Abstract

ThisproposalaimstotestthehypothesisthattypeIIafferentsserveascochlearnociceptors. Takingcuesfromthehumancomplaintofhyperacusisafterhearingloss,wewillexaminethestructure andfunctionoftypeIIafferentsinnormalandpost?traumacochleas. Theworkinghypothesisisthat painfulhyperacusis,noxacusis,includeshyperactivityoftypeIIafferents,byanalogytohyperalgesiaof somaticnociceptiveC?fibers. ThuswewillexaminetypeIIstructureandfunctioninnormalandpost?trauma cochleasofratsandmice.Inparallelwewillinvestigatethepropertiesofsurvivingouterhaircellsinpost? traumacochleas.Ourmethodsinclude:exvivoelectrophysiology,lightandelectronmicroscopy,utilization ofoptogeneticandchemogenetictools,andvalidationandquantificationofmousemodelsinwhichtypeII specificbio?markersareexpressed. Anecessaryfirststepistoextendourexvivoexperimentalapproachtooldercochleassothat changeswroughtbyacoustictraumacanbecomparedtothenormalcondition.Wewillcompare damagingsound,ototoxicantibioticsandgeneticallyencodedbiotoxinstoproduceexperimentally tractableeffectsontissueforexvivoexperiments.ThepropertiesandsynapticconnectionsoftypeII afferentsandouterhaircellswillbeexaminedintheexcisedcochleartissueoftheseanimals.Wewill continuetoexploretypeIIspecificgeneticmousemodels.Genetically?encodedreporterproteins, voltage?andcalcium?sensitiveindicators,biotoxins,andopto?andchemo?geneticmodulatorshave becomehighlyinformativetoolsinneurobiologygenerallyandfortheinnerearspecifically.Our ongoingworkhascharacterizedonemouseline,tyrosinehydroxylasepromoterdrivenCre?recombinase expression.ThreeothercandidatetypeIIspecificCrelineswillbevalidatedandquantified.Withsuch transgenicmodelsitbecomespossibletostudyinnervationpatternsbyexpressionoffluorescent reporterproteins,andtoactivate,eliminate,ormodulatetypeIIactivityforanatomicalandphysiological studies.Cre?dependentexpressionofgenetically?modifiedG?protein?coupledreceptors(DREADDS)will providemiceinwhichtypeIIactivitycanbeincreasedordecreasedbyinjectionofanovelsynthetic ligand,dependingonthespecificconstruct.Varyingcombinationsofsystemicandroundwindowdrug deliverywillbeemployedtoincreasethespecificityofexperimentalmanipulations. Theover?archinggoalofthisprogramofexperimentsistocompletethedescriptionoftypeII afferents,astill?unresolvedcomponentofcochlearinnervation. Theworkinghypothesisisthatthese serveascochlearnociceptors. Ifcorrectthesearealikelyneurobiologicalsubstratefornoxacusis (painfulhyperacusis). BydefiningthebasiccellularandmolecularmechanismsoftypeIIfunctionand plasticity,futuretherapeutictargetscanbeidentifiedtoameliorateorpreventnoxacusis.

Public Health Relevance

. TypeIIcochlearafferentsareinsensitivetosound,butstronglyactivatedbytissuedamage.Thisisa proposaltoexaminethehypothesisthattypeIIafferentsarecochlearnociceptorsthatbecome hypersensitiveaftercochleartrauma.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
1R01DC016559-01
Application #
9402176
Study Section
Special Emphasis Panel (ZRG1-IFCN-B (02))
Program Officer
Cyr, Janet
Project Start
2017-06-16
Project End
2022-05-31
Budget Start
2017-06-16
Budget End
2018-05-31
Support Year
1
Fiscal Year
2017
Total Cost
$401,087
Indirect Cost
$155,774

  Institution

Name
Johns Hopkins University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205

  Publications

Wu, Jingjing Sherry; Vyas, Pankhuri; Glowatzki, Elisabeth et al. (2018) Opposing expression gradients of calcitonin-related polypeptide alpha (Calca/Cgrp?) and tyrosine hydroxylase (Th) in type II afferent neurons of the mouse cochlea. J Comp Neurol 526:425-438
Vyas, Pankhuri; Wu, Jingjing Sherry; Zimmerman, Amanda et al. (2017) Tyrosine Hydroxylase Expression in Type II Cochlear Afferents in Mice. J Assoc Res Otolaryngol 18:139-151