Physiology of Dorsal Cochlear Nucleus Molecular Layer

耳蜗背核(DCN)是对频谱复杂声音进行快速和早期处理的场所， 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中自发活动的增加也与耳鸣有关。 电兴奋性的增加或抑制的减少可以导致DCN神经元活动的增加 因此，耳鸣的潜在机制。而DCN主神经元(锥体细胞)对 声音是由抑制强烈塑造的，对主要抑制的功能操作知之甚少 网络。这项建议的目的是研究DCN中的抑制回路，并阐明它们的 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 DCN局部抑制回路的组织和突触动力学，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--车轮细胞--的突触影响， 取决于目标单元格的类型，以及侧翻单元格是否可以像预测的那样以同步方式启动 从它们的生理和联系来看。我们将检验有关侧翻的空间组织的假设 细胞轴突，以确定这个接受非紧张性输入的系统是否可能在 音调时尚。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中抑制性突触的可塑性。我们将测试车轮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，以及是否存在活性依赖 抑制性突触的短期调制。兴奋性突触存在长期的可塑性。 平行纤维突触分布于锥体细胞和车轮细胞上。我们将测试抑制性突触是否来自 侧翻到锥体细胞，以及侧翻细胞之间，都表现出类似的依赖于活动的可塑性变化。 在第三个目标中，我们将使用我们的实验数据来创建DCN的生物准确电路模型。 我们将使用这个模型来测试有关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，我们将检验中枢性耳鸣的假设 由声创伤产生的信号与抑制性突触强度的降低或是否有关 与增加的内在电兴奋性有关。 在美国，耳鸣是一种影响近20%的人的现象，使人虚弱到近 200万公民。对于有效的治疗，还有大量未得到满足的医疗需求。我们的实验将 直接评估可作为药理学靶点的特定突触系统和受体 对这一顽固问题的治疗和治愈的干预。

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.