Information processing at auditory nerve synapses

描述（由申请人提供）：声音由耳蜗在听神经尖峰的时间内编码。听觉神经纤维通过被称为“尾球”的突触汇聚到耳蜗核的浓密细胞上。这种趋同导致了由丛状细胞传递给高级听觉中心的时间信息的变化，这可能会影响声音的定位和处理。实验表明，丛状细胞尖峰的时间在很大程度上受终球突触电流大小的影响，而终球突触电流在体内受两种主要影响。首先，终球突触在正常频率下被激活时表现出相当大的抑制。其次，它们受制于许多神经调节系统。这两种影响都可以影响浓密细胞携带的信息，但两者都没有得到很好的理解。该项目的具体目标是确定(1)终球突触电流中使用依赖性变化的动力学和机制，(2)突触电流的不同组成部分如何控制丛细胞计时，以及(3)神经调节如何改变这些关系。这项工作将使用膜片钳对取自老鼠和沙鼠的大脑切片中的浓密细胞进行记录。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。还将确定如何通过促进和激活NMDA受体来减轻抑郁症。此外，电流钳和动态钳的研究将测试在高水平活动时延迟释放是否会扰乱丛状细胞的精确定时反应。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通过收敛转换时间信息的机制的重要信息。这项工作将研究耳蜗核细胞处理声音信息的机制。它还将为了解不同受体类型和神经调节系统在神经元计算中的功能作用提供重要的见解。这项工作可能会导致现有的人工耳蜗和直接刺激耳蜗核的人工耳蜗的改进。

DESCRIPTION (provided by applicant): Sounds are encoded by the cochlea in the timing of spikes in the auditory nerve. Auditory nerve fibers converge onto bushy cells in the cochlear nucleus, through synapses called "endbulbs of Held". This convergence leads to changes in the timing information passed on by bushy cells to higher auditory centers, which may affect sound localization and processing. Experiments have indicated that the timing of bushy cell spiking is greatly affected by the size of the endbulb synaptic current, which is subject to 2 major influences in vivo. First, endbulb synapses show considerable depression when activated at normal rates. Second, they are subject to a number of neuromodulatory systems. Both these influences can affect the information carried by bushy cells, but neither is well understood. The specific aims of this project are to determine (1) the dynamics and mechanisms of use-dependent changes in the endbulb synaptic current, (2) how the different components of the synaptic current control bushy cell timing, and (3) how neuromodulation changes these relationships. This work will be carried out using patch-clamp recordings of bushy cells in brain slices taken from mice and gerbils. 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 could be mitigated by both facilitation and the activation of NMDA receptors. In addition, current-and dynamic-clamp studies will test whether delayed release during high levels of activity disrupts the precisely timed responses of bushy cells. Taken together, these studies will provide important information about the mechanisms by which timing information is transformed by convergence of auditory nerve synapses during realistic activity. This work will examine the mechanisms used by cells in the cochlear nucleus to process sound information. It will also provide important insights into the functional role that different receptor types and neuromodulatory systems play in neuronal computation. This work may lead to improvements both in existing cochlear implants and in implants that stimulate the cochlear nucleus directly.