Physiology of Dorsal Cochlear Nucleus Molecular Layer

耳蜗背核分子层的生理学

• 批准号: 7854098
• 负责人: Paul B Manis
• 金额: $ 3.97万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7854098
• 关键词: Acoustic Trauma; Acoustics; Action Potentials; Adult; Affect; Auditory; Auditory system; Axon; Brain; Butyric Acids; Cavia; Cell Nucleus; Cells; Cerebellar Nuclei; Cerebellar cortex structure; Cochlear nucleus; Complex; Computer Simulation; Coupled; Data; Dendrites; Event; Exhibits; Fiber; Fire - disasters; Functional disorder; Future; GTP-Binding Proteins; Glycine; Goals; Inhibitory Synapse; Interneurons; Intervention; Ion Channel; Lead; Long-Term Depression; Long-Term Potentiation; Measurement; Medical; Modeling; Molds; Mus; Neurons; Nuclear; Operative Surgical Procedures; Output; Pathway interactions; Pattern; Pharmacological Treatment; Physiological; Physiology; Plastics; Play; Population; Presynaptic Terminals; Process; Pyramidal Cells; Rattus; Research Personnel; Role; Sensory; Sensory Process; Site; Slice; Structure of molecular layer of cerebellar cortex; Synapses; Synaptic plasticity; System; Testing; Time; Tinnitus; Tweens; Whole-Cell Recordings; base; cell type; dorsal cochlear nucleus; effective therapy; gamma-Aminobutyric Acid; hearing impairment; information processing; insight; network models; neural circuit; postsynaptic; programs; receptor; reconstruction; relating to nervous system; research study; response; sound; synaptic function

The dorsal cochlear nucleus (DCN) is a site for rapid and early processing of spectrally complex sounds, and is the first point in the auditory system where auditory and non-auditory information converges. Increased spontaneous activity in the DCN after hearing loss has also been associated with tinnitus. Increased electrical excitability or decreased inhibition could lead to increased activity of DCN neurons, are thus potential mechanisms for tinnitus. While the responses of DCN principal neurons (pyramidal cells) to sound are strongly molded by inhibition, little is known about the functional operation of the major inhibitory networks. The goals of this proposal are to investigate inhibitory circuits in the DCN, and to elucidate their roles in normal sensory processing as well as in auditory dysfunction. In the first aim, we will study the organization and synaptic dynamics of local inhibitory circuits in the DCN, using paired whole-cell recording. We will test whether the synaptic influence of the most populous inhibitory interneurons, the cartwheel cells, depends on the target cell type, and whether cartwheel cells can fire in a synchronized manner as predicted from their physiology and connections. We will test hypotheses about the spatial organization of cartwheel cell axons to determine whether this system, which receives non-tonotopic inputs, might operate in a tonotopic fashion. These experiments will include morphological reconstruction of cell pairs to elucidate the spatial organization of connections. In the second aim, we will investigate short and long-term synaptic plasticity at inhibitory synapses in the DCN. We will test whether cartwheel cells utilize glycine and GABA as co-transmitters onto the pyramidal cells and other cartwheel cells, and whether there is activity-dependent short-term modulation of inhibitory synapses. Long-term synaptic plasticity is present at the excitatory parallel fiber synapses onto pyramidal and cartwheel cells. We will test whether the inhibitory synapses from cartwheel to pyramidal cells, and between cartwheel cells, exhibit similar activity-dependent plastic changes. In the third aim, we will use our experimental data to create a biologically accurate circuit model of the DCN. We will use this model to test predictions about how changes in synaptic function associated with hearing loss can affect the output of the nucleus. In the fourth aim, we will test the hypotheses that central tinnitus produced by acoustic trauma is associated with decreases in inhibitory synaptic strength, or whether it is associated with increased intrinsic electrical excitability. Tinnitus is a phenomenon that affects nearly 20% of people in the U.S., and which is debilitating to nearly 2 million citizens. There is a significant unmet medical need for effective treatments. Our experiments will directly evaluate specific synaptic systems and receptors that can be targeted for pharmacological intervention for treatment and cure of this persistent problem.

耳蜗背核 (DCN) 是快速、早期处理频谱复杂声音的场所， 是听觉系统中听觉和非听觉信息汇聚的第一个点。 听力损失后 DCN 自发活动的增加也与耳鸣有关。 电兴奋性增加或抑制减少可能导致 DCN 神经元活性增加， 因此耳鸣的潜在机制。而 DCN 主要神经元（锥体细胞）对 声音受到抑制的强烈影响，但人们对主要抑制的功能运作知之甚少 网络。该提案的目标是研究 DCN 中的抑制电路，并阐明它们的作用 在正常感觉处理以及听觉功能障碍中的作用。在第一个目标中，我们将研究 使用配对全细胞记录，研究 DCN 中局部抑制电路的组织和突触动力学。 我们将测试数量最多的抑制性中间神经元、侧手翻细胞的突触影响是否 取决于目标细胞类型，以及侧手翻细胞是否可以按照预测以同步方式发射 从他们的生理学和联系来看。我们将测试有关侧手翻的空间组织的假设 细胞轴突来确定这个接收非音调输入的系统是否可以在 基调时尚。这些实验将包括细胞对的形态学重建，以阐明 连接的空间组织。在第二个目标中，我们将研究短期和长期突触 DCN 中抑制性突触的可塑性。我们将测试侧手翻细胞是否利用甘氨酸和 GABA 作为 锥体细胞和其他车轮细胞上的共递质，以及是否存在活动依赖性 抑制性突触的短期调节。长期突触可塑性存在于兴奋性 平行纤维突触连接到锥体细胞和车轮细胞上。我们将测试抑制性突触是否来自 侧手翻到锥体细胞，以及侧手翻细胞之间，表现出类似的活动依赖性塑性变化。 第三个目标是，我们将利用实验数据创建生物学上准确的 DCN 电路模型。 我们将使用该模型来测试有关突触功能变化如何与听力相关的预测 损失会影响核的输出。在第四个目标中，我们将检验中枢性耳鸣的假设 声损伤产生的声音与抑制性突触强度的降低有关，或者是否与抑制性突触强度的降低有关。 与内在电兴奋性增加有关。 耳鸣是一种影响近 20% 美国人的现象，它使近 20% 的人感到虚弱 200万公民。对于有效治疗的医疗需求存在着巨大的未满足的需求。我们的实验将 直接评估可作为药理学目标的特定突触系统和受体 干预治疗和治愈这一持续存在的问题。