Function and regulation of action potential bursts in the auditory system.

描述（由申请人提供）：听觉脑干耳蜗背核（DCN）中的电路被认为有助于使用单耳线索在垂直平面上定位声音。此外，DCN电路集成了听觉和非听觉输入，以帮助定位声音或抑制自产生的噪声，从而增加外部声音的显著性。我们的长期目标是了解促成这些功能的突触机制。多感觉统合在一定程度上是由抑制性侧翻细胞的高频动作电位爆发控制的；然而，脉冲是如何产生的，以及脉冲抑制对突触后整合的影响，目前仍不清楚。本研究的目的是确定控制突发产生的机制，重点关注位于轴突初始段动作电位起始部位的新发现的低阈值激活钙通道的作用。首先，我们将结合电生理学和双光子成像来识别通过调节初始段钙通道活性来控制神经元输出的信号通路。其次，我们将利用新的电压成像技术来确定钙通道如何在初始段产生脉冲。最后，我们将确定抑制性突触输入如何影响DCN输出神经元的整合，梭状细胞，对比单一动作电位和脉冲的影响。

DESCRIPTION (provided by applicant): Circuits in the auditory brainstem dorsal cochlear nucleus (DCN) are believed to aid in sound localization in the vertical plane using monaural cues. Moreover, DCN circuitry integrates auditory and non-auditory inputs to aid in orientation toward sounds or to suppress self-generated noise, thereby increasing the salience of external sounds. Our long-term goal is to understand the synaptic mechanisms that contribute to these functions. Multisensory integration is controlled, in part, by high-frequency action potential bursts from inhibitory cartwheel cells; yet the way in which bursts are generated, and the effects of burst inhibition on postsynaptic integration, remain unclear. The objective of this proposal is to define mechanisms governing burst generation, focusing on the role of newly-discovered low-threshold activated calcium channels localized to the site of action potential initiation in the axon initial segment. First, we will use a combination of electrophysiology and 2-photon imaging to identify signaling pathways that control neuronal output by regulating initial segment calcium channel activity. Second, we will take advantage of novel voltage imaging techniques to determine how calcium channels contribute to the generation of bursts in the initial segment. Finally, we will determine how inhibitory synaptic input affects integration in the efferent neurons of the DCN, fusiform cells, contrasting the effects of single action potentials and bursts. PUBLIC HEALTH RELEVANCE: Dysfunctions in low-voltage activated calcium channel activity contributes to hyperexcitability in many brain regions, and may be etiological to tinnitus and epilepsy. This proposal examines the function and regulation of low-voltage activated calcium channels localized to the site of action potential initiation. Understanding how these channels affect neuronal output may uncover new avenues for treatment of hyperexcitability conditions.