Circuitry and physiology of unipolar brush cells in the auditory system

 描述（由申请人提供）：耳蜗背核（DCN）将各种多感觉输入与听觉神经信号整合在一起，以计算声音相对于身体位置的位置。DCN的听觉输入损失有助于增强多感觉输入，并可能导致DCN的活动过度，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耳鸣中发生的听觉处理和病理生理学至关重要。来自不同脑区的多感觉输入通过苔藓纤维（MF）传送到DCN。微纤维支配颗粒细胞和单极刷状细胞（UBC）。UBC是一种能神经元，其在其刷状树突处接收单个MF输入，并投射到颗粒细胞的集合体，其平行纤维轴突调节DCN的主（梭形）细胞的活性。最近，Trussell实验室已经表明，UBC对MF输入的反应是显著增加或减少放电数秒，这取决于它们的ON或OFF亚型。ON UBC可以放大来自单个MF输入的信号，同步并增强许多突触后颗粒细胞的放电。因此，除了放大来源不明的特定多感觉通道外，UBC还可能导致与耳鸣相关的病理性增强的DCN活性。为了理解多感觉整合是如何发生的，必须确定UBC输入的性质以及UBC如何将信息传递给DCN回路中的其他细胞。 该提议的目的是测试：（1）将MF投射到UBC的神经元起源于何处以及它们代表什么感觉模态，以及（2）它们提供的信息如何整合到DCN回路中。在目标1中，我将使用最先进的解剖追踪方法来识别支配UBC的MF投影。这将阐明由UBC处理的信号的来源和感觉模态。几个候选区域的项目MFs DCN携带本体感受，运动和更高层次的听觉反馈信息，但目前还不清楚他们是否支配UBC。我会确定是哪个 来源支配UBC以及ON和OFF UBC亚型是否都是靶向的。在目的2中，我将通过在UBC投射源中表达通道视紫红质来表征识别的MF输入到UBC的电生理功能。使用双光子显微镜，我将定义的空间投影模式的UBC轴突DCN和成对的电生理记录，以测试MF输入之间的UBC和突触后颗粒细胞的转换。 这项研究将确定DCN电路的一个主要缺失部分：UBC处理什么信息以及它们对颗粒细胞系统的影响。这些信息的转换UBCs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在兴奋性信号放大中的潜在作用，这项工作可能会为耳鸣提供见解，耳鸣是一种与DCN过度活跃相关的常见疾病。

 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.