Circuitry and physiology of unipolar brush cells in the auditory system

 描述(申请人提供)：耳蜗背核(DCN)将不同的多感觉输入与听神经信号相结合，以计算声音相对于身体位置的位置。失去对DCN的听觉输入有助于增强多感觉输入，并可能导致DCN的多动，这是一种与耳鸣高度相关的事件。阐明DCN的多感觉回路对于理解听觉处理和耳鸣的病理生理学都是至关重要的。来自不同脑区的多感觉输入通过苔藓纤维(MFS)传递到DCN。MFS支配颗粒细胞和单极刷状细胞(UBC)。UBC是谷氨酸能中间神经元，在其刷状树突接受单一的MF输入，并投射到颗粒细胞群，这些颗粒细胞的平行纤维轴突调节DCN主(梭形)细胞的活动。最近，特鲁塞尔实验室表明，UBC对MF输入的反应是显著增加或减少激发数秒，这取决于它们的ON或OFF亚型。在UBC上可以放大来自单个MF输入的信号，同步并增强众多突触后颗粒细胞的放电。因此，除了放大未知来源的特定多感觉通道外，UBC还可能有助于与耳鸣相关的DCN活性的病理性增强。要了解多感觉整合是如何发生的，关键是要确定UBC的输入的性质，以及UBC如何将信息传递到DCN电路中的其他细胞。这项提议的目的是测试：(1)向UBC投射MFS的神经元起源于哪里，它们代表什么感觉模式，以及(2)它们提供的信息如何整合到DCN回路中。在目标1中，我将使用尖端解剖学追踪方法来识别支配UBC的MF投射。这将阐明由UBC处理的信号的来源和感觉模式。将MFS投射到DCN的几个候选区域携带本体感觉、运动和更高水平的听觉反馈信息，但尚不清楚它们是否支配UBC。我会找出哪一个 来源支配UBC，以及是否同时针对On和Off UBC亚型。在目标2中，我将通过在UBC投射来源中表达通道视紫红质来表征已识别的MF输入到UBC的电生理功能。使用双光子显微镜，我将确定DCN内UBC轴突的空间投影模式，并进行成对的电生理记录，以测试MF输入是如何在UBC和突触后颗粒细胞之间转换的。这项研究将确定DCN电路中一个主要缺失的部分：UBC处理什么信息及其对颗粒细胞系统的影响。UBC对这些信息的转换可能在DCN的多感觉整合和声源定位中发挥重要作用。由于UBC在兴奋信号放大中的潜在作用，这项工作可能为耳鸣提供见解，耳鸣是一种与DCN多动相关的常见疾病。

 DESCRIPTION (provided by applicant): The dorsal cochlear nucleus (DCN) integrates diverse multisensory inputs with auditory nerve signals to compute the location of a sound relative to body position. Loss of auditory input to DCN contributes to enhancement of multisensory input and could lead to hyperactivity in DCN, an event highly associated with tinnitus. Elucidating the multisensory circuitry of DCN is critical for both understanding auditory processing and pathophysiology that occurs in tinnitus. Multisensory input from disparate brain regions is carried to DCN by mossy fibers (MFs). MFs innervate granule cells and unipolar brush cells (UBCs). UBCs are glutamatergic interneurons that receive a single MF input at their brush-like dendrite and project to ensembles of granule cells whose parallel fiber axons modulate the activity of principal (fusiform) cells of the DCN. Recently, the Trussell lab has shown that UBCs respond to MF inputs by either markedly increasing or decreasing firing for seconds, depending on their ON or OFF subtype. ON UBCs could amplify the signal from a single MF input, synchronizing and enhancing the firing of numerous postsynaptic granule cells. Thus, in addition to amplifying specific multisensory channels of unknown origin, UBCs could contribute to pathologically enhanced DCN activity that is associated with tinnitus. To understand how multisensory integration occurs it is essential to identify the nature of the inputs to UBCs and how UBCs transmit information to other cells in the DCN circuit. The purpose of this proposal is to test: (1) where the neurons that project MFs to UBCs originate and what sensory modalities they represent, and (2) how the information they provide is integrated in the DCN circuit. In Aim 1 I will use cutting-edge anatomical tracing methods to identify MF projections that innervate UBCs. This will elucidate the source and sensory modality of the signals processed by UBCs. Several candidate regions that project MFs to DCN carry proprioceptive, motor and higher-level auditory feedback information, but it is unclear whether they innervate UBCs. I will Identify which sources innervate UBCs and whether both ON and OFF UBC subtypes are targeted. In Aim 2 I will characterize the function of identified MF input to UBCs electrophysiologically by expressing channelrhodopsin in UBC projecting sources. Using 2-photon microscopy I will define the spatial projection pattern of UBC axons within DCN and make paired electrophysiological recordings to test how MF input is transformed between UBCs and postsynaptic granule cells. This research will identify a major missing piece of the DCN circuit: what information UBCs process and their effect on the granule cell system. Transformation of this information by UBCs is likely to play a major role in multisensory integration and sound source localization in DCN. Because of UBCs' potential role in the amplification of excitatory signals, this work may provide insights into tinnitus, a common disorder associated with DCN hyperactivity.