousactivityofthecultivatedhippocampalneuronscouldbedetectedduringthelatestages ofthecultivation(DIV10-13),wheninterneuronalsynapticconnections aredeveloped.Thus,theMIA-inducedchangesinthespontaneousactivityofhippocampalneuronsmaybeduetoabnormalneuronalnetwork development.Ithasbeenreportedthatstressmayalterthehippocampal networkdevelopment,forexample,itmayreducethenumberofsynaptic connectionsbetweentheneurons via amechanisminvolvingvariousneurotrophicfactors,suchasBDNF(26, 27).Eventhoughtheactualnetworks wereformedin invitro conditions,whichweresimilarforbothgroups, thepreviousexposureoftheneuronsortheirprecursorstothestress hormoneand/orinflammatorycytokinesputativelyaffectedtheirfuture abilitytocreatethenetworks.

ExcitatoryglutamatergicandinhibitoryGABAergicsynapticinputs mediatethespontaneousactivityofcultivatedhippocampalneurons (28).Prenatalstresslikelydecreasedthestrengthoftheexcitatoryand/or increasedthestrengthoftheinhibitorysynapticinputsoftheoffspring hippocampalneurons.Ithasindeedbeenreportedthatprenatalstress increasedthefrequencyoftheminiatureinhibitorypostsynapticcurrents recordedintheoffspringhippocampalneurons(23).

WhileourpresentstudyreportedthatMIAsuppressedthespontaneousactivityoftheoffspringhippocampalneurons,astimulatoryeffect ofmaternalstressexposureonthecultivatedneuronsisolatedfromthe offspringhippocampiwasobservedinourpreviousexperiments(17).As statedabove,thedifferencebetweenthepresentandpreviousstudies’ resultsmightbeexplainedbythestressor’snatureandthetimeofits application.

Hippocampalglutamatecircuitsarefundamentalinmemoryconsolidation,retrieval,andcognitiveperformance(29).Theyalsohaveacriticalroleinanxietyanddepressive-likebehavior(30).Decreasedexcitabilityofthehippocampalglutamateneurons,observedinthisstudy,may explain,atleastinpart,decreasedcognitiveperformance(12)andincreasedanxiety(31)anddepressive-likebehavior(16)intheoffspring oftheMIAdamsreportedinpreviousstudies.Itisknownthatchildren ofwomensufferingfromaninfectiousdiseaseduringpregnancyhavea higherriskoffuturedevelopmentofdepression(1),schizophrenia(2–6), andautism(7).Theresultsofthepresentstudysuggestthattheearly postnatalsuppressionoftheexcitabilityofhippocampalneuronsmight underlinetheseepidemiologicalobservations.Early-lifetherapeuticinterventions,stimulatingneurotransmissionwithinthehippocampalarea,

appliedusingnoninvasive,low-risktechniquessuchastranscranialmagneticstimulation(32),may,therefore,reducetheriskoffuture-lifepsychopathologiesinthechildrenofwomenwhoexperiencedinfectious diseaseduringthepregnancy.However,therisksandbenefitsofthese interventionsmustbeverycarefullyassessed.Animalmodelscanbeused intheseassessments;however,thelimitationofthesemodels,whichresultsfromthedifferencebetweenrodentsandhumanbrains,mustbe considered.SpeakingspecificallyabouttheLPS-basedmodeloftheMIA, itsmajorlimitationisthefactthatitprimarilymodelsbacterialinfection.Atthesametime,fromtheepidemiologicalpointofview,higherrisk mightbeexpectedfromviralinfections.

Inconclusion,ourstudy’sresults,togetherwiththeresultsofprevious studiesfromour(17)andother(23)groups,indicatethatmaternalstress inducessignificantalterationsintheexcitabilitypatternoftheoffspring hippocampalneurons.Thenatureofthematernalstress–inducedalterationsdependsonthetypeofstressorsapplied(e.g.,physicalstressors versusimmuneactivation)andthetimeoftheapplication(e.g.,pregestationalversusprenatal).Interactionsbetweenmaternalandembryonalstresshormones,cytokines,neurotrophicfactors,embryonalligand(glutamateandGABA),andvoltage-dependentionchannelsmightunderlinethenatureofthematernalstress–inducedalterationsoftheexcitabilityoftheoffspringhippocampalneuronalcircuits.

MaterialsandMethods

Animals

Adultfemale(200–250g)andmale(250–300g)WistarratswereorderedfromtheAnimalBreedingfacilityoftheInstituteofExperimentalPharmacologyandToxicology,CentreforExperimentalMedicine,SlovakAcademyofSciences(DobraVoda,Slovakia).Animalswerehoused understandardlaboratoryconditions(temperature:22 ± 2°C,humidity: 55% ± 10%)witha12-hlight/12-hdarkcycle(lightsonat7a.m.).Pelletedfoodandtapwaterwereavailableadlibitum.AllexperimentalprocedureswereapprovedbytheAnimalHealthandAnimalWelfareDivisionoftheStateVeterinaryandFoodAdministrationoftheSlovakRepublic(PermitnumberRo3592/15-221)andcompliedwiththeDirective 2010/63/EUoftheEuropeanParliamentandoftheCouncilontheProtectionofAnimalsUsedforScientificPurposes.

MIA

Afteranacclimatizationperiodof1week,theanimalswereplacedin cageswithonemaleandthreefemalesineach.Vaginalsmearsweretaken dailybetween7and8a.m.andexaminedunderlightmicroscope.Theday spermcellsweredetectedwasconsideredasday0ofgestation.During days15–19ofthegestation,LPS-treateddamswereonceperdaysubcutaneouslyinjectedwithLPSatincreasingdosesof20,20,40,40,and 80 μg/kg,asdescribedpreviously(8, 12).Thethirdtrimesterofgestation waschosenfortheLPSadministrationbecauseitisacriticaldevelopmentalperiodforspecificcentralnervoussystem(CNS)structures(33).Controldamswereinjectedwithsaline.Onday20ofgestation,damswere placedinindividualcages.Thebirthusuallyoccursonday21ofgestation.

PrimaryCultureofHippocampalNeurons

Aspreviouslydescribed,hippocampalneuronswereisolatedfromnewbornWistarratsofbothsexesatthefirstpostnatalday(25, 34).Hippocampiwereremovedandtransferredtoice-coldisolationsolutioncontaining(inmM):137NaCl;5.4KCl;1.1Na2 HPO4 × 2H2 O;1.1KH2 PO4 ;6.1 Glucoseand1Kynurenicacid;pH7.3withNaOH.Tissuewaschoppedand incubatedinapredigestionsolution(LeibovitzL-15Medium;25U/mL Papain;2mMKynurenicacid)for25to30minat37°Cinanatmosphere containing5%CO2 .DigestedtissuewaswashedwithcoldSTOPsolution (isolationsolutionmixedwithaheat-inactivatedfetalbovineserumin aratioof3:1).Finally,hippocampiweretransferredintoincubationmediacontaininghighglucose(4.5g/L)Dulbecco’sModifiedEagle’s(DMEM) Mediumsupplementedwith10%heat-inactivatedfetalbovineserum,antibiotics(75,000IU/Lpenicillinand75mg/Lstreptomycin),2mMMgCl2 , 10nMprogesterone,100 μMputrescine,and12.5mg/mLITSS(25mg insulin,25mgtransferrin,and25 μgNa-selenite).Inincubationmedia,hippocampiwereconsecutivelytrituratedwiththreeglassPasteur

Figure4. Identificationofglutamatepyramidalneuronsinprimarycultures preparedfromneonatalrathippocampiandtheirevokedandspontaneous activity.(A)Characteristicmorphologyofpyramidal(∗ )andnonpyramidal (#)neurons.(B)Sodium(Na+ ),calcium(Ca2+ ),andpotassium(K+ )currents, characteristicforhippocampalpyramidalneurons,recordedimmediatelyafter theopeningoftheneurons,underthewhole-cellvoltage-clampusingvoltage rampfrom 80to +80mVwithaspeedof1.6mV/1msandholdingpotential of 70mV.(C)SingleAPgeneratedbyaDCPof30pAinDIV7cultivatedneurons.(D)APseriesgeneratedbyaDCPof 10pAinDIV10cultivatedneuron. (E)SpontaneousAPgeneratedbyaneuroninDIV13culture.

pipetteswithdecreasingdiameters.Fromthefinalsingle-cellsuspension, hippocampalneuronswereseededatadensityof5 × 104 cells/cm2 on 35mmplasticPetridishescontainingglasscoverslips(Sarstedt,Slovakia) coatedwithpoly-D-lysine(50 μg/1mL/1cm2 )inincubationmediacontainingpenicillin/streptomycin.After24h,themediumwasexchanged foranantibiotics-freemedium.Atdays4to5 invitro (DIV4-5)Cytosine β-D-arabinofuranoside(1 μM)wasaddedtoreducetheproliferationof nonneuronalcells.Neuronswereincubatedinahumidifiedincubatorin anatmospherecontaining5%CO2 at37°CuptoDIV14.Unlessmentioned otherwise,allchemicalswerepurchasedfromSigmaAldrich,Slovakia.

ElectrophysiologicalRecordings

Recordingsweredoneinthewhole-cellpatch-clampconfigurationat roomtemperatureusingaHEKAEPC10amplifier(HEKAElectronics,Lambrecht,Germany).Patchpipetteswithresistancerangingfrom4to5MΩ werefabricatedfromborosilicateglasscapillaries(SutterInstruments, Novato,CA).Pyramidalneuronswereidentifiedbytheircharacteristic physicalappearance(triangularsoma; Figure4A)andthepresenceof potassium(IK) ,sodium(INa ),andcalcium(ICa )currents,measuredimmediatelyaftertheopeningofthecell(Figure4B).Aspreviouslydescribed,AP firingwasmeasuredunderthecurrentclampconditions(25, 34).Theintracellularsolutioncontained(inmM):120K-gluconate;20KCl;2MgCl2 ; 2Na2 ATP;0.25Na2 GTP;10HEPES;pH7.3(withKOH).Theosmolarityofan

intracellularsolutionwasapproximately290–300mOsmol/Linallcases (measuredbyOsmomat030-Gonotec,Germany).Theosmolarityofanextracellularsolutionwassettoavalueof2–3mOsm/Llowerthantheosmolarityofthecorrespondingintracellularsolution.DCPcanactivatea singleAP(Figure4C)orAPseries(Figure4D)inculturedhippocampal neuronsafterDIV4-5.WehaveusedthisprotocolonthedaysDIV8-9, whentheexpressionofvoltage-dependentINa ,IK ,andICa isdeveloped. Intheseexperiments,restingmembranepotentialwasmaintainedat 70mV.EvokedAPserieswereactivatedbyaseriesofsix300-mslongDCPswithamplitudesincreasingwithastepof +50pA.Longer maturationwasnecessaryforthedevelopmentofspontaneousactivity. AfterDIV10-12,hippocampalneuronsinaprimaryculturebecomespontaneouslyactive(Figure4E).TheexperimentsweredoneonDIV13-14 whenabout80%ofalltestedcellswerespontaneouslyactive.Spontaneousactivitywasrecordedfor5minatanintrinsicmembranepotential ofeachcell.Themeanmembranepotentialcorrectedforaliquidjunction potentialwas 65.2 ± 0.4mV.

DataandStatisticalAnalysis

ThefollowingcharacteristicsoftheAPwaveformandneuronalexcitabilitywereanalyzed:membranerestingpotential(Vrest ),APlatencytime (tlat )andthreshold(Vthr ),peak(Vpeak ),andrepolarization(Vrep )potentials,andmaximalascend(Vmax-ascend )anddescent(Vmax-descend )velocities.Vthr wasdetectedasanelectricalpotentialvalueatthetimepoint whereitssecondderivationbytimereachesthelocalmaximum.Thetlat wasmeasuredasthetimebetweenthestartoftheDCPandthedetection ofVthr ,asdescribedpreviously.Vmax-ascend anddescentVmax-descend were detectedasthelocalminimumandmaximumofthederivativeofmembraneelectricalpotentialbytime,respectively,asdescribedpreviously (35).Theeffectsofsex,prenatalLPStreatment,andsex × treatmentinteractiondifferencesforeachparameterwereassessedusingthetwowayanalysisofvariance(ANOVA),followedbytheTukeypost-hoctest. BeforetheanalysisbyANOVA,datanormalityandhomoscedasticitywere verifiedusingShapiro–Wilk’sandLevene’stests,respectively.Theprobabilityof p < 0.05wasconsideredassignificant.

DataAvailabilityStatement

Theoriginalresearchdataareavailableuponrequest.

Acknowledgment

TheauthorsthankMs.EmiliaKocurivaforthetechnicalassistance.

AuthorsContribution

E.D.,L.M.,D.J.,andL.L.plannedthestudyandformulatedtheworkinghypothesis.L.M.,R.M.,andK.C.conductedexperiments.L.M.,R.M.,andE.D. analyzedtheresults.L.M.,L.L.,andE.D.wrotethemanuscript.Allauthors criticallyproofreadthemanuscriptandapproveditforpublication.

Funding

ThisworkwassupportedbytheScientificGrantAgencyoftheMinistryof EducationofSlovakRepublicandSlovakAcademyofSciences(grantnos. VEGA-2/0057/22,VEGA-2/0081/22,andVEGA-2/0045/24)andSlovak ResearchandDevelopmentAgency(grantsnos.APVV-19-0435,APVV-200202,andAPVV-22-0061).Thefundingagencieshadnofurtherrolein thestudydesign,thecollection,analysis,andinterpretationofdata,the writingofthereport,andthedecisiontosubmitthepaperforpublication.Theauthorsdeclarenofinancialinterestinthesubmissionofthis article.

AuthorsDisclosures

Theauthorsdeclarenofinancialinterestinpublishingthisstudy.

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Manicsymptomsinschizophrenia spectrumdisorders

E.M.Tsapakis1 ,D.Paitaridou1 ,M.Koummati1 ,K.Chovardas1 , S.Fylaki1 ,G.Karakatsoulis1 ,andK.N.Fountoulakis1

1 3rdDepartmentofPsychiatry,AristotleUniversityofThessaloniki, 54636,Thessaloniki,Greece

CorrespondingAuthor: EvangeliaMariaTsapakis,BSc(Hons),MBBS, MSc,MRCPsych,PhD,AssistantProfessorofPsychiatry,Aristotle UniversityofThessaloniki,3rdDepartmentofPsychiatry,AHEPA UniversityGeneralHospital,1,KiriakidiStreet,54636Thessaloniki, Greece,Tel.:+302310994632.E-mail: emtsapakis@doctors.org.uk

BrainMedicine March2025;1(2):53–59; doi: https://doi.org/10.61373/bm025r.0005

Thisstudyinvestigatedthepresenceofmanicsymptomsinstable patientsdiagnosedwithschizophreniaspectrumdisorders(SSDs)aimingtoidentifytheirassociationwithclinicalsymptoms.Atotalof75 out-patients,41.3%female[47.81(±10.521)year-old]wereassessed usingtheYoungManiaRatingScale(YMRS),PositiveandNegativeSyndromeScale(PANSS),GeneralizedAnxietyDisorder-7scale(GAD-7), andRiskAssessmentofSuicidalityScale(RASS).ParticipantsweredividedintotwogroupsbasedonYMRSscores:Group1,withoutorwith minimalsymptomsofmania(YMRS ≤ 10)andGroup2,withdistinct manicsymptoms(YMRS > 10).WeperformedstatisticalanalysisusingtheIBMSPSSversion29.0.OuranalysisrevealedapositivesignificantcorrelationbetweenYMRStotalscoreandPANSStotalscore (r2 = 0.516, p = 2.15 × 10 6 ),PANSS-Positivesubscore(r2 = 0.600, p = 1.31 × 10 8 )andPANSS-GeneralPsychopathologysubscore(r2 = 0.444, p = 6.646 × 10 5 ),Bonferronicorrectedat p = 0.0004.Moreover, positivesymptomsasassessedbythePANSS-Positivesubscalescore differedsignificantlybetweenthetwoYMRSgroups[t(73) = 3.982, p = 0.00016, d = 1.040].Linearregressionanalysisshowedthatthe severityofpositivesymptomspredictedtheoccurrenceofmanicsymptoms.Thisstudycouldserveasapilotstudy,observingmanicsymptomsinSSDsandasrecruitmentgoeson,itisexpectedtoyieldmore robustevidenceoftheirprevalenceinSSDsandtheirassociationswith clinicalsymptomsformingthephenotypiccharacterizationbasisfor furtherdimensionalresearchinthepsychopathologyandetiopathogenesisofSSDs.

Keywords: Globalfunctionality,mania,manicsymptoms,neurocognitive functions,PANSS,schizophreniaspectrumdisorders,suicidality,YMRS.

Introduction

Schizophreniaisaseverementaldisordercharacterizedbysignificantalterationsinthought,perception,emotion,andbehavior.Oftenregarded asasinglementaldisorder,itappearstoreflectconsiderableheterogeneity.Schizophreniasymptomsaretypicallygroupedintopositive,negative, anddisorganizedsymptoms,butnosinglesymptomclusterispathognomonicofschizophrenia(1).Whilemaniaisgenerallyeasytorecognize(2),severecaseswithpsychoticfeaturescanbemisdiagnosedas schizophrenia,andmildercasesmaybemistakenforpersonalitydisorders(3).Furthermore,itiscriticaltodistinguishbetweenmaniaand manicsymptoms.Whereasamanicepisodesignificantlyimpactsvarious domainsoffunctioning,mayincludepsychoticsymptoms,andusuallyrequireshospitalization(4),manicsymptomsdonotnecessarilymeetthe criteriaforafull-blownmanicepisode.

Manicsymptomscanappearwithinarangeofpsychiatricdiagnoses, anddonotexclusivelyformpartofmanicepisodes.Therelationshipbetweenschizophreniaandmanicsymptomsremainsanareaoflimited research.Evidence,however,indicatesthepresenceofmanicsymptomsacrossvariousdiagnosticcategories,includingschizophreniaand schizoaffectivedisorder(5).Moreover,vanOsandKapur(2009)proposed changingthecategoricaldichotomyofschizophreniaandbipolardisorder(BD)toadimensionalconceptualization(6).Diagnosisofschizoaffectivedisorderrequiresmeetingcriteriaforamajormoodepisodefor mostofthelifetimeoftheillnessaswellaspsychoticsymptomswithout overtmoodsymptomswithina2-weekperiod(7).Manicsymptomsareoftenpartofschizoaffectivedisorder,butnoconsensuscurrentlyexistsas towhetherthisdisorderlieswithintheschizophreniaspectrumdisorders (SSDs),themooddisordersorboth(8–11).

Manicsymptomscansignificantlyimpacttheclinicalcourseand prognosisofschizophrenia(12)andassuch,theirassessmenthasbeen includedinthemaniadomainoftheClinical-RatedDimensionsofPsychosisSymptomSeverity(CRDPSS)scaleproposedbyDSM-5forassessingtheseverityofpsychoticsymptomsinschizophrenia(13).AKorean studyexaminingthepsychometricpropertiesoftheYoungManiaRatingScale(YMRS)inSSDs,usingareceiveroperatingcharacteristicanalysis,foundtheoptimalcut-offscorefordistinguishingschizophrenia patientswithmanicsymptomsfromthosewithouttobe10,withasensitivityof88.3%andaspecificityof75.6%(14).Thisisincontrastto thecut-offpointof12takentobethethresholdfordiagnosingmaniain mooddisorders(15).TheyconcludedthataYMRSscoreof10indicates mildmaniaseverityontheClinicalGlobalImpression(CGI)scale,makingitareasonablethresholdforidentifyingmanicsymptomsinpatients withSSD.

Overlookingmaniacouldresultinmissedopportunitiestousepharmacologicaltreatmentsandmayleadclinicianstomakeexcessivelypessimisticprognoses(16).Individualswithschizophreniaoftenexperience amoreseverecourseofillnessandhaveworseprognosesthanthose withschizoaffectivedisorder.Furtherresearchisnecessarytocategorizebetterthevariousclinicalphenomenathatfallundertheumbrella ofmanicsyndromesandSSDs.ThisstudyaimstoinvestigatethepresenceofmaniainstablepatientsdiagnosedwithSSDs.Wehypothesized thatinpatientswithSSD,manicsymptomsareassociatedwithclinical psychopathology.

Results

Atotalof75,44male(58.7%)patientswithSSD[meanage43.55 (±11.800)years]and31female(41.3%)patientswithSSD[meanage 47.81(±10.521)years]mettheinclusioncriteria.ThemeanYMRSscore forthetotalsamplewas6.36(±5.753).WedichotomizedourgroupaccordingtotheseverityofYMRSscoringandusedtheYMRScut-offscore of10,suggestedtobeappropriateforthedetectionofmaniainSSDs (Kim etal.,2018).Thetotalsamplewasdichotomizedintotwogroups: Group1,withoutorwithminimalsymptomsofmania(YMRS ≤ 10)and Group2,withdistinctmanicsymptoms(YMRS ≥ 10).Group1(N = 55) hadameanYMRStotalscoreof3.42(±3.004)andGroup2(N = 20)hada meanYMRStotalscoreof14.45(±3.052).ThetwogroupsdifferedsignificantlyintermsoftotalmeanYMRSscoring[M = 11.032[95%confidence interval(CI):9.462to12.602], t (73) = 14.005, p = 2.252 × 10 22 , d = 3.657],asexpected.AsLevene’stestforequalityofvarianceswasnonsignificant(p = 0.807),wecouldsafelyassumethatthedatawerenormallydistributed.A post-hoc powercalculationforindependent t-tests at α = 0.05foundthestatisticalpowertobeequalto1.000.

Descriptivestatisticswereusedtoprovideacomprehensivesummary ofthemeanYMRSindividualitemandtotalscoreforthetotalsample (Table1). Table2 summarizesthedemographiccharacteristicsoftheparticipantswithoutorwithminimalmanicsymptomsandmania.Sexdistributionandfamilyhistoryofmentalillnessdidnotdiffersignificantly betweenthetwogroups(Fisher’sexacttest = 0.147and Fisher’sexact

Received:3October2024.Revised:19November2024and19January2025and22January2025.Accepted:22January2025. Publishedonline:11February2025.

Table1. YMRStotalscoreandYMRSindividualitems’mean(SD)scoresand95%CIofthemeansfor N = 75patientswithSSD

95%CIofMeanStandard YMRSItemsMinMaxMean(N = 75) UpperLowerDeviation(SD)

1.ElevatedMood030.560.390.730.758 2.IncreasedMotorActivity/Energy030.310.160.450.636 3.SexualInterest020.120.020.220.434

4.Sleep030.200.050.350.637

5.Irritability040.610.390.840.971

6.Speech(RateandAmount)060.890.551.241.512

7.Language/ThoughtDisorder030.640.460.820.765 8.ThoughtContent081.030.651.411.652 9.Disruptive/AggressiveBehavior030.370.220.520.653 10.Appearance040.670.460.870.890 11.Insight040.960.631.291.418 TotalYMRSScore0226.365.047.685.753

Table2. Demographicsofthetotalsample(N = 75)dichotomizedaccordingtoYMRSscore

YMRSTotalScore[N,Mean(SD)]Group1(≤10)Group2(>10)

Age(years)45.35(11.409), N = 5545.20(11.719), N = 20

BodyMassIndex(BMI,kg/m2 )27.55(4.879), N = 5026.29(7.459), N = 17

AntipsychoticDose(inOlanzapineEquivalents,mg)19.96(17.416), N = 4822.17(18.183), N = 18

AntidepressantDose(inFluoxetineEquivalents,mg)43.10(37.24), N = 1933.03(18.86), N = 7

BenzodiazepineDose(inDiazepamEquivalents,mg)15.51(8.434), N = 1020.00(7.071), N = 4

TotalNumberofEpisodes2.41(1.643), N = 541.95(1.268), N = 19

TotalNumberofHospitalizations1.20(1.592), N = 550.90(1.483), N = 20

Age(years)atFirstEpisodePsychosis28.40(10.399), N = 5527.70(10.854), N = 20

TotalNumberofSuicidalAttempts1.85(2.430), N = 551.75(2.291), N = 20

TotalIllnessDuration(years)17.15(12.002), N = 5517.50(11.199), N = 20

Sex(N,%)

Male35(63.6)9(45.0)

Female20(36.4)11(55.0)

MaritalStatus(N,%)

Single35(66.0)12(60.0) Married9(17.0)5(25.0)

Separated1(1.9)0(0.0) Divorced6(11.3)1(5.0) LiveswithOther1(1.9)1(5.0) Widow/Widower1(1.9)1(5.0)

Employment(N,%)

UsedtoWork,butNowUnemployed35(64.8)9(45.0) NeverWorked,NorWorkingNow6(11.1)4(20.0) Employee(PrivateorPublicSector)6(11.1)3(15.0) Freelancer(Salesman/SkilledWorker)1(1.9)0(0.0) Doctor/Lawyer/Engineer/Priest/Teacher3(5.6)1(5.0) UniversityStudent1(1.9)1(5.0) ManualWorker/Builder/Farmer/Etc.2(3.7)2(10.0)

FamilyHistoryofMentalIllness no

20(36.4)7(35.0) yes35(63.6)13(65.0)

DrugUseinthePast no

33(60.0)12(63.2) mild15(27.3)3(15.8) severe7(12.7)4(21.1)

DrugUseatPresent no

52(94.5)16(84.2) mild3(5.5)2(10.5) severe0(0.0)1(5.3)

Figure1. SimplescatterplotofPANSS-PositivesubscoreversusmeanYMRStotalscore.

test = 1.000,respectively).Forboth,a post-hoc powercalculationforchisquaretestswith df = 1at α = 0.05andforamediumeffectsizeof0.33, foundthestatisticalpowertobeequalto0.820.

Interestingly,wefoundapositivesignificantcorrelationbetween YMRStotalscoreandthePositiveandNegativeSyndromeScale(PANSS) totalscore(r2 = 0.516, p = 2.147 × 10 6 ),thePANSS-Positivesubscore (r2 = 0.600, p = 1.310 × 10 8 ; Figure1),andthePANSS-GeneralPsychopathologysubscore(r2 = 0.444, p = 6.646 × 10 5 ),butthecorrelationbetweenYMRStotalscoreandPANSS-Negativesubscorefailedto reachsignificance(Table3).Furthermore,independent-samples t-tests wereperformedtoexploremeandifferencesinPANSStotalandsubtest, GeneralizedAnxietyDisorder-7scale(GAD-7),andRiskAssessmentof SuicidalityScale(RASS)scoresbetweenparticipantswithoutorwithminimalsymptomsofmania,andinthosewithmanicsymptoms.Positive symptomsscoring,asassessedbythePANSS-Positivesubscale,wasthe onlypsychopathologymeasurethatstoodthestringentcriterionofthe BonferronimultiplecorrectionandshowedastatisticallysignificantdifferencebetweenthetwoYMRSgroups[PANSS-Positivesubscore mean diff = 6.841(95%CI:3.417to10.265), t(73) = 3.982, p = 0.00016, d = 1.040](Table4).A post-hoc powercalculationbasedondatafromthis independent t-testcomparison,for d = 1.040and α = 0.05,foundthe statisticalpowertobeover0.999,amorethanadequatevaluefordetectinganeffect.Morespecifically,analyzingcorrelationsbetweenindividual

YMRSitemsandthePANSStotalandsubscalescores(Table5),PANSSPositivesubscorewaspositivelycorrelatedwithYMRSitem7onlanguage andthoughtdisorder(r2 = 0.449, p = 5.239 × 10 5 )andYMRSitem11 oninsight(r2 = 0.522, p = 1.593 × 10 6 )ata post-hoc calculatedpower of0.990and0.999,respectively,given α = 0.05.

Finally,linearregressionestablishedthatthePANSS-Positivesubscale scorecouldsignificantlypredicttheYMRStotalscore[F(1,73) = 36.851, p = 5.214 × 10 8 ].TheYMRStotalscoreaccountedfor32.6%oftheexplainedvariabilityinPANSS-Positivescore.

Discussion

Inthisstudy,wefoundanincreasednumberofmanicsymptomsdenoting thepresenceofmaniainjustoveroneinfour(26.7%)stableparticipants withSSDs.AnearlierepidemiologicalstudyfromCanadafoundthatthe prevalenceofanepisodeofmaniainpatientswithschizophreniainthe communitywas17.7%(17),andamorerecentstudyshowedsignificant subthresholdmanicsymptoms(YMRSscore > 7)tobepresentin25.1% ofpatients(18).

InthisgroupofpatientswithSSD,weshowedthatpositivesymptomswereassociatedwithmania.Interestingly,theseverityofpositive symptomswasfoundtopredictthepresenceofmanicsymptoms,such that,thehigherthePANSS-Positivescore,themorelikelythepresenceof manicsymptoms.Ourfindingsreplicateresultsfromapreviousstudyon

r2 )correlationmatrixforYMRSTotalscoreversusPANSStotalscoreandsubscoreswithexact p values 1234

1.YMRSTotalScore

Table3. Spearman(

Table4. ComparisonoftotalscoresandsubscoresforPANSS,GAD-7,andRASSscalesbetweenthetwogroupsaccordingtoYMRSscoring

YMRSTotalScore(N = 75)Group1(YMRS ≤10), N = 55Group2(YMRS >10), N = 20

PANSS-PositiveSubscore,Mean(SD) meandiff = 6.841(95%CI:3.417to10.265), t(73) = 3.982, p = 0.00016, d = 1.040 14.25(6.743)20.95(6.452)

PANSS-NegativeSubscore,Mean(SD) meandiff = 2.282(95%CI: 1.690to6.254), t(73) = 1.145, p = 0.256, d = 0.299 18.86(8.000)21.10(6.851)

PANSS-GeneralSubscore,Mean(SD) meandiff = 6.777(95%CI:1.197to12.358), t(73) = 2.420, p = 0.018, d = 0.632 33.98(11.270)40.65(9.494)

PANSSTotalScore,Mean(SD) meandiff = 15.900(95%CI:4.672to27.128), t(73) = 2.822, p = 0.006, d = 0.737 67.10(22.794)82.70(18.991)

GAD-7TotalScore meandiff = 4.430(95%CI:0.455to8.404), Mann-WhitneyU = 370.50, Z =−2.07, p = 0.038 [Median(IQR),min-maxandMean(SD)]4.00(1–8),min0–max279.80(7.978)

RASSTotalScore,Mean(SD) meandiff = 50.750(95%CI: 104.762to206.262), t(73) = 0.651, p = 0.517, d = 0.172 320.00(284.617)370.75(22.267)

CI:ConfidenceIntervals,GAD–7:GeneralizedAnxietyDisorderAssessment 7,IQR:InterquartileRange,M:mean,max:maximum,min:minimum,PANSS: PositiveandNegativeSyndromeScale,RASS:RiskAssessmentSuicidalityScale,YMRS:YoungManiaRatingScale.

175patientswithschizophreniaaimingtosearchforpatternsinclinical symptomatologysuggestiveofthepresenceofmooddisordersunderthe labelofschizophrenia,alsoshowingthatmoodsymptomscorrelatewith positivesymptoms(18).

Furthermore,toascertainwhethermetabolicvariabilityisassociated withtheclinicalfeaturesofschizophrenia,Malaspina etal.(2021)examinedtheassociationof N-acetylaspartate(NAA)andcholine(Cho)levels withclinicalsymptomsinpatientswithschizophrenia.Theyfoundaposi-

tivecorrelationbetweenmanicsymptoms,asassessedbytheYMRS,and whole-hippocampusmultivoxelaveragecholinemillimolarconcentration ofCho,denotingthatbothmanicsymptomsandpositivesymptomsreflectdemyelination.Onthecontrary,negativesymptomswerecorrelated withdecreasedNAAhippocampallevelsreflectingadifferentpathophysiologicprocess,consistentwithmicrogliosis/astrogliosisand/orlower vitality(19).

Table5. Spearman’s(r2 )correlationmatrixforPANSS-PositivesubscoreversusindividualYMRSitemscoreswithexact p values

1.PANSS-Positive Subscore

2.ElevatedMood [YMRS1]

3.IncreasedMotor Activity[YMRS2]

4.SexualInterest [YMRS3]

5.Sleep[YMRS4]––––

6.Irritability [YMRS5]

7.Speech[YMRS6]–0.473

8.Language/ Thought Disorder [YMRS7]

9.ThoughtContent [YMRS8]

10.Disruptive/ Aggressive Behavior [YMRS9]

11.Appearance [YMRS10]

12.Insight [YMRS11] 0.522 p = 1.593 × 10 6

Significantprogresshasbeenmadeinunderstandingthegeneticsof schizophreniaoverthelast15years,sheddinglightonthecloserelationshipbetweenSSDsandotherconditions,particularlyBDandchildhood neurodevelopmentaldisorders.Aclearerpictureisemerging,suggesting thatclinicalheterogeneitypartlyreflectsetiologicalheterogeneity.For example,severaletiologicalpathwaysareinfluencedbythecatechol-Omethyltransferasegene(COMT), includingprefrontalcognitionoremotionalprocessingintheamygdalaandtheprefrontalcortex,inadditiontootherinsultstothebrainsuchasadolescentcannabisuse.This meansthattheindividualclinicalphenotypemayresultfromacombinationofdistinctsymptomdimensionsandtheirassociatedgeneticrisk factors(20).

COMTisanenzymecatalyzingthebreakdownofdopamineandnorepinephrine,thoughttobeinvolvedinthepathophysiologyofBDand schizophrenia.COMTstriatalactivity,butnotthers4680(COMTVal/Met) functionalpolymorphism,maybeabiomarkerformanicsymptoms(21), andresearchhassuggestedthattheeffectofthisvariantmaybeassociatedwithcomorbidmanicsymptomsinschizophrenia(22).Usingthe OPCRITcriteria(23),anIrishstudyshowedsignificantovertransmission ofthe Val alleleformaniainpatientswithschizophrenia(24).

Interestingly,ithasbeensuggestedthatsecond-generationantipsychotics,withtheexceptionofclozapine,mayinducestatesofagitation oftenresemblingmanicstates,possiblyviatheirantidepressantactions onserotonergicandnoradrenergicneurotransmission(25).

Intheeraofpromotinghealtheconomicsthroughscreening(26),we suggestthatadministeringtheYMRS,arelativelyeasy-to-useandcosteffectivetool,toscreenreadilyformaniainSSDsmayproveavaluable strategyforthebusyclinician.YMRScouldhelpidentifymaniainSSDs, asearlyinterventionmaylowerthecostsoftreatingpoorlyresponding revolving-doorpatients(27)andimprovepatientoutcomes(28),thusdecreasingcostsforthepatientandthementalhealthandwelfaresystems. Addingmoodstabilizers(29)andengagingthepatientinpsychoeducation(30)maypreventfrequentrelapsesassociatedwithhighexpenditure forthepatientandsociety.

Itiscrucial,however,tointerpretourfindingsbyconsideringthe variouslimitationsofthisstudy.First,thesubjectivenatureofYMRS introducesinter-ratervariability,whichcouldaffectthereliabilityand validityoftheassessments.Ithasrecentlybeensuggestedthatimplementingflagsandmitigationstrategiesduringtrialsmayenhancethe valueofYMRSdata,directemphasistowardratertraining,andbolster thereliabilityandvalidityoftrialoutcomes(31).Therefore,futureYMRS assessmentswillhavetobeundertakenbythesametrainedraterforall patients.Thisstudycouldserveasapilotstudy,asamorerepresentativeandlargersamplesizeisrequiredinfuturestudiestoenhancedata reliability.Inthefuture,genotypingeitherforknowngeneticpolymorphismsorwithinagenome-wideassociationstudy(GWAS)protocol,withoutan apriori hypothesis,holdspromisefordisentanglingthedimensionaletiologyofSSDs,partofwhichseemstostemfromthepresence ofmanicsymptoms.Anotherstrategyforfurtheringourunderstanding ofmanicsymptomsinSSDsmaybetofocusonpatientswithdrug-naïve first-episodeSSD,toeliminateanydrug-inducedagitation.

Nevertheless,thisstudyhighlightsthatbyaddressingmanicsymptomscontributingtoandassociatedwithpositivepsychoticpsychopathologyinindividualswithSSDs,wecouldimprovethemanagementofacute SSDepisodesandpromoteremission,especiallyinpoorlyrespondingpatientswithundetected,hencesuboptimallytreatedmanicsymptoms.

Conclusions

Thisstudyexploredthepresenceofmanicsymptomsinpatientswith SSDs.Weshowedtheseverityofpositivesymptomstocorrelatewith anincreasednumberofmanicsymptoms,asassessedbytheYMRS.In thisgroupofpatients,positivesymptomsalsopredictedthepresenceof manicsymptoms.It,therefore,appearsthatinSSDs,YMRScouldbeused asafriendlyandreliablescreeningtoolpromotingindividualizedandprecisionmanagement,increasingthecost-effectivenessofinterventions. Further,beyondcross-sectionalstudies,thehighdegreeofphenomenologicalpleiotropywithinSSDspointstotheneedforextensivetransdiagnosticresearchtodelineatebiologicallydistinctentitiesincorporating

carefullycollectedphenotypicaldatafromdiverseglobalcommunities, withtheapplicationofnewandemergingtechnologies.

MaterialsandMethods

Participants

Allpatientsattendingtheout-patientclinicofthe3rdPsychiatricDepartmentoftheAristotleUniversityofThessaloniki,aged18to66years,with anSSDdiagnosis,accordingtoDSM-5,wereinvitedtoparticipate.Further inclusioncriteriawerestablemedicationforatleast1monthandtheabsenceofanysomaticdisorder.RecruitmenttookplacebetweenJune2023 andJune2024.Allparticipantssignedwritteninformedconsent,followingapprovalbytheResearchandEthicsCommitteeoftheAristotleUniversityofThessaloniki(Prot.No.166/2023,dated6/6/2023).Thisstudyis ongoingasitispartofaninternationalresearchprojectinvolvingcenters from22countriesworldwide.

AssessmentTools

WeusedtheYMRS(32),whichevaluatestheseverityofmanicsymptoms inacutemaniaandiswidelyusedinclinicaltrials(33, 34).Thescale consistsof11itemsbasedonthepatient’ssubjectivereportsoverthe previous48handtheexaminer’sobservationsduringtheinterview.The selectionofeachitemwasbasedonthepublishedaccountsofthekey manicsymptomsinbipolaraffectivedisorder(35).Inthisinstrument,the irritability,speech,thoughtcontentanddisruptive/aggressivebehavior itemsarescoredfrom0to8astheycarrygreaterweightandcompensate forpoorcooperationinseverecases.Therestareratedfrom0to4.

Inaddition,psychopathologywasassessedwiththePANSS(36, 37). Participantswerealsorequiredtocompletetheself-reportGAD-7(38), andtheRASS(39).Sociodemographicinformationforeachpatientand illness-relatedfactorsincludingcurrentmedication,illnessduration,age atfirstepisodepsychosis,numberofattemptedsuicides,familyhistory ofmentalillness,totalnumberofepisodes,andtotalnumberofhospitalizations,werealsorecordedfollowinginterviewswithpatientsandcarers andfurtherconsultationofmedicalrecords,ifrequired.

StudyDesign/Procedures

Assessmentwasperformedduringthreesessionsonseparatedayswithin 1month.Thefirstsessionwasphysician-ledandincludedathorough medicalandpsychiatrichistorytaking.Thesecondsession,usuallyno laterthanaweekafterthesecondsession,waspsychologist-ledunder thesupervisionofapsychiatrist.Itcomprisedtheclinicalinterviewfor assessingpsychopathology,includingcompletionoftheYMRS,byone offourclinicalpsychologyresearchassistants.Self-reportscaleswere completedduringthethirdandfinalsession(Figure2).

StatisticalAnalyses

AllanalyseswererunusingtheIBMStatisticalPackageforSocialSciences (IBMSPSSversion29.0).Descriptivestatisticsforthewholegroupwere summarizedasmeanandstandarddeviation(SD)forYMRStotalandindividualitemscores.WethendichotomizedoursampleaccordingtoYMRS totalscoresettingthecutoffat10assuggestedpreviously(14).Using theindependent-samples t-test,weexaminedindividualitemscoredifferencesbetweenthedichotomizedgroups.Toexaminethestatistically significantdifferencesindemographicsandthePANSS,GAD-7,andRASS scoresbetweenpatientsdiagnosedwithSSDswithandwithoutmania, weconductedindependent-samples t-testsforcontinuousvariablesand chi-square(χ 2 )testsforcategoricalvariables.UsingSpearman’s r2 ,we alsoexploredcorrelationsbetweenYMRSscoringandPANSStotaland subscalescores.Lastly,alinearregressionmodelwasdevelopedtomeasuretheassociationbetweentheseverityofpositivesymptomsaccordingtoPANSStotalscoringandthepresenceofmanicsymptoms.Toaccountfor125comparisonsintotal,includingtheSpearman’scorrelations (r2 ),weusedBonferronicorrectionbysettingthelevelofsignificanceat p < 0.05/125,thatis, p < 0.0004. Post-hoc statisticalpowerwascalculatedusingG∗ Powerversion3.1.9.7(40)at α = 0.05.

DataAvailability

Dataavailabilityisrestrictedduetohumansubjectinvolvementandis non-public.Alldatausedintheanalysisareavailableuponreasonable requesttothecorrespondingauthor.

Figure2. Recruitmentflowchart.

Acknowledgments

AspecialthankstoAnna-MariaAndreopoulou,SophiaAthanasiou, StylianiStai,ThaliaDeligianni,MarilizaPapadatou,andEvangeliaVlachou forhelpingwithdataentry.

AuthorContributions

E.M.T.oversawclinicalresearchcoordinationandorganized,managed andanalyzedthedatabaseofresults.Shewastheprimaryauthorofthe manuscriptandorchestratedandcontributedtotheintellectualconceptualizationoftheperspectivepaper;shealsoparticipatedasaclinicalsupervisorindatacollection.Shealsoactedasresearchcoordinator.D.P.and M.K.conductedsemistructuredinterviewsonparticipants,collectedclinicaldataundersupervisionandeditedthemanuscript.K.C.andS.F.collectedclinicaldataandcollatedrelevantdataandeditedthemanuscript. G.K.conductedallprimaryassessmentsandscreening.K.N.F.conceptualizedtheresearchproject,wastheprimaryinvestigatorofthisstudyand contributedtothewritingandeditingofthismanuscript.

FundingSources

Thisarticlewasnotfundedbyexternalsources.

AuthorDisclosures

Theauthorshaveconfirmedthatnoconflictofinterestexists.Thecorrespondingauthorhadfullaccesstoallthedatainthestudyandhadfinal responsibilityforthedecisiontosubmitforpublication.Themanuscript hasbeenreadandapprovedbyallauthors.

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