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 传递受体。在这个建议中，我们将重点放在听神经耳蜗核（CN）接口 特别关注三个主要投射神经元的突触回路： 耳蜗背核、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神经元的会聚突触输入中起着关键作用。 源它们构成了神经元群的一部分，神经元群启动了上行听觉通路， 听觉信息被传递到更高的中心。在这项建议中，我们有两个具体目标。在 目的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， FC、GBC和SBC突触后膜上谷氨酸受体的亚基组成与 听觉神经突触本研究将使用卡铂诱导的感音神经性耳聋来测试 假设谷氨酸突触的分子组成在耳聋后会发生变化。我们将 用免疫金标记和电镜观察耳聋对神经元分布的影响， 这些细胞上的受体亚基类型与听力同窝出生的婴儿相比。在目标2中。我们将 确定传导性听力损失是否会导致 在FC、GBC和SBC的突触后膜上的谷氨酸、甘氨酸和GABAA受体。我们将测试 声刺激减少导致类似类型的受体重塑的假设。使用 耳塞，我们将试图确定“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。所提出的研究结合了三维重建 形态计量学分析结合光、电镜下免疫细胞化学定量分析 显微镜水平。通过这些研究，我们将确定直接的形态和分子 感音神经性和传导性听力损失引起的耳蜗核主要神经元的变化。 这些研究的结果可能揭示耳聋引起的分子变化的本质， 听神经活动它们将直接关系到试图保留或取代 听力（通过人工耳蜗植入）在先天性耳聋的情况下，并可能导致治疗范例， 耳鸣该研究将为脑神经可塑性研究领域做出新的贡献 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.