The objective of this proposal is to study the molecular mechanisms by which acetyicholine (ACh) released from olivocochtear efferents influences cochlear outer hair cells (OHCs). The nicotinic ACh, receptor (nAChR) on OHCs contains the a9 nAChR subunit, and may also contain the newly discovered al0 nAChR. At least two hypotheses have been proposed concerning the contribution cochlear efferents make to hearing: 1) they protect the cochlea from acoustic overstimulation, and 2) they enhance sound recognition in the presence of background noises. In the last project period we investigated the first hypothesis by devising a test of the cochlear efferent reflex strength and found that reflex strength is positively correlated to the expression of a9 nAChR. Furthermore, we discovered that animals with stronger efferent reflexes exhibited less cochlear damage upon noise exposure. The proposed experiments will extend those studies to test whether a9 and al0 subunits of the nAChR form a heteromeric complex and whether modulating expression of this complex in adulthood can influence recovery of cochlear function after acoustic overstimulation. The first specific aim is to determine if a9and alO nAChRs form functional heteromeric receptors in cochlear hair cells in vivo using coimmunoprecipitation and immunohistochemical techniques. The second specific aim will determine if upregulation (or downregulation) of a9, al0, or a9 + alO nAChR expression in adult guinea pig hair cells strengthens (or weakens) the efferent reflex and reduces (or increases) susceptibility to noise damage. These experiments will use a modified adenovirus to deliver a9 and a10 overexpression, dominant negative, and antisense constructs mRNAs directly to the scala tympani of adult guinea pigs. Control studies performed in Xenopus oocytes will be used to validate the receptor coimmunoprecipitation techniques and to verify that dominant-negative and antisense receptor constructs inhibit responses to ACh. Information gained from these studies will contribute to future drug therapies that target cholinergic receptors of the cochlear efferent system with the goal of diminishing noise-induced hearing loss in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
2R01DC003086-06
Application #
6383266
Study Section
Special Emphasis Panel (ZRG1-IFCN-6 (01))
Program Officer
Watson, Bracie
Project Start
1996-09-30
Project End
2004-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
6
Fiscal Year
2001
Total Cost
$242,818
Indirect Cost
Name
University of Miami School of Medicine
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33146
Walton, Joseph P; Dziorny, Adam C; Vasilyeva, Olga N et al. (2018) Loss of the Cochlear Amplifier Prestin Reduces Temporal Processing Efficacy in the Central Auditory System. Front Cell Neurosci 12:291
Dickerson, Ian M; Bussey-Gaborski, Rhiannon; Holt, Joseph C et al. (2016) Maturation of suprathreshold auditory nerve activity involves cochlear CGRP-receptor complex formation. Physiol Rep 4:
Safe, Theresa M; Luebke, Anne E (2016) Prenatal low dosage dioxin (TCDD) exposure impairs cochlear function resulting in auditory neuropathy. Hear Res 331:7-12
Luebke, Anne E; Stagner, Barden B; Martin, Glen K et al. (2015) Influence of sound-conditioning on noise-induced susceptibility of distortion-product otoacoustic emissions. J Acoust Soc Am 138:58-64
Luebke, Anne E; Holt, Joseph C; Jordan, Paivi M et al. (2014) Loss of ?-calcitonin gene-related peptide (?CGRP) reduces the efficacy of the Vestibulo-ocular Reflex (VOR). J Neurosci 34:10453-8
Luebke, Anne E; Stagner, Barden B; Martin, Glen K et al. (2014) Adaptation of distortion product otoacoustic emissions predicts susceptibility to acoustic over-exposure in alert rabbits. J Acoust Soc Am 135:1941-9
Mihaila, Camelia; Schramm, Jordan; Strathmann, Frederick G et al. (2011) Identifying a window of vulnerability during fetal development in a maternal iron restriction model. PLoS One 6:e17483
Bogart, L J; Levy, A D; Gladstone, M et al. (2011) Loss of prestin does not alter the development of auditory cortical dendritic spines. Neural Plast 2011:305621
Polesskaya, Oksana; Cunningham, Lisa L; Francis, Shimon P et al. (2010) Ablation of mixed lineage kinase 3 (Mlk3) does not inhibit ototoxicity induced by acoustic trauma or aminoglycoside exposure. Hear Res 270:21-7
Luebke, Anne E; Rova, Cherokee; Von Doersten, Peter G et al. (2009) Adenoviral and AAV-mediated gene transfer to the inner ear: role of serotype, promoter, and viral load on in vivo and in vitro infection efficiencies. Adv Otorhinolaryngol 66:87-98

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