The goal of this proposal is to make a detailed and ultra-structural analysis of olivocochlear and intra-cochlear circuits in the auditory system of the CBA/J, DBA/2J. CBA/J mice represent a model for normal hearing; DBA/2J mice exhibit early onset, progressive hearing loss that is a model for presbycusis. We are interested in understanding the brain alterations that are initiated by hearing loss. Normal acoustic processing relies on a homeostatic balance between excitatory and inhibitory neurons that operate within structurally and functionally defined circuits. The role of inhibition within the auditory pathways, however, remains largely unknown. We will apply electrophysiological and anatomical (immunocytochemical, pathway tracing and ultrastructure) methods to study inhibitory circuits in mice with normal hearing (CBA/J) and mice with early onset, age-related hearing loss (DBA/2J). By comparing parallel sets of data from these two strains of mice, we seek to determine how altered inhibitory circuits aggravate basic hearing loss and to consider data-based therapeutic strategies.
[...] If hearing loss results in modest but nevertheless quantifiable abnormalities in synaptic organization, then it becomes important to identify the changes and to understand how inhibitory circuits are altered. By comparing data on inhibitory circuits from normal hearing mice and those with presbycusis, we propose to determine the kinds of structural changes triggered in the brainstem that accompany hearing loss. Specifically, we propose to determine if hearing loss likewise upsets the synaptic organization of the MSO as with congenital deafness. [...]
[...] These interneurons would be smaller in size (e.g., Morest, 1975; Winer et al., 1999) and presumably would immunostain for the inhibitory neurotransmitter, GABA (Huang et al., 1999). The implication of feedback excitation to inhibitory neurons is that sideband thalamocortical activity would be suppressed. The number of interneurons in the rat MGv, however, is relatively small compared to cat (Winer et al., 1999) so it will be important to determine this issue in the mouse. If such a numerical difference is also found in the mouse, •acoustic sharpening? [...]
[...] Rapid changes in ultrastructure during deafferentation-induced dendritic atrophy. J Comp Neurol 281:234-258. Deitch JS, Rubel EW. 1989b. Changes in neuronal cell bodies in N. laminaris during deafferentation-induced dendritic atrophy. J Comp Neurol 281:259-268. Dorman MF, Spahr AJ Speech perception by adults with multichannel cochlear implants. In: Waltzman SB, Roland Jr. JR, editors. Cochlear Implants 2nd Edition. New York: Thieme Medical Publishers, Inc. p 193-204. Doucet JR, Ross AT, Gillespie MB, Ryugo DK Glycine immunoreactivity of multipolar neurons in the ventral cochlear nucleus which project to the dorsal cochlear nucleus. [...]
[...] Moreover, the differential effects of deafness on synaptic structure and organization for these separate cell types suggest diminished coordinated activity within the auditory pathways. If hearing loss results in modest but nevertheless quantifiable abnormalities in synaptic organization, then it becomes important to identify the changes and to understand how inhibitory circuits are altered. Experimental Design and Methods pages) Exactly which experiments will be done? What are the critical methods? Is everything in place to carry out the proposed research? If not, what are the steps required to get to that stage? [...]
[...] The goal of this project will be to map the distribution of excitatory and inhibitory synapses on the cell body of these two separate cell populations of the cochlear nucleus. We also seek to determine the source of inhibitory inputs to these cells. In the two mice strains, we will place small, stereotaxic dye injections into the lateral, ventral or medial nuclei of the trapezoid body, guided by electrophysiological recordings (Fig. 7). These three nuclei stain for glycine and are hypothesized to be a major source of inhibition for bushy cells, and histological processing will confirm the location of the injection site. [...]
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