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.

背部耳蜗核（DCN）是快速和早期处理频谱复杂声音的位点， 这是听觉系统中听觉和非审计信息收敛的第一点。 听力丧失后，DCN的自发活性增加也与耳鸣有关。 增加的电兴奋性或抑制作用降低可能导致DCN神经元的活性增加，为 因此耳鸣的潜在机制。而DCN主神经元（锥体细胞）对 声音被抑制强烈模压，对主要抑制作用的功能操作知之甚少 网络。该提案的目标是调查DCN中的抑制回路，并阐明其 在正常的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 使用配对的全细胞记录，DCN中局部抑制回路的组织和突触动力学。 我们将测试人口最多的抑制性中间神经元，卡特轮细胞的突触影响，是否是 取决于目标细胞类型，以及卡车轮细胞是否可以按照预测 从他们的生理和联系。我们将测试有关卡特轮的空间组织的假设 细胞轴突确定该系统是否接收非TONOTOPIC输入，可以在一个 吨位时尚。这些实验将包括细胞对的形态重建，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中抑制突触的可塑性。我们将测试Cartwheel细胞是否利用甘氨酸和GABA作为 共递射击器上的锥体细胞和其他卡特轮细胞，以及是否存在活性依赖性 抑制突触的短期调制。兴奋性存在长期突触可塑性 平行纤维突触到锥体和卡特轮细胞上。我们将测试是否来自 卡特轮到锥体细胞，在卡特轮细胞之间表现出相似的活动依赖性塑性变化。 在第三个目标中，我们将使用我们的实验数据来创建DCN的生物准确的电路模型。 我们将使用此模型测试有关突触功能如何与听力相关的预测 损失会影响核的产出。在第四个目标中，我们将测试中央耳鸣的假设 通过声学创伤产生的与抑制性突触强度的降低有关，或者是否是 与内在电兴奋性提高有关。 耳鸣是一种影响美国近20％的人的现象，几乎使人衰弱 200万公民。对有效治疗有很大的未满足医疗需求。我们的实验会 直接评估可以针对药理学的特定突触系统和受体 治疗和治愈此持续问题的干预措施。