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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DC011741-04
Application #
8676488
Study Section
Auditory System Study Section (AUD)
Program Officer
Cyr, Janet
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Weisz, Catherine J C; Glowatzki, Elisabeth; Fuchs, Paul Albert (2014) Excitability of type II cochlear afferents. J Neurosci 34:2365-73
Fuchs, Paul Albert (2014) A 'calcium capacitor' shapes cholinergic inhibition of cochlear hair cells. J Physiol 592:3393-401
Copley, Catherine O; Duncan, Jeremy S; Liu, Chang et al. (2013) Postnatal refinement of auditory hair cell planar polarity deficits occurs in the absence of Vangl2. J Neurosci 33:14001-16