Molecular neuroanatomy of the cochlear nucleus in deafness

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Our long-term goal is to understand the role of hearing and deafness in the distribution and expression of transmitter receptors. In this proposal, we will focus on the auditory nerve-cochlear nucleus (CN) interface with a special focus on the synaptic circuitry of three principal projection neurons: the fusiform cell (FC) in the dorsal cochlear nucleus, and globular and spherical bushy cells (GBC and SBC) in the anteroventral cochlear nucleus. These cells play key roles in the integration of converging synaptic inputs from diverse sources. They form part of the neuron population that initiates the ascending auditory pathways by which auditory information is communicated to higher centers. In this proposal, we have two specific objectives. In Aim 1, we will determine whether and to what extent hearing loss leads to changes on the expressionand subunit composition of glutamate receptors at the postsynaptic membrane of FC, GBC and SBC opposed to auditory nerve synapses. This study will use carboplatin-induced sensorineural deafness to test the hypothesis that the molecular composition of the glutamate synapse will change after deafening. We will use immunogold labeling and electron microscopy to examine the effects of deafness on the distribution and type of receptor subunits on these cells as compared to that found in hearing littermates. In Aim 2. we will determine whether conductive hearing loss leads to changes in the expression and subunit composition of glutamate, glycine and GABAA receptors at the postsynaptic membrane of FC, GBC and SBC. We will test the hypothesis that a reduction in acoustic stimulation leads to similar types of receptor remodeling. Using ear plugs, we will attempt to determine the effects of "hearing reduction" on the expression of glutamate, glycine and GABA receptors on these CN neurons. The proposed research combines 3-D reconstruction and morphometric analysis together with quantitative immunocytochemistry at the light and electron microscopy level. Through these studies we will determine the immediate morphological and molecular changes caused by sensorineural and conductive hearing loss on the main neurons in the cochlear nucleus. The results of these studies may reveal the nature of molecular change induced by deafness and loss of auditory nerve activity. They will have direct relevance to strategies that attempt to preserve or replace hearing (via cochlear implants) in cases of congenital deafness, and may lead to treatment paradigms for tinnitus. The proposed research will make novel contributions to the field of glutamatergic brain plasticity and auditory neurobiology.