Recent studies of noise-induced and age-related hearing loss show that loss of synapses between cochlear nerve terminals and inner hair cells (IHCs), rather than hair cell damage, is often the first degenerative event. Noise exposures causing only temporary threshold shifts, and no loss of hair cells, nevertheless cause rapid and permanent loss of IHC synapses, followed slowly by death of spiral ganglion neurons (SGNs). A similar view of the importance of synaptopathy has emerged with respect to the aging ear. Even without purposeful noise exposure, loss of IHC synapses in mice progresses steadily throughout life, long before the loss of hair cells and SGNs, and similar findings are emerging from post-mortem studies of human ears. Thus, understanding the mechanisms that underlie the formation, maintenance, and regeneration of the IHC-SGN synapse are key to understanding the cellular and molecular basis of acquired hearing loss and thus in the development of rational therapies. Using cell-specific, inducible gene recombination in several novel mouse transgenic lines, we showed that neurotrophin 3 (NT-3) derived from cochlear supporting cells is a key regulator of IHC synapse formation and maintenance in the neonate, and that neonatal NT-3 overexpression in supporting cells enhances synaptic and functional recovery after acoustic overexposure in the adult. Here we will test the hypotheses that 1) NT-3 is critical for regulation of IHC synapses in the adult, and 2) that age- related or noise-induced cochlear neuropathy can be modulated by up- or down-regulating NT-3.
Aim 1 will determine the roles of NT-3 in regulating IHC synapses in the adult and aging ear by genetically inducing supporting-cell NT-3 overexpression or deletion in the adult cochlea and assessing the effects on cochlear structure and function over short (wks) and long (months) survival.
Aim 2 will test the hypothesis that increases or decreases in cochlear NT-3 can influence the severity of, or recovery from, noise-induced cochlear neuropathy using genetic and pharmacological approaches. We will over- or under-express NT-3 in supporting cells by genetic means either 1 wk before or 1 day after a neuropathic noise exposure and monitor cochlear function via ABRs and DPOAEs at different intervals, out to 6 months. For the pharmacological approach, NT-3 will be delivered via round window application in a slow-release gel. For both aims, we will monitor changes in cochlear function via ABRs and DPOAEs, and cochleas will be collected either for RT-PCR analysis of NT-3 expression and/or for histological analysis of hair cell and SGN counts as well as IHC synapse number and morphology.

Public Health Relevance

According to the NIDCD, 36 million adults in the United States (17% of the population) report some degree of hearing loss. The two most common causes of hearing loss are noise exposure and aging. In spite of the high incidence of noise-induced and age-related hearing loss, the mechanisms that underlie their pathogenesis remain poorly defined, and there is a lack of therapeutic approaches to treat them. This project will use new and powerful transgenic mouse models to investigate the cellular and molecular processes underlying noise- induced and age-related hearing loss and will test the potential of a specific trophic factor as a hearing loss therapeutic.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Freeman, Nancy
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Long, Patrick; Wan, Guoqiang; Roberts, Michael T et al. (2018) Myelin development, plasticity, and pathology in the auditory system. Dev Neurobiol 78:80-92
Casaccia, Patrizia; Corfas, Gabriel (2018) Introduction to the special issue on myelin plasticity in the central nervous system. Dev Neurobiol 78:65-67
Schaefer, Stacy A; Higashi, Atsuko Y; Loomis, Benjamin et al. (2018) From Otic Induction to Hair Cell Production: Pax2EGFP Cell Line Illuminates Key Stages of Development in Mouse Inner Ear Organoid Model. Stem Cells Dev 27:237-251
Zhao, Xiao-Feng; Kohen, Rafi; Parent, Rachel et al. (2018) PlexinA2 Forward Signaling through Rap1 GTPases Regulates Dentate Gyrus Development and Schizophrenia-like Behaviors. Cell Rep 22:456-470
Wan, Guoqiang; Corfas, Gabriel (2017) Transient auditory nerve demyelination as a new mechanism for hidden hearing loss. Nat Commun 8:14487
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
Suzuki, Jun; Corfas, Gabriel; Liberman, M Charles (2016) Round-window delivery of neurotrophin 3 regenerates cochlear synapses after acoustic overexposure. Sci Rep 6:24907
Wan, Guoqiang; Corfas, Gabriel (2015) No longer falling on deaf ears: mechanisms of degeneration and regeneration of cochlear ribbon synapses. Hear Res 329:1-10
Long, Patrick; Corfas, Gabriel (2014) Neuroscience. To learn is to myelinate. Science 346:298-9
Mellado Lagarde, Marcia M; Wan, Guoqiang; Zhang, LingLi et al. (2014) Spontaneous regeneration of cochlear supporting cells after neonatal ablation ensures hearing in the adult mouse. Proc Natl Acad Sci U S A 111:16919-24

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