# Single-Neuron Marking in the Study of Abnormal Cochleas

> **NIH NIH R01** · MASSACHUSETTS EYE AND EAR INFIRMARY · 2020 · $632,403

## Abstract

Summary - Abstract
Recent work in our laboratories has shown, in both noise-induced and age-related hearing
loss, that the most vulnerable elements in the inner ear are synaptic connections between hair
cells and cochlear neurons, and that this synaptopathy can be widespread (> 50%) even in
cochlear regions with no hair cell loss. Although this primary neural degeneration has little effect
on auditory/cochlear thresholds (thus, a “hidden hearing loss”), partial de-afferentation of
surviving inner hair cells is likely a major cause of difficulties understanding speech in a noisy
environment and may be a key elicitor of tinnitus. Synaptic loss silences the affected neurons,
absent a cochlear implant, however the slow death of the cell bodies and central projections
offers a long therapeutic window. Indeed, we have recently shown that neurotrophin-based
therapies can elicit synaptogenesis and partial functional recovery even in the adult ear.
Here, we extend our prior work on cochlear synaptopathy in both basic-science and
translational directions via four closely coupled Aims in our mouse model of noise-induced
synaptopathy. Aim 1 is a neurophysiological and intracellular labeling study of single auditory
nerve fibers (ANFs) testing the hypothesis that, by eliminating ANFs with high thresholds and
low spontaneous rates (SRs), synaptopathy compromises stimulus coding in the presence of
background noise. We also use the single-unit data to optimize a diagnostic test for hidden
hearing loss based on the dynamic range of masking as revealed by auditory evoked potentials.
Building on preliminary results showing 100% transfection efficiency of inner hair cells following
cochlear injection of a designer adeno-associated virus, Aim 2 uses virally mediated
neurotrophin overexpression to extend the trauma-treatment interval over which synaptopathy
can be rescued in the adult ear, beyond the success we have already shown at 24 hrs post
exposure. In Aim 3, we return to neurophysiology and intracellular labeling to ask whether
regenerated ANFs from Aim 2 recapitulate normal ANF response properties, especially with
respect to the robustness of stimulus coding in noise. Lastly, Aim 4 uses a novel behavioral
assay for tinnitus to ask whether synaptopathy per se is necessary for the generation of tinnitus,
and whether the synaptopathy repair achieved in Aim 2 can also reduce or eliminate the tinnitus
percept in animals.

## Key facts

- **NIH application ID:** 9850086
- **Project number:** 5R01DC000188-39
- **Recipient organization:** MASSACHUSETTS EYE AND EAR INFIRMARY
- **Principal Investigator:** M. Charles Liberman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $632,403
- **Award type:** 5
- **Project period:** 1982-04-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850086

## Citation

> US National Institutes of Health, RePORTER application 9850086, Single-Neuron Marking in the Study of Abnormal Cochleas (5R01DC000188-39). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9850086. Licensed CC0.

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