Noise-induced hearing loss is an incurable, often progressive disease that impairs the quality of life. This project, using animal models, has provided evidence for degeneration of synaptic endings in the brain, besides loss of cochlear hair cells, as a major factor in this disease. This research offers preliminary data that the balance between excitatory and inhibitory endings in the cochlear nucleus shifts over time towards excitation and hyperactivity. The overall hypothesis is that these shifts provide a structural basis for tinnitus and hyperacusis after noise exposure. The project will characterize the degenerative process, at the cell and molecular levels, and trace changes in synaptic organization, including the exciting discovery that new synapses can form after the initial damage. The experiments aim to uncover factors that protect synapses or promote recovery after noise. Light and electron microscopy are used to examine damage in the cochlear nucleus of mice. Changes in the proportion of excitatory and inhibitory endings will be quantitated over 1-120 days after noise exposure. Synaptic vesicle histochemistry with light microscopy will show the numbers and locations of endings. Electron microscopy will show the proportion of endings with excitatory or inhibitory cytology using stereological approaches to test the hypothesis. Immunocytochemistry by light and electron microscopy will identify molecules underlying these changes. Transmitter-related molecules, including excitatory and inhibitory receptors and transporters, will be localized to specific types of neurons and synapses and tracked over the survival period. These data will pinpoint where and when in the cochlear nucleus an excitotoxic process may occur in cells. Neurotrophic factors and receptors will be identified and localized to indicate a role for trophic mechanisms. The role of fibroblast growth factor will be evaluated in a transgenic mouse that over expresses this factor. The hypothesis is that this factor protects against damage, and neurotrophins promote new growth of synapses. The results should lead to proposals for new therapies.

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
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University of Connecticut
Anatomy/Cell Biology
Schools of Medicine
United States
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Leung, Alan W; Kent Morest, D; Li, James Y H (2013) Differential BMP signaling controls formation and differentiation of multipotent preplacodal ectoderm progenitors from human embryonic stem cells. Dev Biol 379:208-20
García-Hernández, Sofía; Potashner, Steven J; Morest, D Kent (2013) Role of fibroblast growth factor 8 in neurite outgrowth from spiral ganglion neurons in vitro. Brain Res 1529:39-45
Feng, J; Bendiske, J; Morest, D K (2012) Degeneration in the ventral cochlear nucleus after severe noise damage in mice. J Neurosci Res 90:831-41
Feng, J; Bendiske, J; Morest, D K (2010) Postnatal development of NT3 and TrkC in mouse ventral cochlear nucleus. J Neurosci Res 88:86-94
Wang, S J; Furusho, M; D'Sa, C et al. (2009) Inactivation of fibroblast growth factor receptor signaling in myelinating glial cells results in significant loss of adult spiral ganglion neurons accompanied by age-related hearing impairment. J Neurosci Res 87:3428-37
Hill, Gerhard W; Morest, D Kent; Parham, Kourosh (2008) Cisplatin-induced ototoxicity: effect of intratympanic dexamethasone injections. Otol Neurotol 29:1005-11
D'Sa, Chrystal; Gross, Julia; Francone, Victor P et al. (2007) Plasticity of synaptic endings in the cochlear nucleus following noise-induced hearing loss is facilitated in the adult FGF2 overexpressor mouse. Eur J Neurosci 26:666-80
Hurd, L B; Hutson, K A; Morest, D K (1999) Cochlear nerve projections to the small cell shell of the cochlear nucleus: the neuroanatomy of extremely thin sensory axons. Synapse 33:83-117
Bilak, S R; Morest, D K (1998) Differential expression of the metabotropic glutamate receptor mGluR1alpha by neurons and axons in the cochlear nucleus: in situ hybridization and immunohistochemistry. Synapse 28:251-70
Josephson, E M; Morest, D k (1998) A quantitative profile of the synapses on the stellate cell body and axon in the cochlear nucleus of the chinchilla. J Neurocytol 27:841-64

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