Circuitry and physiology of unipolar brush cells in the auditory system

听觉系统中单极刷细胞的电路和生理学

• 批准号: 8980416
• 负责人: Timothy S Balmer
• 金额: $ 5.07万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8980416
• 关键词: Acoustic Nerve; Area; Auditory; Auditory system; Axon; Brain region; Brush Cell; Cell physiology; Cells; Cytoplasmic Granules; Dendrites; Disease; Dyes; Event; Feedback; Fiber; Functional disorder; Fusiform Cell; Glutamates; Head; Hyperactive behavior; In Vitro; Inferior; Interneurons; Label; Lead; Light; Location; Mediating; Methods; Microscopy; Modality; Motor; Mus; Nature; Neurons; Pattern; Physiology; Play; Pontine structure; Positioning Attribute; Presynaptic Terminals; Process; Proprioception; Rabies; Recombinants; Relative (related person); Research; Research Training; Role; Sensory; Signal Transduction; Source; Synapses; System; Testing; Tin; Tinnitus; Viral; Work; anatomical tracing; auditory feedback; body position; calretinin; cell type; dorsal cochlear nucleus; external ear auricle; fluorophore; granule cell; insight; metabotropic glutamate receptor 2; mossy fiber; multisensory; neurotransmission; patch clamp; postsynaptic; presynaptic; public health relevance; research study; response; signal processing; somatosensory; sound; two-photon

 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.

 描述（由申请人提供）：耳蜗背核（DCN）将多种多感觉输入与听觉神经信号相结合，以计算声音相对于身体位置的位置。 DCN 听觉输入的丧失会导致多感觉输入的增强，并可能导致 DCN 过度活跃，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。来自不同大脑区域的多感觉输入通过苔藓纤维 (MF) 传送到 DCN。 MF 支配颗粒细胞和单极刷细胞 (UBC)。 UBC 是谷氨酸能中间神经元，在其刷状树突处接收单个 MF 输入，并投射到颗粒细胞群，其平行纤维轴突调节 DCN 主（梭形）细胞的活动。最近，Trussell 实验室表明，UBC 对 MF 输入的响应是显着增加或减少几秒的发射，具体取决于它们的 ON 或 OFF 子类型。 ON UBC 可以放大来自单个 MF 输入的信号，同步并增强大量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 还可能有助于病理性增强与耳鸣相关的 DCN 活性。要了解多感官整合如何发生，必须确定 UBC 输入的性质以及 UBC 如何将信息传输到 DCN 电路中的其他细胞。 该提案的目的是测试：（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式，以及（2）它们提供的信息如何集成到 DCN 电路中。在目标 1 中，我将使用尖端的解剖追踪方法来识别支配 UBC 的 MF 投射。这将阐明 UBC 处理的信号的来源和感觉方式。将 MF 投射到 DCN 的几个候选区域携带本体感觉、运动和更高级别的听觉反馈信息，但尚不清楚它们是否支配 UBC。我将确定哪个 来源支配 UBC 以及 ON 和 OFF UBC 亚型是否都是目标。在目标 2 中，我将通过在 UBC 投影源中表达通道视紫红质，以电生理学方式表征已识别的 UBC MF 输入的功能。使用 2 光子显微镜，我将定义 DCN 内 UBC 轴突的空间投影模式，并进行配对电生理记录，以测试 MF 输入如何在 UBC 和突触后颗粒细胞之间转换。 这项研究将确定 DCN 回路的一个主要缺失部分：UBC 处理哪些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 的多感官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，这项工作可能会提供对耳鸣（一种与 DCN 过度活跃相关的常见疾病）的深入了解。