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bioRxiv · 10.1101/2024.09.12.612688

Virally-Mediated Enhancement of Efferent Inhibition Reduces Acoustic Trauma in Wild Type Murine Cochleas.

Slika, E.·Fuchs, P. A.·Beers Wood, M.
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Abstract

Noise-induced hearing loss (NIHL) poses an emerging global health problem with only ear protection or sound avoidance as preventive strategies. In addition, however, the cochlea receives some protection from medial olivocochlear (MOC) efferent neurons, providing a potential target for therapeutic enhancement. Cholinergic efferents release ACh (Acetylycholine) to hyperpolarize and shunt the outer hair cells (OHCs), reducing sound-evoked activation. The (9)2(10)3 nicotinic ACh receptor (nAChR) on the OHCs mediates this effect. Transgenic knock-in mice with a gain-of-function nAChR (9L9T) suffer less NIHL. 9 knockout mice are more vulnerable to NIHL but can be rescued by viral transduction of the 9L9T subunit. In this study, an HA-tagged gain-of-function 9 isoform was expressed in wildtype mice in an attempt to reduce NIHL. Synaptic integration of the virally-expressed nAChR subunit was confirmed by HA-immunopuncta in the postsynaptic membrane of OHCs. After noise exposure, 9L9T-HA injected mice had less hearing loss (auditory brainstem response (ABR) thresholds and threshold shifts) than did control mice. ABRs of 9L9T-HA injected mice also had larger wave1 amplitudes and better recovery of wave one amplitudes post noise exposure. Thus, virally-expressed 9L9T combines effectively with native 9 and 10 subunits to mitigate NIHL in wildtype cochleas. One Sentence SummaryViral transduction of a gain-of-function nAChR enhances the native cholinergic inhibition to protect the cochlea from noise-induced hearing loss.

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Slika, E., Fuchs, P. A., Beers Wood, M.. 2024-09-15. Virally-Mediated Enhancement of Efferent Inhibition Reduces Acoustic Trauma in Wild Type Murine Cochleas.. https://doi.org/10.1101/2024.09.12.612688

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