Acoustic overexposures causing only temporary threshold shifts can cause permanent loss of auditory nerve (AN) fibers, despite no loss of cochlear hair cells. This primary neuropathy, seen as an immediate retraction of synaptic terminals on inner hair cells (IHC), followed by slow death of neuronal cell bodies, is selective for the subgroup of AN fibers with high thresholds and low spontaneous rates (SRs). This explains why ABR thresholds can recover despite loss of ~40% of AN fibers. Preliminary results suggest this neuropathy is elicited even by moderate-level exposure (84 dB SPL), especially in the absence of olivocochlear (OC) feedback, and that selective low-SR fiber loss may lead to hyperacusis, tinnitus and hyperactivity in central circuits. Recent human studies also suggest that low-SR neuropathy may be associated with tinnitus;and AN masking studies in animals suggest it should contribute to difficulties hearing in a noisy background. We pursue these clinically important issues, from cochlea to colliculus and from mouse to human, in five Specific Aims:
Aim 1 uses the confocal to examine AN/IHC synapses in humans to ask whether the low/high SR dichotomy is present in our ears and to quantify primary neuropathy in the aging ear.
Aim 2 is a neurophysiological study of masking in the AN of noise-damaged ears designed to assess the impact of low-SR neuropathy on coding of signals in noise and to develop an ABR-based assay to diagnose the loss of low-SR fibers.
Aim 3 uses tract-tracing techniques to examine the central projections of low-SR fibers, to test the hypothesis that they represent the major ascending input to OC reflex circuitry.
Aim 4 uses selective OC lesions to test the hypothesis that a major role of the OC system is to minimize primary neuropathy in everyday acoustic environments.
Aim 5 combines neurophysiological studies of the inferior colliculus with behavioral measures based on the acoustic startle responses to test the hypothesis that low-SR neuropathy leads to central hyperactivity, hyperacusis and tinnitus.

Public Health Relevance

Damaging effects of intense noise are assessed by measuring threshold shifts;however there can be permanent nerve loss in the inner ear, even if thresholds fully recover. Our recent discovery of this noise-induced neurodegeneration has inspired new hypotheses as to the mechanisms underlying tinnitus (ringing in the ears), hyperacusis (reduced sound-level tolerance) and problems hearing in a noisy environment. This proposal takes a multidisciplinary approach to the testing of these new hypotheses in animal models and human autopsy material.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
2R01DC000188-32A1
Application #
8504303
Study Section
Special Emphasis Panel (ZRG1-IFCN-B (02))
Program Officer
Cyr, Janet
Project Start
1982-04-01
Project End
2018-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
32
Fiscal Year
2013
Total Cost
$669,370
Indirect Cost
$254,179
Name
Massachusetts Eye and Ear Infirmary
Department
Type
DUNS #
073825945
City
Boston
State
MA
Country
United States
Zip Code
02114
Liberman, M Charles; Epstein, Michael J; Cleveland, Sandra S et al. (2016) Toward a Differential Diagnosis of Hidden Hearing Loss in Humans. PLoS One 11:e0162726
Suzuki, Jun; Corfas, Gabriel; Liberman, M Charles (2016) Round-window delivery of neurotrophin 3 regenerates cochlear synapses after acoustic overexposure. Sci Rep 6:24907
Valero, Michelle D; Hancock, Kenneth E; Liberman, M Charles (2016) The middle ear muscle reflex in the diagnosis of cochlear neuropathy. Hear Res 332:29-38
Chambers, Anna R; Resnik, Jennifer; Yuan, Yasheng et al. (2016) Central Gain Restores Auditory Processing following Near-Complete Cochlear Denervation. Neuron 89:867-79
Tong, Benton; Hornak, Aubrey J; Maison, Stéphane F et al. (2016) Oncomodulin, an EF-Hand Ca2+ Buffer, Is Critical for Maintaining Cochlear Function in Mice. J Neurosci 36:1631-5
Mehraei, Golbarg; Hickox, Ann E; Bharadwaj, Hari M et al. (2016) Auditory Brainstem Response Latency in Noise as a Marker of Cochlear Synaptopathy. J Neurosci 36:3755-64
Maison, Stéphane; Liberman, Leslie D; Liberman, M Charles (2016) Type II Cochlear Ganglion Neurons Do Not Drive the Olivocochlear Reflex: Re-Examination of the Cochlear Phenotype in Peripherin Knock-Out Mice. eNeuro 3:
Liberman, Leslie D; Liberman, M Charles (2016) Postnatal maturation of auditory-nerve heterogeneity, as seen in spatial gradients of synapse morphology in the inner hair cell area. Hear Res 339:12-22
Liberman, M Charles (2016) Noise-Induced Hearing Loss: Permanent Versus Temporary Threshold Shifts and the Effects of Hair Cell Versus Neuronal Degeneration. Adv Exp Med Biol 875:1-7
Flores, Emma N; Duggan, Anne; Madathany, Thomas et al. (2015) A non-canonical pathway from cochlea to brain signals tissue-damaging noise. Curr Biol 25:606-12

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