Tinnitus is a phantom sound perception that affects about 17% of adults in the United States. There are currently no FDA-approved drugs for tinnitus treatment. Both human imaging studies and animal research suggest that tinnitus is linked to hyperactivity in central auditory neurons following cochlear insult. Tinnitus- related hyperactivity has commonly been described as an elevated spontaneous firing and increased neural synchrony. The goal of this study is to elucidate the cellular mechanism(s) responsible for hyperactivity and to identify pharmacological therapy for controlling hyperactivity to relieve tinnitus symptoms. Recent research has identified two possible mechanisms that may be responsible for tinnitus-related hyperactivity: down- regulation of GABAergic inhibition and changes in the intrinsic properties of affected neurons. Little is known about the relative contributions of these two mechanisms to the hyperactivity. We will address this question by studying intrinsic properties of auditory neurons in conjunction with intracellular labeling and immunostaining for GABAergic neurons. ?Residual inhibition?, the brief suppression of tinnitus after presentation of loud sounds, can be induced in about 80% of tinnitus patients. We discovered that the mechanism of residual inhibition is likely explained by sound-evoked suppression of spontaneous firing in central auditory neurons, and that metabotropic glutamate receptors (mGluRs) play a critical role in this suppression. We propose that elevated spontaneous firing and neural synchrony are neural correlates of tinnitus and that their suppression should bring relief from tinnitus. Our preliminary data indicate that systemic application of the group II mGluR agonist Eglumegad reliably suppresses spontaneous firing in inferior colliculus (IC) and auditory cortex (AC) neurons in mice for about two hours. Sound-evoked activity is negligibly affected by this drug. Similar drug effects were observed in the amygdala, a brain structure likely to be involved in tinnitus-related distress. Furthermore, Eglumegad applied systemically suppressed tinnitus in mice for more than one hour. Three hypotheses will be tested. First, we hypothesize that mice show tinnitus-related hyperactivity like other animal models. Conventional extracellular and multi-electrode array recordings will be used to assess spontaneous, sound-evoked firing and neural synchrony in neurons of the AC, IC, and amygdala in tinnitus positive and control mice. Second, we hypothesize that excitatory and inhibitory neurons are differentially affected by hyperactivity. Intracellular recordings using sharp microelectrodes will be conducted in the IC of awake mice followed by intracellular labeling with neurobiotin and then immunochemistry to distinguish GABAergic vs non- GABAergic neurons. Third, we hypothesize that activation of group II mGluRs can reduce hyperactivity in the AC, IC, and amygdala and also suppress tinnitus and tinnitus-related distress. Eglumegad will be injected systemically. Spontaneous, sound-evoked firing and neural synchrony will be assessed in neurons before and after drug injection. Tinnitus-related distress will be evaluated by marble-burying and vocalization tests.

Public Health Relevance

This research is aimed to provide insight into the neural mechanisms responsible for percept of phantom sounds or tinnitus. This research is also expected to develop therapeutic strategies for tinnitus treatment which may affect approximately 50 million tinnitus patients in the US.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC016918-03
Application #
10064143
Study Section
Auditory System Study Section (AUD)
Program Officer
Miller, Roger
Project Start
2019-01-01
Project End
2023-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
3
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Northeast Ohio Medical University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
077779882
City
Rootstown
State
OH
Country
United States
Zip Code
44272