The role of dendritic inputs in high-fidelity temporal processing of phase-coding neurons in the mammalian anteroventral cochlear nucleus

耳蜗前腹核的球状丛状细胞(SBC)以微秒级的精度编码听觉刺激的时间结构。为此，听觉脑干电路显示出显著的任务专门化程度，特别是在用于超快和精确处理听觉信息的生物物理、细胞和突触硬件方面。然而，听觉脑干系统进化到在广泛的刺激条件下具有最佳功能，这需要神经元功能的快速适应。对此，同样终止于AVCN的抑制性和调节性输入是潜在的候选者。在DFG优先计划1608的最后一个资助期，我们发现乙酰胆碱是AVCN中时间编码神经元兴奋性的调节剂。在SBC中应用乙酰胆碱瞬时地(毫秒到秒)和强直地(几分钟)去极化静息膜电位。因此，它在两个不同的时间尺度上起作用。我们已经可以证明，快速去极化是由离子亲和性α-7 AChR介导的。在这个项目的第二个资助阶段，我们现在想要详细说明乙酰胆碱在AVCN中作用的细胞机制。最初，我们想把重点放在紧张性调节反应的突触后效应器上。接下来，我们想要系统地分析是否可以证实对保持突触的终球的突触前释放概率有调制作用的迹象。最后，我们想要研究联合胆碱能影响对SBC输出尖峰的时间敏锐度的影响。这些实验将在沙土鼠听觉脑干的急性脑片制备中进行。我们将结合膜电位/电流的全细胞记录、药物的局部施压和轴突连接的电刺激来解决我们的问题。除了体外实验，我们还希望应用一个数据受限的球形丛生细胞的计算机模型，该模型是在资金第一阶段创建的。这将使我们能够系统地研究调制输入和树突刺激在各种模拟声音刺激范例下的影响。这项拨款申请中提出的实验的目的是研究一种赋予听觉系统超快和精确的听觉脑干电路刺激特异性适应性的机制。

Spherical bushy cells (SBC) of the anteroventral cochlear nucleus code the temporal structure of the auditory stimulus with microsecond precision. For this the auditory brainstem circuitry shows a remarkable degree of task-specific specialization, especially regarding the biophysical, cellular and synaptic hardware for ultrafast and precise processing of auditory information. Auditory brainstem systems evolved however to optimally function over a wide range of stimulus conditions, which demands rapid adaptability of the neuronal function. For this, inhibitory and modulatory inputs that also terminate in the AVCN are potential candidates. In the last funding period of DFG priority program 1608 we identified acetylcholine as a modulator of the excitability of time-coding neurons in the AVCN. Application of acetylcholine to SBC transiently (milliseconds to seconds) and also tonically (several minutes) depolarizes the resting membrane potential. It thus acts on two different time scales. We could already show that the rapid depolarization is mediated by ionotropic alpha-7 AChR.In the second funding phase of this project we now want to elaborate on the cellular mechanisms by which acetylcholine acts in the AVCN. Initially we want to focus on postsynaptic effectors of the tonic modulatory response. Next, we want to systematically analyze whether indications of a modulatory effect on the presynaptic release probability of the endbulb of Held synapse can be confirmed. Finally, we want to study the effect the combined cholinergic influence has on the temporal acuity of the SBC output spiking.These experiments will be performed in acute slice preparations of the gerbil auditory brainstem. A combination of whole-cell recordings of membrane potentials/currents, local pressure application of pharmacological agents and electrical stimulation of axonal connections will be used to address our questions. In addition to the in-vitro experiments we want to apply a data-constrained computer model of the spherical bushy cells, which was created in funding phase 1. This will allow us to systematically study the effect of modulatory inputs and dendritic excitation under a wide variety of simulated sound-stimulus paradigms.It is the objective of the experiments proposed in this grant application to study a mechanism that imparts stimulus-specific adaptability to the ultra-fast and precise auditory brainstem circuitry of the auditory system.