# Activity-Dependent Influences on Auditory Circuits

> **NIH NIH R01** · MASSACHUSETTS EYE AND EAR INFIRMARY · 2020 · $602,115

## Abstract

Project Summary
Ludwig van Beethoven poignantly expressed the perceptual and social burden of hearing loss in an 1801 letter
to a friend stating, “But that jealous demon, my wretched health, has put a nasty spoke in my wheel…for the last
three years my hearing has become weaker and weaker. My ears continue to hum and buzz day and night.
Sometimes I can scarcely hear a person who speaks softly…but if anyone shouts I can’t bear it. Heaven alone
knows what is to become of me.” Beethoven’s self-described maladies can be identified as tinnitus, threshold
shift and hyperacusis, respectively. Hyperacusis presents as two distinct neurological disorders: i) “noxicusis”,
in the form of excruciating sound-triggered ear pain or ii) a generalized auditory hypersensitivity that makes even
moderately intense sounds seem uncomfortably loud. The neurobiological causes of this second, more common,
type of hyperacusis have yet to be defined. This project will develop a mouse model of noise-induced hearing
loss to reveal neural circuit changes that cause auditory perceptual hypersensitivity. Studies pursuant to Aim 1
will develop a suite of head-fixed operant behavioral assays to track the emergence of perceptual hypersensitivity
following noise-induced high-frequency hearing loss. Studies in Aim 2 will use chronic 2-photon calcium imaging
of genetically targeted excitatory and inhibitory neurons in auditory cortex to pinpoint the emergence of cortical
hyperactivity relative to perceptual hypersensitivity. Complementary single unit electrophysiology studies will
contrast cortical hyperexcitability elicited with acoustic stimuli versus optogenetic stimuli that bypass the ear and
brainstem to directly activate neurons in the auditory thalamus. Aim 3 will test the hypothesis that auditory cortex
hyperexcitability is necessary and sufficient for auditory perceptual hypersensitivity by expressing stabilized step
function opsins to temporarily induce or reverse cortical hyperexcitability independent of hearing loss. Studies in
Aim 4 will address the distributed downstream effects of excess central gain by tracking the emergence of noise-
induced hyperexcitability in descending cortical efferents as well as local cell bodies in the amygdala and dorsal
cortex of the inferior colliculus. By tracking the precise chronology of hyperexcitability within and beyond the
auditory pathway alongside sound-triggered defensive behaviors such as freezing, it will be possible to identify
a direct link between sensory plasticity and disorders of anxiety and stress that are commonly observed in
individuals with hyperacusis. This association can be causally tested by inducing or reversing cortical
hyperexcitability and noting a potential reversal in subcortical makers of excess loudness growth. Taken
together, this proposal will leverage modern neuroscience tools to perform causal hypothesis testing on neural
circuit changes that underlie a common hearing disorder. Sensory hypersensitivity ...

## Key facts

- **NIH application ID:** 9997470
- **Project number:** 2R01DC009836-11
- **Recipient organization:** MASSACHUSETTS EYE AND EAR INFIRMARY
- **Principal Investigator:** Daniel B. Polley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $602,115
- **Award type:** 2
- **Project period:** 2009-07-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997470

## Citation

> US National Institutes of Health, RePORTER application 9997470, Activity-Dependent Influences on Auditory Circuits (2R01DC009836-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9997470. Licensed CC0.

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