This is a proposal to determine the functional properties of till-now-mysterious type II afferents of the mammalian cochlea. Although comprising only a small fraction (5-10%) of all cochlear afferents, their unique arborization to outer hair cells, and termination pattern in the auditory brainstem strongly imply a functional role quite distinct from that of the type I afferents. Limited data suggest that type II afferents have a very high acoustic threshold, perhaps signaling only traumatic or painful levels of sound. Further extending an analogy to somatic pain fibers, type II afferents are activated by ATP that can be released during cochlear trauma, as it is in damaged skin. This project will involve giga-ohm-seal intracellular recording from type II afferents in cochlear segments ex vivo to characterize the excitability and synaptic function of type II afferents. Basic membrane properties, action potential threshold and initiation site, and the size and distribution of synaptic inputs will be determined. Quantal analysis will determine outer hair cell synaptic strength. Pre- and postsynaptic structures associated with recorded fibers will be immunolabeled posthoc. These data will be incorporated into an anatomically-correct, compartmental model to obtain an estimate of the acoustic stimulus required to activate the type II afferent. To explore further a possible role in cochlear trauma, type II recordings will be made in cochleae that have been damaged by loud sound and/or exposure to ototoxins. Hearing loss can lead to hyperacusis and the phantom percept of tinnitus. The analogy to peripheral sensitization and 'phantom limb pain'prompts parallels with somatic neuropathy. Delineation of the functional role of type II afferents adds essential, long-missing information on cochlear function that will enhance theories of auditory pathogenesis, and may provide new therapeutic targets.

Public Health Relevance

Hearing loss and the associated pathologies of hyperacusis and tinnitus result from loss of cochlear hair cells, and altered activity in cochlear afferent neurons. This proposal will determine the responsiveness, signaling and pharmacology of type II cochlear afferents that have until recently been entirely mysterious. Auditory pathogenesis may result from an altered balance of activity between small type II, and large type I afferents, by analogy to neuropathic pain in the somatic nervous system, thus providing the type II afferent as a novel therapeutic target.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Study Section
Auditory System Study Section (AUD)
Program Officer
Cyr, Janet
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Johns Hopkins University
Schools of Medicine
United States
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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
Martinez-Monedero, Rodrigo; Liu, Chang; Weisz, Catherine et al. (2016) GluA2-Containing AMPA Receptors Distinguish Ribbon-Associated from Ribbonless Afferent Contacts on Rat Cochlear Hair Cells. eNeuro 3:
Fuchs, P A; Glowatzki, E (2015) Synaptic studies inform the functional diversity of cochlear afferents. Hear Res 330:18-25
Liu, Chang; Glowatzki, Elisabeth; Fuchs, Paul Albert (2015) Unmyelinated type II afferent neurons report cochlear damage. Proc Natl Acad Sci U S A 112:14723-7
Fuchs, Paul Albert (2015) How many proteins does it take to gate hair cell mechanotransduction? Proc Natl Acad Sci U S A 112:1254-5
Weisz, Catherine J C; Glowatzki, Elisabeth; Fuchs, Paul Albert (2014) Excitability of type II cochlear afferents. J Neurosci 34:2365-73
Fuchs, Paul Albert; Lehar, Mohamed; Hiel, Hakim (2014) Ultrastructure of cisternal synapses on outer hair cells of the mouse cochlea. J Comp Neurol 522:717-29
Fuchs, Paul Albert (2014) It takes two to tango. Channels (Austin) 8:167
Fuchs, Paul Albert (2014) A 'calcium capacitor' shapes cholinergic inhibition of cochlear hair cells. J Physiol 592:3393-401

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