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部位， 并且是听觉系统中听觉和非听觉信息会聚的第一点。 听力损失后DCN的自发活动增加也与耳鸣有关。 电兴奋性增加或抑制性降低可导致DCN神经元活性增加， 因此是耳鸣的潜在机制。而DCN主神经元（锥体细胞）对 声音强烈地受到抑制的塑造，但对主要抑制性的功能运作知之甚少。 网络.本研究的目的是研究DCN中的抑制性回路，并阐明它们的作用机制。 在正常感觉处理和听觉功能障碍中的作用。在第一个目标中，我们将研究 组织和局部抑制电路的DCN的突触动力学，使用配对的全细胞记录。 我们将测试数量最多的抑制性中间神经元，侧手翻细胞， 这取决于目标细胞类型，以及侧手翻细胞是否能像预测的那样以同步方式激发 从他们的生理和连接。我们将测试关于侧手翻的空间组织的假设 细胞轴突，以确定这个系统，它接收非tonotopic输入，是否可能在一个 色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 共同传递到锥体细胞和其他车轮细胞，以及是否有活动依赖性 抑制性突触的短期调节。长时程突触可塑性存在于兴奋性的 平行纤维突触连接到锥体细胞和侧手翻细胞上。我们将测试是否抑制突触从 侧手翻到锥体细胞以及侧手翻细胞之间表现出类似的活性依赖性塑性变化。 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。 我们将使用这个模型来测试关于突触功能的变化如何与听力相关的预测 损耗会影响原子核的输出。在第四个目标中，我们将测试中枢性耳鸣的假设， 声创伤产生的抑制性突触强度降低，或者是否 与增加的内在电兴奋性有关。 耳鸣是一种影响近20%的美国人的现象，这会使人虚弱到 200万公民有效治疗的医疗需求显著未得到满足。我们的实验将 直接评估特定的突触系统和受体，可以靶向药理学 治疗和治愈这一长期问题干预措施。