Information Transfer at Auditory Nerve Synapses

项目概述：与正常活动时的所有突触一样，听神经纤维与耳蜗核丛状细胞形成的终球突触在突触强度上表现出使用依赖性变化。在正常的听神经放电速率下，终球突触表现出相当大的抑制，这可能对丛状细胞的行为作用产生重大影响，这些行为作用包括传递和改善听神经尖峰的时间以进行声音定位；然而，在生理条件下，这些变化的动力学尚不清楚。这个项目的具体目的是确定突触强度的使用依赖性变化的动态，以及它们背后的机制。这项工作将使用膜片钳记录小鼠脑切片中的丛状细胞。抑郁的机制将首先考虑，通过测试突触前囊泡耗竭和突触后受体脱敏和饱和的贡献。此外，还将研究终末球一种不寻常的凹陷形式，这被认为与突触前钙流入减少有关，但从未直接测试过。它还将确定抑郁症是如何通过恢复过程和促进来减轻的，以及这些过程如何依赖于突触前钙水平。此外，该突触的高水平活动可导致显著的延迟释放。目前的钳子研究将测试延迟释放是否会破坏浓密细胞的精确定时反应。突触前钙水平对延迟释放的贡献也将被检查。综上所述，这些研究将提供关于听觉神经突触在现实活动中转换时间信息的机制的重要信息。相关性：这项工作可能有助于提高人工耳蜗植入的效率，通过识别听神经刺激的模式，将有效，或无效，当由耳蜗核处理。这项工作还将为直接刺激大脑的植入物提供信息，用于缺乏听觉神经功能的患者。

DESCRIPTION (provided by applicant): Project Summary: Like all synapses during normal activity, endbulb synapses formed by auditory nerve fibers onto cochlear nucleus bushy cells show use-dependent changes in synaptic strength. At normal auditory nerve firing rates, endbulb synapses show considerable depression, which can have a major impact on the bushy cell's behavioral role of relaying and improving the timing of auditory nerve spikes for sound localization; however, the kinetics of these changes are not well understood under physiological conditions. The specific aims of this project are to determine the dynamics of use-dependent changes in synaptic strength, as well as the mechanisms underlying them. This work will be carried out using patch-clamp recordings of bushy cells in mouse brain slices. The mechanisms of depression will be considered first, by testing the contributions of presynaptic vesicle depletion and postsynaptic receptor desensitization and saturation. In addition, an unusual form of depression at the endbulb will be examined, which has been proposed to involve reduced presynaptic calcium influx, but has never been directly tested. It will also be determined how depression is mitigated by both recovery processes and facilitation, and how these processes depend on presynaptic calcium levels. In addition, high levels of activity at this synapse can lead to significant delayed release. Current clamp studies will test whether delayed release disrupts the precisely timed responses of bushy cells. The contribution of presynaptic calcium levels to delayed release will also be examined. Taken together, these studies will provide important information about the mechanisms by which timing information is transformed by auditory nerve synapses during realistic activity. Relevance: This work may help to improve the efficiency of cochlear implants, by identifying patterns of auditory nerve stimulation that will be effective, or ineffective, when processed by the cochlear nucleus. This work will also provide information for implants that stimulate the brain directly, for patients who lack a functioning auditory nerve.