The focus of this research is the synaptic nests of the mammalian cochlear nucleus. The unifying hypothesis is that the nests are structured so as to mediate plastic changes in response to acoustic overstimulation and damage to the auditory system. These newly discovered nests consist of aggregations of closely packed synaptic endings which are unusual in not being separated from each other by glial processes. The nests occur throughout the cochlear nucleus and may reach their greatest development in the human. Their fine structure and lack of astrocytic processes having high-affinity glutamate transporters may endow the nests with an unusual potential for producing plastic changes to ongoing stimulation and to damaging levels of noise. A specific hypothesis is that overstimulation produces structural and histochemical changes, including chronic degeneration and new growth of synaptic endings in the nests and the regions associated with them. To see if the balance of excitatory and inhibitory input is thereby disturbed, the analysis will focus on the relative proportions of the different types of synaptic ending in the nests, the transmitter-related molecules associated with them, their origins, and the plastic changes they undergo in response to noise damage. Electron microcopy will be used to characterize the fine structure and quantify the types of synaptic endings in the nests of the chinchilla and mouse cochlear nucleus. The origins of the major inputs for each type of ending will be determined with anterograde-labeling and silver-degeneration methods. Immunocytochemistry and in situ hybridization will be used to identify the transmitter-related molecules associated with each type of ending. These normative data will be used as a basis for determining changes in the relative proportions of ending types in the nests following exposure to noise. These findings will suggest ways of perturbing the degenerative and regenerative changes of these endings, including the insertion of small lesions, cells or latex microspheres for delivery of growth factors, and single gene deletions or overexpression. These changes may account for some of the auditory dysfunction in human nerve deafness caused by noise, including tinnitus and loudness recruitment. The perturbation experiments should lead directly to proposals for new therapies in this disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC000127-20
Application #
6175635
Study Section
Special Emphasis Panel (ZRG1-IFCN-6 (01))
Program Officer
Freeman, Nancy
Project Start
1979-07-01
Project End
2004-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
20
Fiscal Year
2000
Total Cost
$242,092
Indirect Cost
Name
University of Connecticut
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Farmington
State
CT
Country
United States
Zip Code
06030
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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