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.

Public Health Relevance

- Public Health Relevance ?Hidden hearing loss? is the permanent damage to nerve fibers connecting the sensory cells of the inner ear to the brain, which occurs in noise-induced and age-related hearing loss well before changes in the threshold audiogram. This nerve damage is likely a major contributor to difficulties understanding speech in a noisy environment that characterize many types of sensorineural hearing impairment and may also be a key elicitor of tinnitus. The research proposed here will directly address how the signal-carrying capacity of the auditory nerve is compromised in hidden hearing loss, how the condition can be diagnosed non-invasively and whether the underlying nerve damage predisposes the subject to the development of tinnitus. The proposed research will also extend our work on the development of therapies for this type of neural damage. The ultimate success of these therapies holds promise to improve the hearing abilities of millions of people with sensorineural hearing loss and to eliminate the suffering that tinnitus produces.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
Project #
Application #
Study Section
Auditory System Study Section (AUD)
Program Officer
Cyr, Janet
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts Eye and Ear Infirmary
United States
Zip Code
Hickman, T T; Smalt, C; Bobrow, J et al. (2018) Blast-induced cochlear synaptopathy in chinchillas. Sci Rep 8:10740
Shrestha, Brikha R; Chia, Chester; Wu, Lorna et al. (2018) Sensory Neuron Diversity in the Inner Ear Is Shaped by Activity. Cell 174:1229-1246.e17
Currall, Benjamin B; Chen, Ming; Sallari, Richard C et al. (2018) Loss of LDAH associated with prostate cancer and hearing loss. Hum Mol Genet 27:4194-4203
Wedemeyer, Carolina; Vattino, Lucas G; Moglie, Marcelo J et al. (2018) A Gain-of-Function Mutation in the ?9 Nicotinic Acetylcholine Receptor Alters Medial Olivocochlear Efferent Short-Term Synaptic Plasticity. J Neurosci 38:3939-3954
Gao, Xue; Tao, Yong; Lamas, Veronica et al. (2018) Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents. Nature 553:217-221
Shaheen, Luke A; Liberman, M Charles (2018) Cochlear Synaptopathy Changes Sound-Evoked Activity Without Changing Spontaneous Discharge in the Mouse Inferior Colliculus. Front Syst Neurosci 12:59
Heeringa, Amarins N; Wu, Calvin; Chung, Christopher et al. (2018) Glutamatergic Projections to the Cochlear Nucleus are Redistributed in Tinnitus. Neuroscience 391:91-103
Valero, Michelle D; Hancock, Kenneth E; Maison, St├ęphane F et al. (2018) Effects of cochlear synaptopathy on middle-ear muscle reflexes in unanesthetized mice. Hear Res 363:109-118
Valero, M D; Burton, J A; Hauser, S N et al. (2017) Noise-induced cochlear synaptopathy in rhesus monkeys (Macaca mulatta). Hear Res 353:213-223
Suzuki, Jun; Hashimoto, Ken; Xiao, Ru et al. (2017) Cochlear gene therapy with ancestral AAV in adult mice: complete transduction of inner hair cells without cochlear dysfunction. Sci Rep 7:45524

Showing the most recent 10 out of 116 publications