Understanding normal and abnormal brain development requires knowledge of the cellular events whereby differential experience influences the ontogeny of neural structure and function. Research in this area of auditory neuroscience has achieved a new level of clinical importance through universal newborn screening and enormously increased use of cochlear implants in congenitally and prelingually hearing impaired infants. This application seeks continued funding for a research program aimed at understanding the cellular events whereby the integrity and bioelectric activity of the inner influences development of brainstem auditory pathways. Two separate lines of investigation are proposed. 1. We will continue investigating the intercellular and intracellular signaling pathway(s) that underlie a critical period for susceptibility to neuronal death following the elimination of excitatory synaptic input to the mammalian cochlear nucleus. We propose a series of experiments to further examine developmental changes in transcription and protein expression in the murine cochlear nucleus over the period of hearing development. This pattern will be compared with data from similar analyses of cochlear nucleus tissue from several mutant mouse models of early onset inner ear structural and functional pathologies causing deafness. These studies will provide a library of biomarker profiles for better understanding of normal and hearing deprived cochlear nucleus development that can be used to assess disease states and attempts at remediation. 2. We combine single cell labeling, electrophysiology, calcium imaging and dynamic structural imaging methods to study the cellular pathways underlying afferent regulation of dendritic structure. We also test the hypothesis that a protein responsible for transporting intracellular calcium to the extracellular environment, PMCA2, is essential for maintenance of normal dendritic stability. These studies make use of the unique spatially segregated binaural innervation of n. laminaris cells to allow spatial resolution of the relationships between afferent stimulation, calcium homeostasis, calcium regulatory proteins and structural dynamics of dendrites.

Public Health Relevance

This project encompasses three interrelated areas: development of auditory information processing, neuroembryology of the auditory system, and the effects of experience on brain development. It is imperative that we understand how the various parts of the auditory system develop normally, in order to be able to therapeutically intervene in cases of congenital hearing loss. It is estimated that 10 to 20 percent of the US population have hearing impairments that significantly affect quality of life. Furthermore, 1 out of every 1,000 babies born in this country is seriously hearing impaired.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC003829-14
Application #
8373891
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
1999-05-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
14
Fiscal Year
2013
Total Cost
$444,960
Indirect Cost
$159,729
Name
University of Washington
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Seidl, Armin H; Rubel, Edwin W; Barría, Andrés (2014) Differential conduction velocity regulation in ipsilateral and contralateral collaterals innervating brainstem coincidence detector neurons. J Neurosci 34:4914-9
Wang, Yuan; Sakano, Hitomi; Beebe, Karisa et al. (2014) Intense and specialized dendritic localization of the fragile X mental retardation protein in binaural brainstem neurons: a comparative study in the alligator, chicken, gerbil, and human. J Comp Neurol 522:2107-28
McBride, Ethan G; Rubel, Edwin W; Wang, Yuan (2013) Afferent regulation of chicken auditory brainstem neurons: rapid changes in phosphorylation of elongation factor 2. J Comp Neurol 521:1165-83
Seidl, Armin H; Sanchez, Jason Tait; Schecterson, Leslayann et al. (2013) Transgenic quail as a model for research in the avian nervous system: a comparative study of the auditory brainstem. J Comp Neurol 521:5-23
Kashima, Daniel T; Rubel, Edwin W; Seidl, Armin H (2013) Pre-target axon sorting in the avian auditory brainstem. J Comp Neurol 521:2310-20
Tabor, Kathryn M; Coleman, William L; Rubel, Edwin W et al. (2012) Tonotopic organization of the superior olivary nucleus in the chicken auditory brainstem. J Comp Neurol 520:1493-508
Tabor, Kathryn M; Wong, Rachel O L; Rubel, Edwin W (2011) Topography and morphology of the inhibitory projection from superior olivary nucleus to nucleus laminaris in chickens (Gallus gallus). J Comp Neurol 519:358-75
Sorensen, Staci A; Rubel, Edwin W (2011) Relative input strength rapidly regulates dendritic structure of chick auditory brainstem neurons. J Comp Neurol 519:2838-51
Burger, R Michael; Fukui, Iwao; Ohmori, Harunori et al. (2011) Inhibition in the balance: binaurally coupled inhibitory feedback in sound localization circuitry. J Neurophysiol 106:4-14
Seidl, Armin H; Rubel, Edwin W (2010) A simple method for multiday imaging of slice cultures. Microsc Res Tech 73:37-44

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