Molecular neuroanatomy of the cochlear nucleus in deafness

我们的长期目标是了解听力和耳聋在分布和表达中的作用 传送器受体。在本提案中，我们将重点介绍听神经-耳蜗核(CN)的界面 特别关注三个主要投射神经元的突触回路：脑内梭形细胞(Fc) 耳蜗背核和前腹侧的球状和球状丛状细胞(GBC和SBC) 耳蜗核。这些细胞在整合来自不同来源的汇聚的突触输入方面发挥着关键作用 消息来源。它们构成启动上升听觉通路的神经元群体的一部分，通过这些通路 听觉信息被传递到更高级的中枢。在这项提案中，我们有两个具体目标。在……里面 目标1，我们将确定听力损失是否以及在多大程度上导致表达的变化和 Fc、Gbc和Sbc突触后膜谷氨酸受体的亚单位组成 听神经突触。这项研究将使用卡铂诱导的感觉神经性耳聋来测试 假设谷氨酸突触的分子组成在耳聋后会发生变化。我们会 用免疫金标记法和电子显微镜观察耳聋对其分布和功能的影响 这些细胞上的受体亚基的类型与在听力低下儿童中发现的亚基类型相比较。在目标2中，我们将 确定传导性听力损失是否会导致基因表达和亚单位组成的改变 Fc、Gbc和Sbc突触后膜上的谷氨酸、甘氨酸和GABAA受体。我们将测试 一种假说，认为减少声刺激会导致类似类型的感受器重塑。vbl.使用 对于耳塞，我们将尝试确定“听力降低”对谷氨酸表达的影响， 这些CN神经元上的甘氨酸和GABA受体。建议的研究结合了3-D重建 和形态计量学结合定量免疫细胞化学在光和电子 显微镜水平。通过这些研究，我们将确定即时的形态和分子 感音神经性和传导性听力损失对耳蜗核主要神经元的影响。 这些研究的结果可能揭示由耳聋和失聪引起的分子变化的本质。 听神经活动。它们将与试图保存或替换的战略直接相关 先天性耳聋患者的听力(通过人工耳蜗植入)，并可能导致治疗范例 耳鸣。这项拟议的研究将为谷氨酸能脑可塑性领域做出新的贡献。 和听觉神经生物学。

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.