Auditory System Myelin Patrick Long1

Page 1of29 between this versionandtheVersionrecord. Pleasecitethis articleasdoi:10.1002/dneu.22538. through thecopyediting, typesetting, paginationandproofreadingprocess, whichmayleadtodifferences This istheauthormanuscript acceptedforpublicationandhasundergone full peerreviewbuthasnotbeen 1 Long Patrick AuditoryTitle: Short Myelin System MyelinTitle:Development, Plasticity, Pathologand ⌘ § 2

University of Michigan,University1150 Medical of D West. Center Surgery

University,NanjingJiangsu Nanjing, Province, Chin Kresge HearingResearch Kresge Instituteand Departmentof MOEKeyof Laboratory ModelDiseaseStu Animals for denotes equalcontribution denotes Address for Correspondence: Gabriel Corfas, PhD Gabriel Address Correspondence:for

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Accepted Article,Guoqiang Wan

Email: [email protected]: Fax:734-764-0518 734-615-2222Tel: MIArbor, 48109-5616Ann Medical 1150 Drive Center West Building,Medical Rm.SciencesI 5428 UniversityThe Michigan of Hearing Kresge ResearchInstitute

a. a. 1 r.,Arbor,Ann MI 48109,USA and Corfas Gabriel y in the Auditoryy the in System OtolaryngologyHead Neck- and dy,Model Animal Center Research of 1 ⌘

deprivation specificalters myelin segmentsalong o influencedby experience throughout life,we review processing.Additionally, keepinginincre with the auditorycircuit function, howand various myelin p auditorysystemduring development, ofthe role mye currentlyaboutknownauditorymyelin the insystem and essentialiscircuits healthy auditory for syst Myelinthe precise allowsand rapid for of a timing Abstract

Accepted Article

This article isprotected by copyright. All rights reserved. Developmental Neurobiology John Wiley& Sons,Inc. 2 em em function. In this wereview whatdiscussis asing recognitionasing that myelindynamicisis and ction potential ction propagation alongneuronal athologiescompromise auditoryinformation f the brain’s the auditorycircuit. f the growingevidence auditorythe that sensory with a onfocus of the timing myelination lin in supporting peripherallincentral supporting andin Page 2of29 Page 3of29 nuclei in the pons nucleithe in superior as known the olivary co (AVCN)nucleus respondtosoundand timing intensit cochlear nucleusof the (CN)theinauditory brains potentialsAction thenpropagatealong the cochlear ganglionspiral neurons(SGNs), primary sensorythe soundtransduce waveselectrochemical signalsinto Introduction inferior the colliculustheinmidbrain,which (IC) inarrivaldifferences of athe soundtime between The AuditoryThe Pathway processing. auditorycontributes to howand function conditions auditory of the highlightingsystem, developmen key surprising myelinthat is auditornumerousvital to betweencommunication Givenneurons.the importance conduction increases velocity axons andalong is pi evenslight as a ofloss precisiontemporal can dis alongauditoryspeed circuitsexquisitely be must w precision. Forexample, precision. auditorycircuitstheinbr Aintegration.order definingof audito feature the thedetectionwithofsound byhair cochlear cells environment. acoustic Auditory processing involves asinformation, soundsuch intensity,pitch, and ti The auditorysystemThe is responsibleprocessing a for

AcceptedauditorypathwayThe 1A,B) beginsat the(Figs. co Article

This article isprotected by copyright. All rights reserved. Developmental Neurobiology John Wiley& Sons,Inc. is a key pointa is key of integration localizatioofsound 3 ryitsisextraordinary system temporal ainstem can detectainstemcan microsecond-level ming tocreate ming a faithfulrepresentationof the y functions. Here,ywefunctions. provide overview brief a and endingattheandcerebral cortex higher for tort auditory tort perception. Myelin significantly thetwoears tem. Neurons intem. theanteroventral cochlear mplex circuits(SOC). Theseproject then to ell timed toensureproper timed auditory ell function that compromisethat myelin disruptauditory votal to the rapid andtherapid votal coordinated to nerve axons,which neuronssynapse onto ts in thets understandingof how myelin a tunedfinelyinterplay eventsstarting of neurons neurons that form thecochlear nerve. drivethat neurotransmitter ontorelease yprojectbilaterallyand collectionofa to chlea, where chlea, innercells earhair oftiming auditoryin it is circuitry, not complex spectrumofacoustic . . Accordingly,conduction the n

cell type are similar,cell typeare these two cell havetypes di nervous central system(CNS). biophysical the While i.e.Schwannsystems, cellsperipheral nervothe in Differentmyelinsources intheauditory pathway: p inbrain. areas the whichreceivesMGNinput integrates from andthe au of(MGN)thethalamus. level highest The ofauditor information.in IC providesThe turn the main audit 2014). individualaxon,an myelinatemayoligodendrocyte a different mechanisms,and whereasSchwann each cell myelinby thesecellsproduced differs proteininc cellsneuralderive crestthe whilefrom oligodendr 1998). Myelination1998). theCNSby segment oligodendrof andperipheral oncentral projections ofthecochle exclusivelyis brainstem central of the type(Toesc comprisedofperipheral whilemyelin proteins myeli the themyelinaxonbetween segmentalong c the SGN Schwannoligodendrocyte.Histological cell to exami calledCNS-PNS transitional1992) zone (Fraher, (Fi hairinnervateouterare cellsunmyelinated. and As (>90%), hairtheyinnervateinnerhave cells and la Different classesDifferent of cellsproduce glialmyelin in

AcceptedspiralThe containsganglion twooftypes neurons. Article

This article isprotected by copyright. All rights reserved. Developmental Neurobiology John Wiley& Sons,Inc. 4 fferent developmental origins fferent Schwann(i.e. omposition;their maturationregulatedisby ocytes deriveocytes thesubventricular from zone); a, 1996). Ina, rodents, appearmyelin markers ar nerve ar simultaneouslyetal., (Knipper oryinput tothemedial geniculatebody rge diameter rge myelinatedaxons.Type cells II us system (PNS) and system (PNS) us inoligodendrocytes the typeISGN axonsCNS enter at so-the the n between the transitionalbetween n the zone and y processing beginsy processing atauditory the cortex, nation ofnation cochlearthe rat nerve showed that g. 1), their myelinationg. changes from s 60s many as axons (Nave and Werner, the peripheral andtheperipheral central nervous properties ofproperties myelingeneratedby each ditoryinformation with multiple association ocytes is initiatedisocytes in proximityclose to the eripheral vs eripheral central engages andengages myelinatesonly single a Type IcellsareType abundantthe most ellbody and the transitionalzone is Page 4of29 Page 5of29 prior to the onset prior to the ofhearing et(Wangal.,2013). centralprogresses to peripheralthe and processes the mouse cochlea,myelination by Schwannsta cells axonsbefore projecting totheapical turn (Sanchez wherein gradient theSGN axonsproject that to the 2001).Linthicum, patternTheof humanSGN myelinat starting week, along distal first the axon segment Benacerraf,but1983),Schwann cellsbegin myelinat Humans respond to auditorystimulistartin uteroin AuditoryPeripheral Development Myelin interactionbetween auditory experience,auditory c ismyelination contemporaneous that with languagea suchcenters as theauditory andcortex associated occursbrainstem neartheonset ofhearing. Additio Specifically,development. myelination along the co The Timing of AuditoryTheof Timing Pathway Parallel Myelination brainstem the et(Wang2013). al., CNS-PNSzone transitional between postnataldays 7 (Rosenbluth,myelin sheath 1962)SGN and cellbody example, SGN cellbodiesratsin arecoveredby t a 1997). Remarkably,1997). SGN cellbodiesseveralin mamma bodiesare coveredby a ofrimsatellite thin cell The timeline ofauditorytimelineThe system myelinationmirrors

Acceptedhumans, SGNs,In likebipolarother sensoryneurons Article

This article isprotected by copyright. All rights reserved. Developmental Neurobiology John Wiley& Sons,Inc. 5 cytoplasmetal.,(Liu 2015;etal., Tylstedt and thenprogressingandproximally (Mooreand g at24-25ofgweeks gestation (Birnholzand delRey Sanchezand 2006).Fernandez, In ircuit ircuit maturationand myelination. nally, in humans,innally, higher auditoryorder chlear nervechlear withintheandauditory basal turn ofturnbasal thecochlea aremyelinated betweenpostnataldaysand 8 10, days just whitetractsundergomattera patternof hinand morphologically heterogeneous ingSGN axons ataround the 15th fetal cquisition, suggestingimportantan rts nearbirthatrts the cellSGNsbodyand of myelinationobservedis the time around ionalsocochlea’s followsthe tonotopic and P8 andP8 and thenextends centrally toward in key milestones auditory functional lianarespecies myelinated.For s that of Auditorysofthat Function , have , myelinatedbuttheircell axons

in the prosimian primatethe in galago ( observedconsistenthumansinis with myelin staini arcuate the al.,fasciculus) (Suet 2008). seqThis matterwhite tractsinvolvedlanguagein ability (i primary the in auditorycortex slightly precede mye age andyearsof at thenaprogress slower intrate primary auditoryIn the cortex, myelininten signal andradiations theofspleniumcorpus arecallosum white subcortical tractsassociatedmatter with aud increased indicative myelinationMGNof begi the in haslateroccursand a protracted more timeline. MR functional maturationoftheauditorybrainstem aft 2007). delayedal., onsetofThe myelinbychange M updelayed theauditoryfurther pathway i appearing inchanges byseenmyelin 37thbe can the fetal wee thatchanges appearapproximately laterweeks 11 th Incontrast,1995). studiesMRIusing tovisualize weeksbetween and26 fetal 29 and increase intenin stainshistological auditorythroughout the brainst earlythe26thweek as (Moorefetal etal.,1995). Central AuditoryCentral Development Myelin myelinationthedrivingmechanismsand it remain un birthin of thecatcochlea (Romandetal.,1980).

Relative to the Relativethe auditorybrainstem, to myelination of

Accepted Articlehumanauditory In the brainstem, myelinationcoinci

This article isprotected by copyright. All rights reserved. Otolemurgarnetti) Developmental Neurobiology John Wiley& Sons,Inc. 6 .e. Brocas,.e. andthe angular Wernickes, gyrus The implicationsfunctional ofcellbody em and midbrainem (CN,SOC and beginningIC) uentialpatternof white developmentmatter change sities most about1.5rapidly to up becomeMyelin sheaths visible by standard auditorysystemmyelin signal detectintensity er initial myelinationer oftheneurons. lination of corticallination association of and regions asprocessingitory the such auditory o adulthoodo (Suet al., Myelin2008). changes , and , the IC partiallyMGN are myelinated at ng observed primates.otherinng Forexample, nningat10 of ageweeks whilein changes n theICn near the38th week (Sanofetal et detectable by24etweek (Sano al.,2008). I detects in changes I intensities signal RI measurements indicatesmeasurements possibleRI k in the CN and SOCtheinCNand areslightlyandk known. known. sity1up yearof ageto (Mooreetal., an those observedan those histologically. These structures higherstructures theinauditory pathway des withdes onsetandhearing asoccurs Page 6of29 Page 7of29 at birthand doesat notreachlevelsadult-like until and reachbirth maturity age,bybut weaning myelin

neuropathy inneuropathyanimals isthese elevate inreflected affecting without hair cellsurvival al., et (Naito display 2003) remarkably auditoryneuropathsimilar inperipheralmutations the myelin22 (Pmp2protein Schwann of cellswith diphtheria birth toxin at (Zh and structureRodents function. with peripheral dys withStudies1983). myelin-deficient highlianimals SGNspostnatal mouse, attain must myelinationbefor MyelinCochlearandNerve Function Auditory Theof Myelin Role in SystemFunction etal.,1996; Hafidi al.,2014).Saliu et immunoreactivitysecondduring increase the to thir andtheinstance,inrat gerbilSOC,myelin exgene myelinin development thecomparablemouseis towh auditorybrainstem,reaching adult-like levels by P expressionincreases, myelinand conductithickness duringcortex this periodtime (Hackettet al.,201 second postnatalweekthe becomesand detectable th birth at et(Dinhal.,2014), buttheonsetof myel brainstem, the mouse positiveOlig2 oligodendrocyte onsetofhearing, the whichplacetakes betweenpos Similar to humans, Similarto ofthemyelinationcentra murine

AcceptednerveCochlear essentialismyelination toperipher Article

This article isprotected by copyright. All rights reserved. Developmental Neurobiology John Wiley& Sons,Inc. 2003;Zhou etal.,1995b). auditoryThe 7 in gene expression does notgene beginin until about nearpuberty (Miller al., et 2013). 5; Kolsonetal., 5; As2016). myelin gene ou etal.,1995a;ouZhou et1995b) or due al., to 35 (Sinclairetal.,2017).35 CNS timeline The for ght the importance ght ofthe myelinnervecochlear in d auditoryd brainstem response(ABR) myelinationbycaused direct either ablation pression and myelinand pression protein d postnatalweekd (Ehmann etal.,2013; ation in the auditory the incortexation nearly is absent 2) gene (bt hamster) (bt2) gene (Naitoetal.,1999, y; i.e.significanty; neuronaland myelin loss on velocityon partsin increase alsoofthe canprogenitors be seenauditoryinnuclei tnatal days10 tnatal and 12(Ehret,1976). Within epotentials action canelicited be (Anniko, at is observedotherisin rodents.at For roughoutbrainstem the auditoryand al auditoryalsystem function. In the l auditorylpathway coincideswith also

MyelinSoundLocalizationand initial sound-drivenof the nervespikes. playsrolecritical notaonly potential action in Corfas,and(Wan 2017). studiesindicate These that evidencedpotentials, as ABRbywave reduced ampl 1 ofSGNDisruption heminodes significantly impairst ofSGN heminodesfeatures matureafter theonset of 2016;Rutherford,Rutherford etal.,2012; and Wan cellstothecloseinner hair cells(IHCs) arethe etal.,2005).(Hossain Recentstudies indicate tha synaptichair inputs from cellsandby generating t Ranvier of bipolar the flanking SGN. structurThese sodiumvoltage-gated channels at thecentraland pe velocity. theseinanimalslatencies consistentis withcri a thresholdsmyelin-deficitin animals neuron reflect abnormalABRand thresholds latenciesand (Jyothi e phosphatasereceptor(PTPRC),typeC also display r Congenic2006).Ly5.1 whichmice,specific a carry the maturation ofauditoryand theprolothresholds proteinjunctionconnexin 29 causes(Cx29)peripher 1995a) al., Fig.(Refer descriptionto a 1C offor ABRthresholds, reduced amplitudesprolonged and AB

Accepted the andAt molecular cellularlevel, myelination of Article

propagationbutinalsoand generation integration initial generatorsspike of and SGNs (Kim 8 ABRwaveforms).loss Inaddition, of the gap tical role ofrole tical myelinationnerveinconduction al dysfunction, dysfunction, al theprolongation ofABR ransmitting actionransmitting potentials to theCN t the heminodes t the formedbySchwann the first ngation ofauditoryngation (Tanglatencieset al., es form voltage es form generatorsthat respondto hesynchronized ofactionconduction allelicprotein variantof tyrosine Corfas,2017). structuralandThe molecular al myelinopathyal withdelay associated a in peripheralmyelination axonsof of SGNs ripheral axonalripheral initialand segments nodes hearing inhearing rats Rutherford,(Kimand 2016). t al., t abnormal2010).ABR While emarkable myelinincochleapathology the SGNs is accompaniedis SGNs by of clustering itudes and itudes increased wave latencies 1 R latenciesR al.,1999; Zhou (Naito et et Page 8of29 Page 9of29

interaural intensity interaural differences (IIDs) differthat (KlumppEady,littlebyand 10differ as as – µs 20 and humansaremaximallyµs, able ~700 to disreach Because precision. of ofthespeed sound,interaura aresimple,computations butpractice,in localizin thetworeaching ears (seereview and PecGrothe by horizontalbirdsplane, and mammalscompare thearr noisyanalyzinginand settings, complexacoustic s Spangleretal.,1985). precise,contralaterally driven inhibitory to input Importantly,theMNTB modulatesalsoactivity level inexcite neurons theipsilateral LSO and inhibitn ofthisBecause circuit arrangement, sounds arrivin incontralateral(GBCs) the nucleuscochlear (Harri ofnucleusmedial the trapezoidwhich body (MNTB), contralaterallydriven input.inhibitoryInhibitory byIIDs integratingexcitatory input fromipsilater narrowwindowtimeand Brown,1968; (Goldberg Yina Stotler,1953; 1975; MSO1966). neurons fire Warr, in cells (SBCs) the ipsi- contralateraland cochlea MSOITDs, neuronscompare of excitatory the timing nucleisynapticintegrate pathwaysinput from that SOC: the superiormedialolive lateraand(MSO) the The abilityThelocalize to importantis sounds for tra

Accepted Article In themammals,detection ofITDs and takesIIDs pl

This article isprotected by copyright. All rights reserved. Developmental Neurobiology John Wiley& Sons,Inc. by asdBlittle 1 as (Mills, 1960). input LSO is to the providedin by neurons the MSO neurons (Banksand 1992; Smith, 9 al SBCsal(Cantand Casseday, with 1986) eurons in eurons the contralateral LSO 2003).(Tollin, g sounds withsounds binauralg cues requires extreme r nuclei(Cantand r Casseday, Lindsey, 1986; 1956). Similarly, discriminatehumanscan originate atoriginate thetwoears (Fig.1B). detect To son and Warr, 1962;and son Spangleretal.,1985). Warr, g withintensityg one greater earat will tend to cenes. localizeTo alongthesounds s in theinMSO s by providinga temporally l time differencestimel (ITDs) humansfor whenthesebinauralinputs arrive within a cking threatsunderstandingorprey, speech l superiorlolive Neurons(LSO). these in in turn aredriventurnin bushyby globular cells ka, 2014). Conceptually,2014). ka, these synaptic input drivensynapticinput bybushy spherical ivaland intensitiestimes ofsounds criminate soundcriminate sourceswith ITDs that nd Chan,LSOnd 1990).neurons detect ace in ace twospecialized nucleithein

velocity along lowvelocity along etal., axonsfrequency (Ford 20 high their frequencycounterparts, the combination tolowresponding frequencyhave sounds shorterint thepatternthat of alongGBCmyelin axonstuned is travel must arelative greater (Guinanet distance GBCs lowresponsive to soundfrequency project to t arrangedsuch cellsthat tohighresponding frequen and Rubel, 2016).Rubel,and contralateralvelocity along help projections to ov axon diameterslarger thantheiripsilateral projec pathway, ITD axons SBCsprojecting tofrom thecont provideandinto insights the underlyingmechanisms of patterns myelinationallowthe o tuning fine for providesynapticoutput nearwithsimultaneous timi axonstoipsilateralprojecting the contralaterand axonthanSBCs,diameters which was predicted to re 2013).was It al., recently axonsthat of the found same ortimeslightly excitationbefore (Brandet a inhibitorypathway overcomes theseadditional steps excitatory the pathway.of One the mysteries thein Fig. 1).LSO (see theinhibitory Thus, pathway invo directlywhereas GBCs MNTB, whichexcite the turin

In both and In ITD pathways,IID projecting GBCs toth As mentionedabove,AsAVCN directexcitatorSBCssend

Accepted Article circuitryThe needed for localizationsound present

This article isprotected by copyright. All rights reserved. Developmental Neurobiology John Wiley& Sons,Inc. 10 f velocitiesf conduction circuitsalongneuronal al SOC travel must varying distancesbut ercome a ercome greater relativetravel (Seidl distance GBCs have internodes GBCs longer and greater tions, whichtions, predictedisto raise conduction

al., 1972). Intheal., itgerbil,was recentlyshown l., 2002; l., Sanes,Grotheand1993; Roberts et 15). auditorybrainstem hashow been the lvessynapseextra andan neuron relative to ofwhich ledto faster relative conduction ng. Recent ng. studies suggest distinctthat cytargetthesoundMNTB; medialhowever, totheirsite of termination suchaxonsthat toprovide inhibition arrivesthat atthe ernodesand axonslargerdiameter than sound localizationsound circuitry. In the gerbil he lateralhe MNTB and thereforeaxons their n providesn MSO inhibitory and to input ralateralMSO haveinternodes andlonger sult in sult action faster velocitypotential in s distinctanatomical s challengesas econtralateral MNTB aretonotopically yprojections to theMSOLSO and Page 10of29 Page 11of29 deprivationassociatediswith myelinin deficits t experience.Imagingstudies individuals of conwith cellprogenitorsurvival themousebarrel cortex in whiskerthrough trimmingreduces myelinlevels(Bar nerve optic etal.,2016).(Etxeberria Inthesomat processing.Inthevisual monocularsystem,depriva Experiencemyelininfluencesalso alongpathways in oligodendrocyteeach in theprefrontalmedialcorte socialdeprivation reducebothmyelin thicknessand experientialdeprivation,which causes regional spe influencedbyof multipleexperience. forms Myelin MyelinPlasticityAuditory the Central in System oftheexcitatoryspeed pathway additio the despite GBCs patternet(Fordal.,2015). This ofmyelinati

mechanism usedmechanism tocalibrateprocessing temporal in requirements(Stange-Marten etal.,2017). Thus,sp localizationgerbilsound areabsentin circuit the Interestingly,a comparative recent studytha found correlatedifferences with divergentconduction vel axoncontralateral projections relative ipsilate to pathway boththat distance andfound internode axon velocityconduction along timing localizaand sound Myelin in the auditoryMyelin the inpathway similarlybemay aff Myelinproventobe has dynamic much more thanprev

Accepted Articlespecies appearalsoOther to relydifferentialp on

This article isprotected by copyright. All rights reserved. Developmental Neurobiology John Wiley& Sons,Inc. 11 ral projections (Seidletal.,2010)and these heauditorycortexunderlying and white matter whichmouse, notpossessdo similar ITD osensory system, lossosensorysystem, oftactile sensoryinput al.,2014).(Hill et

on may helpmaytheinhibitoryon pathwaythe match ocities (Seidletocitiesal.,2014; Seidl etal.,2010). plasticityclearlyis inapparent ofthe context t t the myelinadaptationsidentifiedin the genital deafness genital indicate auditorythat x (Liu et al., xet 2012;Makinodan(Liu etal.,2012). nalsynapticstep. cific myelincific Fordeficits.example, ofperiods tion circuitry. Studies circuitry. intion thechick ITD the number oftheinternodesnumber by generated tion reduces internode reduces alongtion length the ecializationsrepresentmaymyelinina key rera etal.,2013)reraand oligodendrocyte volvedsensoryprimaryin information sound localizationsound pathways. diameter aresignificantlydiameter along greater atterns of atterns myelination to regulate ectedby alterationsauditoryin sensory iouslyand appearsimagined tobe

(Tremblay et al.,2012).(Tremblay et aberrant myelinultrastructuretheinprimary audit deafness associated due tomutations theincadheri auditory affect corticalmyelin. C57BL/6Inbred mic Kim et2014; al.,2009). usingStudiessuggest mice fractionalanisotropyin theHeschl's and the gyrus inchanges propertiesthe microstructural whitein as earlyinfancyappeared as etal.,2011).(Smith hearing adultsnormal (Emmorey etal.,2003;Hribar matterwhite ratiosto ingreymatter Heschl's gyru MRI-volumetrictracts. measurementsofthebrains o

might be compromisedmight by lossevenhearing partial ( auditorymyelin along brainstem circuitry throughou myelineven inthickness suggesting mice, adult tha axons projectingalong totheMNTB (Sinclairetal. thresholdsvia earpluggingmicein during the time maintenancealongauditory circuitry.brainstem It temporal processingtemporal (de Villers-Sidanial.,2010 et viatraining conditioningoperantaged in rats and expressiondeclinemyelin inprimary gene the in au which beganat training et(Bengtsson al., 2005; St trainingmusical during childhood.increasesThese increaseddetected white connectivitymatter thein Auditoryenrichment promotealsomay inmyelination

Acceptedalsois There evidence hearingthat impairment jeop Article

isassociatedwith improvedcorticalcircuit s and superiorand s temporal gyrus relative to matter withmatter deaf subjects showingdecreased surroundingtemporal lobe(Hribaretal., Diffusor imagingtensor detectedalso(DTI) was recently elevatingshown auditorythat ). Thus, while). Thus, auditoryexperience insufficient , 2017). Moveover,, earplugging reduces e havee a predisposition genetic toage of hearing onsetofhearing reducesmyelin thickness eeleetal.,2013). Additionally, age-relatedan corpuscallosum individualsin with extensive t life andlife t themyelinthat alongthesecircuits t auditory t experience is tosustainneeded correlatedwithduration ageandtraining the ditorycortexpartially is byreversed auditory ed age-relatedthat hearing loss alsomay etal.,2014)and thesemyelin deficits n 23 (Kanen gene etal.,2012)and show Sinclairetal.,2017). f congenitally adultsf showeddeaf reduced ardizesmyelin develomentand thebrain.Several DTIstudies Page 12of29 Page 13of29 myelin in the developingmyelin the in aging brain.and diminishmaylevels myelin, certain ofaud of forms

MyelinPathologyAuditory thePeripheral in System myelinationauditory along circuitry. or altered reduced neuralauditoryactivity during auditoryexperience promoteoligodendrocyte differe al.,2012).is Itet possibleelevated that levels cortex prefrontal myelinbe appear mediatedbyto a etal.,2008;(Taveggia Xiaoandetal.,2010), the asmyelination, neuregulin-1such (NRG1)brain- and astrocytes from (Ishibashi al., Neuronset 2006). a indirectly promotes bymyelination inducing release synthesisetal.,2011).(Wake Activity raalsomay activityonglutamateactivates oligodendreceptors promote myelinFordevelopment.example, glutamate thebyrelease inducing ofvarious neuronally-deriv etal.,2016;LeeMensch etal.,2015; etal., Wake alongaxonsformational and (Barres Raff,1993; Dem shownbeen has promoteboth oligodendrocyte to prog damaged by bothdamaged mutationsenvironmentalgenetic and Nonetheless, emergingisthere evidence thethat my drivenbeen by research conditions into comprothat cellcochlear ourunderstanding types, of periphera How might Howauditoryexperience influencemight myelint in

AcceptedessentialGiven the role cellsplayhair d soundin Article

John Wiley& Sons,Inc.

and/or patternsand/orofneuronal activity during 13 deprivationinadequatelymay stimulate effects of effects socialdeprivation on medial

2011). Activity2011). myelin regulate may formation ise levelsiseneuronally-derived of whichATP, lso expressneurotrophiclso promotefactors that ed factors actonfactors that edoligodendrocytes to itory exposureitorypromotemay and/or maintain rocyte lineagerocyte cellstopromote myelin protein l auditorylsystem pathologieshas primarily ofcytokineleukemia inhibitory (LIF) factor reductionNRG1in expression (Makinodan mise mise cochlear cellhair function. ntiationand myelination.Consequently, elin along thecochlearelin nervealong bealsomay derivedneurotrophic factor (BDNF), etection and etection their fragilityrelative toother erensetal.,1996; et al.,2014; Gibson releasedby heightenedneuronsduring enitors cellproliferationand myelin insults andaltered that peripheral heauditorysystem? Neuronal activity

demyelinationetal., (Starr 2003). ofSGNslosssignificant SGNdistaland with fibers withneuropathy inputs,reducedneural post and mor neuropathy motor and deafness (Starretal.,2003). gene, myelinzero protein (MPZ),was tobe found mu consistent latencies, with ofPMP22therole Schin changeprominent ABRin recordingsofthesepatient Charcot-Marie-Tooth cause disease with deafness(Ko dominantmissenseA inmutation the a as peripheraldefined hearing deficitoccursthat neuropathy observedneuropathyin patients. some GBS additi In Corfas,and 2017). Thus,heminodaldisruption mayb remyelinateand SGNs,heminodes disruptebut remain usingstudyrecent mousemodels showed whenthat Sc (Takazawalatencies al.,2012), suggestiveet pe of graduallysomeinpatients,recover theirABR wavef Takazawaal.,2012;Ueda et Kuroiwa,and Int2008). showABRsal., abnormal et 1988; (NelsonRopper and autoimmunean mechanism.Although theincidenceis (GBS)syndromea is peripheral causedneuropathy by Peripheral NeuropathyPeripheral peripheral auditorythe system. myelinauditory impairs Here function. we provide a

Myelinalsomay deficits underliesomeofacq forms

Accepted ArticleMyelina is pathologycommon cause ofperipheral au

in the presence the inofhealthy hair cochlear cells. theremaining displaying fibers apparent wannAnother myelination. cell SGN myelin rmanent rmanent myelinpatients. deficits these in Our summary ofpathologies affectthat myelin in Patientsin pedigree this developed auditory ormsshow interpeakpersistentin increases tem analysisonetem caseof showed a riguingly, althoughriguingly, hearing thresholds on, animal on, studies showedcochlear that s is s theprolongation ABRwave of tated in aintated with familyhereditary sensory e the underlying the causee oftheauditory vachetal.,1999). Interestingly, the most Schwannpossibly celldamage, through relativelyportionofGBSa low, patients Chiappa,1986;Schiffet al., 1985; dABRandlatencies prolonged (Wan hwannlost, cellsare theyregenerate uiredhearing loss.Guillain-Barre ditoryneuropathy whichhumans,in is (PMP22) wasgene to found Page 14of29 Page 15of29 AcousticTrauma (Leeetal.,2012)iron or hyperbilirubinemiae (Ye nervedemyelination auditoryneuropathyand alsois

Ototoxins themyelinthat sheathmayprimary a targetbe of n etal.,2014). (Tagoe Considering onsettherapid o 3 hr/dayat noise3 days) for sufficientis to caus osmiophilicet(Rossi myelin al.,1976).bodies Int approximatelyaccount for ofandSGNs, 95% Schwann atnoise12white hr/day30 days), myelinfor sheat cochlear damagemyelinby acoustic to Aftertrauma. humans (Rask-AndersenStudiesetal.,2000). in ani cochlear nervealong the showsalso dam significant et al.,2002). et characterizedis and by myelin withinloss day1 af al.,2004).Ruijven Myelinopathyet ofonealso is perikaryabegintoshrink and beginmyelin sheaths nerves(Carozzial.,2015). a et after week Within carboplatin,inducehearing andloss arelinked to compounds. Platinum-basedthese chemotherapeutic ag supporting (e.g. andcells) structures (e.g.synaps thesensorytargeting cells.hair However, emerging Acoustic trauma isAcoustic trauma primarily with associated cochle

AcceptedOtotoxicsuchdrugs,as chemotherapeuticagents, re Article

This article isprotected by copyright. All rights reserved. Developmental Neurobiology John Wiley& Sons,Inc. 15 e perinodaldysmyelination theincochlea ense noisedBense (110 SPL single14.8 kHztone tal.,2012). the primary the of features carboplatinototoxicity

cisplatintreatmentSGNin pigs, guinea es and es myelinmaysheath) affected bybealso Schwanncellperipheraltoxicityotherin ter carboplatinter chinchillasin treatment (Ding hs can hs detach from thetypewhichSGNs, I f noise-induced myelinis it damage,f possible oise overexposure.oise evidence otherthatindicates cochlear cells toswell detachmentmyelincausing (van observedhearingin causedloss by of lack age afterprolongedage noise exposurein mal models illustrate models mal thesusceptibility of prolonged exposurenoisedB (100 SPL ar hair cellar loss, however, themyelin cells begin todevelop cellsbegin intensely ents,including cisplatinand sultsensorineuralin bylosshearing

completeremissionetal.,(Hellmann 2011). r These demyelinationobservedaisin of minorityMS patie thresholdset(Dotyal.,2012). suddenAlthough sen Comprehensivestudiesthatindicate MS notleadoes velocityconduction theinaffectedarea resulting auditoryand hearing information processing. Acute ofdestruction myelinaffectcan that any of region DemyelinatingDisease effectsdeleterious oftheloss myelinhavemay on into insight of the role myelinaud in facilitating CNS abnormal myelinexhibitalso auditory impaired connectivityneuronal itnotcircuity,of surpriis observed in older humanobservedolderin cochleae yearsof(>60 age) in reduction myelin proteinbasic(MBP) expression perikarya of eventualthe andof SGNsloss (Cohene ofmyelincochlear nervesheaths loosenandthe unr at6 increases months andat peaks 26.5months (Hoe pigs, numberguinea the degenerating of myelinshea Myelin Pathology in the Central AuditoryMyelinPathology theCentral in System Aging

Multiplechronic(MS)a autoimmunesclerosisis dis As myelinAs regulatesaction potential conduction vel

Accepted ArticleMyelintheincochleapathology of hallmone is the

This article isprotected by copyright. All rights reserved. Developmental Neurobiology John Wiley& Sons,Inc. itoryprocessinginformation illuminatetheand singneurologicalthat disorders associatedwith 16 in a hostofcognitiveain and sensorydefects. the CNS including the those responsible for

healthyauditory function. nts, suchlossnts,hearing largely undergoes sorineural hearingsorineural loss casesinof episodic and lossand ofMBP+ nervearecochlear fibers demyelinating lesionsdemyelinating significantlycan slow eportsindicate centralauditorythat avel with age, whichavel age, withtoleads demyelination system system function. offerconditionsThese t al., 1990). Similarly,tal.,1990). a significant ths of nerveths the cochlear significantly d tochronicallyd hearingelevated etal.,2012).(Xing ffding and Feldman,ffding 1988). Inmice, the arks ofarksage-related hearing loss.In ocitythereforethetimingand and ease characterizedease by the focal

Page 16of29 Page 17of29 AuditoryDisordersProcessing impairedwhichreflectmay conduction velocity alon binaural processing stimuli detectionimpaired and themyelinauditory along circuitry theinbrainste amplitudeVdiminished peak (Chiappaetal.,1980). MS.with Specifically,someMS patientsexhibit inc relativelydeficitsin subtle processingtemporal o demyelinationnothavedoes onimpactsignificant t

Abnormalities in CNSin Abnormalities alsomyelin contributemight neurodevelopmentalotherin disorders. Forexample, auditory attending to stimuli APD.in toattentiontied and processitop-down information cortex andprefrontal cingulateanterior et(Farah thalamo-corticalcommunication. samestudyThe also auditory the radiations et(Farahal.,2014), and r processing.DTIstudies children of diagnosedwith display patients myelinin abnormalities b multiple auditory of signal timing (Kopp-Scheinpflugand Tem potential has firing beenas aproposed candidate m APDcases most do not underlyinghave clear a cause centralauditory the systemsince patientsexhibit discrimination.definingA characteristicof APDis difficulties includinglistening deficitsin attent disorder processing (APD)ais heterogeneous develo

Accepted ArticleDevelopmentalabnormalities CNSinmyelin impa also

This article isprotected by copyright. All rights reserved. Developmental Neurobiology John Wiley& Sons,Inc. ion,comprehension language speechand 17 m. MSm. alsopatientscan display in deficits f auditoryinformation appearf be associatedto educedmyelin theseinregions disruptcould al., 2014), whichal., areas are of thebrain closely appearsymptomsthat duetobe to defects in normal cochlear andnormal hearing thresholds. While

rain regionsrain associated auditorywith reased ABR reased peakI-Vand latencies ng and which ng inunderliemaydifficulties of ITD andof ITD (FurstIIDs Levine,and 2015), APDincreaseddetected meandiffusion in hedetectionsound andHowever, reception. g sound localizationsound g pathways. These ABRchanges These suggest compromised echanism couldthat jeopardize the fidelity pel, 2015).pel, Inline with hypothesis, this APD hypersensitivity sounddistorted and to pmental disordercharacterized pmental by found decreased anisotropy found thein , decreased , temporal actioninprecision totheauditorydysfunction observed ir auditory ir function. Auditory

Zeniseketal.,2015). Onelinkbetween abnormal my deficitsauditoryin linked to sensoryprocessing ( schizophrenia,andbipolardisorder, chronic depres Psychiatric Disorders Psychiatric ASDshouldbe explored.further possibility Thus, the CNSin impairments that myeli connectivitymatter areasincludibrain multiplein reduced processingtemporal ofauditory stimuli (Fo (Gomesetal.,2008; ASDO'Connor,2012).patients auditoryperceptionare wellindividuindocumented Directions Future andchanges how theymightcontribute toAVHare no auditorybundles, whilefiber decreaseothers found al.,2015). However,et of some thesestudies found durationofAVH history the et(Hublal.,2004;Kno connectivityinchanges auditory along bundle fiber ofsymptompsychiatricillness.DTI studies of schi pathophysiologyillness the isauditory of verbal h developmentaldisorderscan jeopardizehearing and auditorysystembyand eventhatfindings subtle pe auditoryby that the fact circuit myelinationcoinc ofmyelinthe role behavior.neuralin circuit The Abnormalities in CNSinAbnormalities myelinin are found multiple p

AcceptedtemporallyThe nature precise ofthe auditorysyste Article

This article isprotected by copyright. All rights reserved. Developmental Neurobiology John Wiley& Sons,Inc. 18 ides withides the functional developmentofthe importanceof myelinunderscoredauditioninis Kahkonenetal.,2007;McLachlan etal.,2013; ng the temporal lobesthetemporal ng (Traversal., et 2012). allucinationswhich(AVH),a is common

zophrenia patients withzophrenia patients AVHhave found chel et al., et chel2012;Mulert al.,2012; et Wigand s and shownand s that vary thesechanges with n contribute toauditorycontribute n deficitsin processing s. Thus,s. theprecise nature ofthese myelin sion (Fields,sionand 2008), theseconditions are ss-Feig etal.,2017)and ss-Feig decreasedwhite withals spectrumautism disorder (ASD) rturbations in rturbations myelin toanddiseasedue increasesthein fractionalanisotropyof havebeenalso foundtoexhibit both elinauditoryindysfunctionand mental auditoryinformation processing.Despite tunderstood m makes it uniquely it m makes investigate suited to sychiatricdisordersincluding Page 18of29 Page 19of29 function. ourabilityenhance both auditory to treat disorder withinauditorycircuitry? Overcoming these gaps i ofbrain areas the al.,2007). (RoychangesDoet i processing?information Myelinhave beendeficits s conductioninchanges velocity, alteratiohow might soundbrainstem localization circuitry influenalso underliedeficitsmyelinin impairedhearingin ind numerous and questionsarestillwaiting to be addr recognition,we this areonly apprecia to beginning

Accepted Article

This article isprotected by copyright. All rights reserved. Developmental Neurobiology John Wiley& Sons,Inc. 19 ividuals?thecomplex Are of patterns myelin in ced byced experience? Moreover, beyond s and s myelinimpairpathologiesthatauditory

n myelinn similarlyneurotransmission alter te how te myelinto auditorycontributes function n knowledge has knowledge potentialn the to significantly ns in myelin affect othermyelinin ns aspectsaffect ofauditory essed.Forinstance, what mechanisms hownalterneurotransmission to otherin

cells, peak cells, I correspondstoevoked potentials in S throughcochlea the midbrain.summating The potent evokeddetect electrical atvariouspotentials stag a.k.a.(ABR),Brainstem AuditoryResponsesEvoked ( cortex. cortex. subsequent nucleiincluding before the IC reaching projections LSO and (red) to the MSO.Auditory info AVCN(green) extendGBCs excitatoryprojections to pons.AVCN SBCsthe (blue)extendexcitatory projec of representation thecentralauditory pathway high neurons. ofnucleusmedial the trapezoidMGN:medial body;g GBC: globularbushySBC: cell; bushyspherical cell AVCN:anteroventralcochlear nucleus;lateral LSO: from etal.,2016).(Liberman myelination of SGNmyelination axonsof beginsatCNS-PNS the tran cellsactivatehair SGNs projectthat CN in to the A) Auditory1.The Figure Pathway CNand to IC,the respectively. Schematic representationof peripheralSchematic SGN myelina C)

Accepted ArticleAuditory besystem functioncan Audusingmeasured

Fig.1B is adaptedisFig.1B etal.,2015).from (Cope 1C Fig. Developmental Neurobiology John Wiley& Sons,Inc. 20 theauditorybrainstem. Oligodendrocyte es alongtheearly es auditorypathway,the from

GNs while GNs IIIcorrespondandABR peaks IV lighting ITD and lighting ITD circuitryIID at thelevel of theMGNprojecting and tothe auditory ; SOC:superiorolivary ; MNTB:complex; rmation thenpassesseveralthrough superiorolive; MSO:superiormedialolive; eniculatenucleus; SGNs: spiral ganglion theMNTB,which inhibitorythensend ial(SP) activation innerreflects hair of tions to the LSO andtions to the MSO theinSOC. BAER). methodThiselectrodes uses to sitionalzone (arrow). tion. Intheauditory tion. periphery, cochlear itoryBrainstem Responses B) Schematic is adaptedis Page 20of29 Page 21of29 Behav126,314-324.Neurosci 2012.Pure-tone D.L., auditory thresholdsarenot c R.L., Doty,Tourbier, Davis, Rotz, I., J.,S., Cuzz brainstem:normaldevelopment effectsand ofunilat Koppel,M.L., Dinh, S.J.,M.J., Cramer, Korn, K.S., Otolaryngology:JARO 3, 68-79. in damage chinchillaearsafterinnercarboplatin. McFadden,L., Ding,S.L., Salvi, R.J., 2002. Calpai Natl SciUProc Acad 9887-9892. S 93, A 1996.Lubetzki,C., Inductionofmyelination the in C.,Demerens, Logak,Stankoff, B., M.,Anglade, P., training.operantProcNatl SciUAcad A S 107,139 Recoveryfunctionalandof structuralage-related c Villers-Sidani,de Alzghoul,E., Zhou,L., Simp X., Neurolprocessing.Pract 15,302-308. Baguley, Cope, T.E., D.M., 2015.Griffiths, T.D., T 15,165-172.technique in degeneration andspiral Scarpa's of C57Bganglia Park,Cohen, J.C.,G.M., Grasso,J.S., 1990. Compar patientsresponses200in with sclerosis.multiple Harrison,Chiappa,K.H., Brooks, E.B.,J.L., Young, wedo What about knowNeurosciencemechanisms? lett Canta,Carozzi,V.A., A., 2015. Chiorazzi,A., Chem and lateral superiormedialolivary Comp J nuclei. N.B., Casseday,Cant, 1986. J.H., Projections from essential microsecondfor interauraldifferenctime A., Behrend,Brand, O., Marquardt, McAlpine,T., D. 516-518. Birnholz,Benacerraf, J.C., 1983. B.R., developThe 1148-1150. haspiano practicing regionallyeffectson specific S.L.,Bengtsson,Nagy, Z., S.,Skare, Forsman,L., activityelectrical Nature axons. in361,258-260. B.A., Barres, Raff,M.C., Proliferation 1993. ofol deprivation.Dev297-314. Neurobiol 73, Organizationofmyelin theinmousesomatosensory b K., Barrera, Chu,Abramowitz,P., Steger, J., R., R ofSociety journal the 12,Neuroscience2819-28for slicesof the rat nucleusmedial ofthetrapezoid b M.I., Banks, P.H.,Smith, 1992.Intracellular recor 95,263-276. laryngologica M.,1983.Anniko,Early developmentand maturation References

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This article isprotected by copyright. All rights reserved. Developmental Neurobiology John Wiley& Sons,Inc. childrensuspectedofauditory processing 22 P.J., Vogel, Monje,P.J., M.,H., 2014.Neuronal afferentsby glycinergic in thesuperiormedial Garbett, K., Garbett, Zhang,Polley,P., Mirnics,D.B., ts. ProcNatl ts. SciAcad U 100, 10049-AS

gle Auditory gle SuperiorinUnits Olivary Naturecommunications 8073. 6, psychiatricand tion disorders. Trends Ranvier andnode internode inproperties S.K., 2014.Altered white matter Damasio, H., Damasio, 2003.A morphometricanalysis multiple sclerosis.multiple HandbClin 129,Neurol sound localization storymammals--ain of -316. uditoryBMC 16, 606.Genomicsforebrain. ge function in childreninge function spectrumautismwith inhresholds thehouse mouse(Mus , M.T., Stone,, 2017.Audition-specific W.L., Clement-Ziza, M.,Ushakov,K., Avraham, S.R., Mei,S.R., Redmond, F., S.A., Ullian, E.M., rophysiol639-656. 31, .K.,Lin, G.L., L.S., Miller, Inema, I., Wood, rten, A., Sinclair,A., Kopp-Scheinpflug, J., C., rten, izationsuperiorofthedog olivary complex: nce :theofficialnce journalSociety of the for f therat.Morphometric f studiesat cranial pic Organization. J4,147-&.IntNeurosci g superior olivaryBiolg J Chem complex. in Responsein toVisual AltersStimuli Optic yelinationtheinmammalian brain. oryhypersensitivity theautistic in .,E.,Friauf, Nothwang,H.G., 2013. Time- Page 22of29 Page 23of29 corpus patientsincorpus callosum and unaffected relative Interhemispherichypoconnectivity schizophrenia:in Prvulovic,Uhlhaas,C.,Haenschel,D., P., Pantel, C.,Knochel, Oertel-Knochel,Schonmeyer,V., R., Ro 3709-3718. 125, expression at transitionthe glial VIIIzone of the U.,Zimmermann, 1998. hormoneThyroid affects Schwa M.,Bandtlow, Knipper, Kopschall,Gestwa,C.,L., I AcoustThresholds. J Am Soc28,859-860. R.G., Klumpp, Eady,H.R., 1956.Some Measurements o ofneuroscienceJournal official journal: the of t AuditoryNerve beforeSpike Initiator after Devand K.X., Rutherford,Kim, 2016.M.A., MaturationofNa anisotropyearlyinNeuroreport deafness. 20,1032- D.J.,Park, Kim, S.Y.,Lee, Kim, J., Park, D.H., H. 283,80-88.Hearing research backgroundGeneticeffectson age-related hearing l K.L.,Longo-Guess, Kane, C.M., Gagnon, L.H.,Ding, EEG.andPsychiatry MEG J Neurosci 32,316-322. Dysfunctionearlyin auditoryprocessing in major d S.,Kahkonen, Rytsala,H.,Yamashita, Suominen,H., CompNeurol J mice. 518,3254-3271. Lang,2010.H.,R.A.,Unmyelinated auditorytype I Li,V.,Jyothi, M.,Kilpatrick, L.A.,Smythe, L N., Astrocytespromotemyelination responseinelect to Ishibashi, Dakin,T.,Stevens, K.A., Lee,B.,P.R., hallucinations.ArchGen Psychiatry658-668. 61, Dierks, Lovblad,2004.PathwaysK., T., makethat v Koenig,D.,Hubl, Strik, Federspiel, T., A., Kr W., whitegreyand in matter adults. Hearingearly deaf M., Hribar, D.,Suput, Carvalho,Battelino,A.A., S ofneuroscienceJournal official journal: the of t ofcochleargenerator the nerve?Voltage-gated sodi Antic,Hossain, Yang,S.D.,Y., W.A., Rasband, M.N. light rats: inmicroscopy. Comp 276,Neurol J 537-5 Feldman,Hoeffding,V., 1988.ChangeswithM.L., ag 17,1518-1527.Neurosci oligodendrocyte generationaduring critical tempor Hill,Patel,K.D.,R.A., Goncalves,GrutzendlC.M., sclerosis:multipleclinical possiblecourseandpa Steiner,M.A.,Hellmann, Mosberg-Galili, I., 20 R., pathways the Compmedulla.Neurol J of 119,341-379 J.M.,Harrison, 1962. studyA Warr, of the W.B., co developingsuperiorolive.lateral Res Brain 736, 3 Katz,A.,Hafidi, J.A.,Sanes, D.H., 1996.Differen

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This article isprotected by copyright. All rights reserved. Developmental Neurobiology John Wiley& Sons,Inc. aRue,A.C., Zhou,Schulte,D., B.A., Schmiedt, 23 heSocietyNeuroscience 36,2111-2118.for heSocietyNeuroscience 25,6857-6868.for th nerveprior to cochlea Developmentfunction. eis,Boesch,R., Maier,C.,Schroth, S.E., G., Kozlov,Stewart,C.L.,S.V., R.D.,Fields, 2006. J., 2009.Alterations J., ofwhite diffusionmatter expressiontial ofMAG, inMBPL1 and the thogenesis.ActaNeurol 124,Scand245-249. ., Vovk,A.,., 2014.Structural alterationsofbrain

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This article isprotected by copyright. All rights reserved. Developmental Neurobiology John Wiley& Sons,Inc. 24 .,McCarley,Pelavin, P., R.W.,Kubicki,M., H., 2013. H., Developmentof myelinationand r, D., Kaur, J.,Kaur,D., Vialou,r, V., M.K., Lobo, Dietz, tem ofa prosimian primatetem (Otolemur garnetti). ., Yang,2016.., I.H., Subcellular Optogenetic , 5010-5015. m, H., Senn,H.,Blumer,P., m, M.,Schrott-Fischer, 1621-1623.

son, S.J.,2013. son, Auditoryprocessing and n ofthehumann auditory differentnerve: time n ofaxonn terminalscochlear nucleusfrom the tional considerations relatedtocochlear . adult. Impaired myelination theinprefrontal V.E., 1999.uniqueimonis, pointA inmutation ,Mayer-Proschel, M.,2012. deficiencyIron ., Mazzeo,., Herman,L.,Rimer, K., L.A., xonsNovelMicrofluidicain Tones. JAmAcoust Soc32,Tones. 132-134. 12. Aperiod critical12. socialexperience-for cat. Jthe Comp Neurol 81-103.f 160, nerve. The nerve.of Journal The neuroscience : the mans. PloS11,e0162726.mans.one 380-385. s: a roles: ofinterhemispheric auditory ourseofaxonal theinmyelinationhuman ath number ofath individual oligodendrocytes in ra, A.N., ra, J.,Qian, Mathers,Spirou, P.H., - and post-somatic- segmentsofhuman the ls of otology, of lsrhinology, and laryngology g, H., Maison,H., S.F.,g, 2016. a Toward usborn,ElManira, J., Lyons, D.A.,A., -31. Hearing order. research 330,213-220. ring calyxring helddevelopment. Devof n. Science n. 337,1357-1360. temporal precisionneuronal signalingof thanddisease deafness. American 17-1324. Page 24of29 Page 25of29 Barre Barre syndrome.Neurology 35,771-773. J.A.,Cracco,Schiff, Cracco,R.Q., J.B.,1985. Bra Otorhinolaryngol72,1479-1486. centralauditory the pathwaybrain: thehigher of M M.,Kuan, C.C.,Sano, Kaga,K., Itoh,K., K., Ino, 1105-1115. auditorybrainstem nucleipathway:and MRIevaluati M.,Kaga, K.,Sano, C.C., K., Kuan, Ino, Mima,K., nerve:cochlear a study. morphometric Hearing resea SanchezSanchez delRey,A., J.M.,Fernandez, 2006. Jdevelopment.Comp Neurol 522,971-985. induceddecreasecellin proliferationtheinmedia S.,Saliu,Adise,A., Kudelska,S.,Xian, Rodri K., journalofofficialSociety the Neuroscience 32 for timingreleaseby spiral neuronsofganglion co the M.A.,Rutherford, N.M.,Chapochnikov, Moser, 20 T., neuropsychiatricdisorders. ProcAcadNatl SciU S altersoligodendrocytes myelindopaminergicand fun Moore,C., Chen, H., O'Donnell,Brunner,P., Co D., Murtie, Roy,J.C.,K., El-Khodor, B.F., Edgar, N., 81,270-277.oto-laryngologica Robecchi,Rossi, M.G.,Penna,G., M.,1976. Effects 329-359. 12, J., 1962.Rosenbluth, structure Theofacousti fine 587-590. 36, A.H., Chiappa,Ropper, 1986.EvokedK.H., potential cellsofganglion development.the duringkitten Ac Romand,M.R.,Romand,R., Mulle,Marty, R., C., 198 feedforwardinhibition theinsoundmammalian local M.T.,Roberts, Seeman, Golding,S.C., N.L.,2013. A 139. humancorrelationsain ear withinner noise-induce H.,Rask-Andersen, Ekvall, Scholtz,A.,L., Schrott Biobehav836-854. 36, Rev 2012.O'Connor,K.,Auditory processingautism in s syndrome.Guillain-Barre Neurology1263-1266. 38, K.R., Nelson, Massey,Gilmore, R.L., 1988.A.,Acou RevAnnu Cell503-533. Dev 30, Biol Nave,H.B.,K.A., 2014. Myelination Werner, of the hamster. the 'bt' mutant 176,17-2Hearing research Murofushi,R., Naito, T., M.,Kaga,Mizutani,2 K., 136,44-48.Hearing research electrocochleograms,and cochlear microphonics t in Murofushi,R., Naito, T., M.,Kaga,Mizutani,1 K.,

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This article isprotected by copyright. All rights reserved. Developmental Neurobiology John Wiley& Sons,Inc. 25 guez-Contreras, A.,guez-Contreras, 2014.Naturallesion- and Mima, K., 2008.K., Mima, Early myelinationin patterns Sardi, S.P., Hooks,Sardi, B.M., Benoit-Marand,M., , 4773-4789. 003. Myelin-deficiency 003. theincochlear nerveof Auditory 999. brainstem responses,

l nucleus ofnucleustheltrapezoid bodyhearing during instemauditory potentialsevoked in Guillain- c ganglia inganglia the c rat. ofcell biologyJournal The -Fischer, A.,-Fischer, 2000.Structural/audiometric RI evaluation RI Pediatr study. J Int chlea. The ofneuroscience chlea. Journal The : the oto-laryngologica ta 90,391-397. 2007.Early patternsmyelinationin the nervoussystem: andmechanisms functions. d hearing loss.hearingHearing d 141,research 129- A 104,8131-8136.A rfas, rfas, G.,2007.Loss of signaling erbB in 4. pectrumdisorder: a review.Neurosci ization circuitry. Neuron circuitry. ization 78,923-935. ofacoustic traumaon corti's Acta ganglion. on study.Jon IntPediatr Otorhinolaryngol71, nerve stic conduction in abnormalities mechanisticunderstandingof ofthe role s in Guillain-Barrein s syndrome.Neurology he myelin deficient mutanthamster 'bt'. 12.Spikeencodingof neurotransmitter ction,potentiala mechanism for rch 212, rch 251;author reply 252-253. 0. Early stagesof0. myelinationspiral the in Development ofthehuman fetal

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rmined by rmined assessment.quantitativeMRI Int J sensitivea for of Journalperiod. The coincidencedetector neurons. Journal of The Brooks, S.,Brooks, F.,Linthicum, Kim,C.S., Winnier, of facial andof acousticnervefacial Internallesions. oligodendrocyte myelination.56,284-Glia on. Journalon. The ofneuroscience :theofficial ells and connectionsellsand ofsuperior olivary the Maitra,Eaton,R., K.P., J.C.,Egelhoff, erential axonmyelination of theincollaterals timing processingspatialfor preciselyis e Heschl'se of gyrus hearingimpaired and nn, M.,2014.Auditory nn, nerveperinodal 008. Myelination 008. progressionlanguage-in .L.,Falls, A., Toews, D.L.,Einheber, S., rayama, T., Ohtsu,M.,rayama, T., Harada,H., Totani, patternsinauditory the brainstem.Proc Natl nisms adjustinginterauralnisms for time ditory neuropathy withditoryneuropathynovel a in mutation urology 126,1604-1619.urology ournal ofneuroscienceournal :theofficial journal ionofbrainstem axons theintrapezoid , 2012. , Suddendeafness and diplegiafacial 238,249-262.urol ve of mice. neuroscience Journal The of : projections ofprincipal cellsof the medial hwannandiscells, it required the for I., Yi, Chen,H.,I., P., D.L.,Paul,Lin, X.,

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This article isprotected by copyright. All rights reserved. Developmental Neurobiology John Wiley& Sons,Inc. unctionalinrole source sound localization. 27 D., Majewska, D., A.K., 2012.Effects ofaging and thout a ofhistorypsychotic thout Bipolarfeatures. Aadministration. quantitativehistological ivitysuperiormedialin Jolive cat. of

Ma,X.,Xiao, Luo,H., Bojrab,X.,2nd,D., Hu, , Chen, Z.N.,, Li,Zhang, C.Y., S.K.,Yin, W.T., E.N., Snyder,E.N., J.S.,2015.Allen,AuditoryD.N., arch 88,98-106. arch iffusion tensor iffusion imaging spectrumautismin localprotein synthesis initialand eventsin itory cortices.itory60,541-558.Glia M.E.,Mulert,2015.C., Auditoryverbal thway schizophrenia. Biol chronic in J World Neural 7. interactionin thehumanspiral cochleartherat and vestibularnerves. ons in the anterior ventraltheinanterior ons cochlear nucleus nervoussystemmyelination viadirect a tricallyauditoryevoked responsebrainstem ., Destiche,Bigler,Doran,D., E.D.,S., ., -1651. atal guinea pigs viapigsatal auditoryguinea nerve fiber ar nerveattheperipheral-central ar nervous demyelinationnew a as formechanism , Schulte, , B.A., Lang,2012. H., Age-related 505-512. 202. s in s syndrome].Guillain-Barre NerveBrain se, M.,Kilpatrick, se, Murray,2010. S.S., T.J., ., 2004.., sequenceTime ofdegeneration . auditoryPloSnerve. 7,e34500.one 213. eicht,Karch, S.,R.,G., Eckbo, Pelavin,

88,87-97.research physiologicalauditorymeasures of systemmicein w Assouline,R., Zhou, J.G.,Abbas, P.J., Messing, A.

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, , Gantz,B.J.,1995b. Anatomical and ith peripheral ith myelindeficiency.Hearing Page 28of29 Page 29of

several subsequent nuclei including the IC before r severalnucleisubsequent IC includingthe ABR peaks III and IV correspond peaks and a III ABR CN the to IV projections which then sendinhibitory then which the to (red) projections globularspherical cell; bushy bushy SBC: activate SGNs that project SGNs tothat in auditor the activate CN the potential (SP) reflectsinner potentialof hairce (SP) activation various stages along the early auditory pathway, fr early the along stages various auditorypathway, Auditory Evoked Responses (BAER). This method This ResponsesEvoked Auditory uses (BAER). A) Schematic representation A) peripheral of myeli SGN Auditory system function can function system Auditory be usingmeasured Audi pathway highlighting and circuitrypathway l the ITD at IID begins at the CNS-PNS transitional CNS-PNS begins the at zone (arrow). B) AVCN: anteroventral cochlear anteroventral AVCN: lateral nucleus; LSO:

to the LSO and in the AVCN GBCs SOC. LSO MSO the to (green) ex

Acceptedtrapezoidgeniculate body; medial nucleus; MGN: SGN Article

This article isprotected by copyright. All rights reserved. Fig. 1C is adapted from(Liberman is adapted 2016). Fig.1C etal., Developmental Neurobiology Figure 1. The Auditory Pathway Pathway Auditory Figure The 1. 98x65mm (300 x 300 DPI) (300 30098x65mm DPI) x John Wiley& Sons,Inc. cell; SOC: superior cell;medial complex; n olivary MNTB: SOC: nd IC, respectively. nd e from(Cope is IC, adapted Fig.1B lls, peak I corresponds evoked to potentials I lls,in SGN peak eachin LSO thro MSO. passes and informationthen Auditory LSO y brainstem. Oligodendrocyte brainstem. y axo myelination SGN of evel of the pons. AVCN SBCs (blue) evelAVCN SBCs pons. the extend of excitator om the om midbrain.summating the through The cochlea

nation. In the the auditoryperiphery, cochlearhairce In nation. Schematic representation centralauditory the of Schematic superiormedial superior olive; MSO: olive; GBC: tory Brainstem Responses (ABR), a.k.a. Brainstem ResponsesBrainstem (ABR),toryBrainstem a.k.a. electrodesdetect to evoked electrical potentials a g the MGN and projecting and C) auditoryMGN cortex. g the the to tend excitatory projections to the MNTB, projectionsMNTB, the tendexcitatoryto s:spiral ganglion neurons. ucleus of the the ucleus of t al., 2015). al., t

s while s ugh ugh lls y y ns ns t t