Molecular neuroanatomy of the cochlear nucleus in deafness

耳聋耳蜗核的分子神经解剖学

• 批准号: 7534324
• 负责人: Maria Eulalia Rubio
• 金额: $ 28.37万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-16 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7534324
• 关键词: 3-Dimensional; Acids; Acoustic Nerve; Acoustic Stimulation; Address; Affect; Auditory; Biological Models; Brain; Carboplatin; Cell Nucleus; Cells; Cochlear Implants; Cochlear nucleus; Conductive hearing loss; Dendrites; Development; Disease; Ear; Electron Microscopy; Event; Fiber; Fusiform Cell; GABA Receptor; Gene Expression; Gene Targeting; Glutamate Receptor; Glutamates; Glycine; Goals; Hearing; Human; Kinetics; Label; Lead; Learning; Light; Memory; Molecular; Nature; Nerve; Nerve Fibers; Neuraxis; Neuroanatomy; Neurobiology; Neurons; Neurotransmitter Receptor; Play; Population; Postsynaptic Membrane; Process; Research; Role; Sensorineural Hearing Loss; Sensory; Signal Transduction; Source; Structure; Synapses; Synaptic plasticity; Testing; Tinnitus; auditory pathway; congenital deafness; deafness; dorsal cochlear nucleus; experience; gamma-Aminobutyric Acid; hearing impairment; immunocytochemistry; information processing; nerve supply; neural circuit; novel; novel therapeutics; postsynaptic; presynaptic; receptor; receptor expression; reconstruction; response; transmission process

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.

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 发射机受体。在此提案中，我们将重点关注听觉神经 - 螺旋核（CN）界面 特别关注三个主要投影神经元的突触电路：梭形细胞（FC） 前耳蜗核以及前腹膜中的球形和球形灌木细胞（GBC和SBC） 耳蜗核。这些单元在整合不同的突触输入的集成中起着关键作用 来源。它们构成了神经元种群的一部分，该神经元启动了上升的听觉途径 听觉信息将传达给高等中心。在此提案中，我们有两个具体的目标。在 AIM 1，我们将确定听力损失是否会导致表达式变化和 FC，GBC和SBC的突触后膜上谷氨酸受体的亚基组成反对 听觉神经突触。这项研究将使用卡铂诱导的感觉性耳聋来测试 假设聋兰氨酸突触的分子组成将在震耳欲聋后发生变化。我们将 使用免疫金标记和电子显微镜检查耳聋对分布的影响和 这些细胞上的受体亚基类型与听力同窝仔相比。在AIM 2中。我们将 确定导电性听力损失是否导致表达和亚基组成的变化 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 声学刺激减少导致相似类型的受体重塑的假说。使用 耳塞，我们将尝试确定“减少听力”对谷氨酸表达的影响， 这些CN神经元上的甘氨酸和GABA受体。拟议的研究结合了3-D重建 以及形态计量分析以及在光和电子处的定量免疫细胞化学 显微镜水平。通过这些研究，我们将确定直接形态和分子 耳蜗核中主要神经元的感觉和导电性听力损失引起的变化。 这些研究的结果可能揭示了聋和丧失引起的分子变化的性质 听觉神经活动。他们将与试图保存或替换的策略有直接的相关性 在先天性耳聋的情况下听证（通过人工耳蜗），可能导致治疗范例 耳鸣。拟议的研究将为谷氨酸能脑可塑性做出新的贡献 和听觉神经生物学。