Cholinergic inhibition of cochlear hair cells is aimed at understanding the basic molecular mechanisms by which efferent neurons of the brainstem release acetylcholine (ACh) to inhibit hair cells and suppress cochlear sensitivity. This central feedback mechanism is particularly highly specialized in the mammalian cochlea where it is proposed to provide gain adjustment, improved signal to noise ratio, extended dynamic range and perhaps to protect from acoustic overstimulation. During development, temporary efferent contacts on inner hair cells are thought to modulate and shape spontaneous activity to help shape central connectivity. Finally, emerging evidence shows that efferent synaptic contacts return to aged or damaged inner hair cells, a process of great interest but presently unknown functional significance. The molecular mechanisms of inhibition may provide clues to these developmental and age-related changes. The hair cell's ACh receptor allows calcium entry that activates nearby potassium channels. This process is regulated by a near-membrane synaptic cistern. Ongoing work suggests that this cistern acts as a calcium sink during normal operation, but during periods of high activity executes calcium-induced calcium release that extends and prolongs cytoplasmic calcium signals. One consequence of prolonged calcium signaling is the activation of nitric oxide synthase to produce the diffusible messenger, nitric oxide (NO). NO causes retrograde facilitation of efferent transmitter release, thereby strengthening these contacts. Mechanisms that regulate efferent synaptic strength are of interest in the context of development, and the changes in synaptic organization that take place in aged or damaged cochleas. In addition to frank hair cell loss, it is clear that afferent denervation of inner hair ells is an important pathogenic change. The adventitious re-innervation of inner hair cells by efferent neurons may prevent afferent dendrites from re-claiming their territory on the hair cell. Understanding the determinants of efferent synapse formation provides tools for manipulating that process, perhaps to ameliorate one consequence of cochlear trauma.

Public Health Relevance

Hearing loss involves a variety of pathogenic mechanisms. Rearrangements of neuronal contacts can occur even without the frank death of sensory hair cells. The present proposal aims to understand better those synaptic rearrangements so as to identify potential therapeutic targets to ameliorate, or reverse, these forms of hearing loss.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC001508-24
Application #
8850839
Study Section
Auditory System Study Section (AUD)
Program Officer
Cyr, Janet
Project Start
1992-09-30
Project End
2019-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
24
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
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Boero, Luis E; Castagna, Valeria C; Di Guilmi, Mariano N et al. (2018) Enhancement of the Medial Olivocochlear System Prevents Hidden Hearing Loss. J Neurosci 38:7440-7451
Zachary, Stephen; Nowak, Nathaniel; Vyas, Pankhuri et al. (2018) Voltage-Gated Calcium Influx Modifies Cholinergic Inhibition of Inner Hair Cells in the Immature Rat Cochlea. J Neurosci 38:5677-5687
Moglie, Marcelo J; Fuchs, Paul A; Elgoyhen, Ana Belén et al. (2018) Compartmentalization of antagonistic Ca2+ signals in developing cochlear hair cells. Proc Natl Acad Sci U S A 115:E2095-E2104
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Rohmann, Kevin N; Wersinger, Eric; Braude, Jeremy P et al. (2015) Activation of BK and SK channels by efferent synapses on outer hair cells in high-frequency regions of the rodent cochlea. J Neurosci 35:1821-30
Goutman, Juan D; Elgoyhen, A Belén; Gómez-Casati, María Eugenia (2015) Cochlear hair cells: The sound-sensing machines. FEBS Lett 589:3354-61
Zachary, Stephen Paul; Fuchs, Paul Albert (2015) Re-Emergent Inhibition of Cochlear Inner Hair Cells in a Mouse Model of Hearing Loss. J Neurosci 35:9701-6

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