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（由应用程序提供）：背部耳蜗核us（DCN）将潜水员的多感官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官输入，并可能导致DCN的多动症，DCN（这是与耳鸣高度相关的事件。阐明DCN的多感官电路对于理解耳鸣中发生的听觉加工和病理生理学至关重要。来自不同大脑区域的多感官输入通过苔藓纤维（MFS）携带到DCN。 MFS支配颗粒细胞和单极刷细胞（UBC）。 UBC是谷氨酸能中间神经元，在其刷状的树突上接收单个MF输入，并投影到颗粒细胞的集合，其平行纤维轴突调节了DCN的主（fusiorper）细胞的活性。最近，Trussell Lab表明，UBCS通过显着增加或减少点火来响应MF输入，这取决于其开启或关闭亚型。在UBC上可以扩增单个MF输入的信号，同步并增强众多突触后颗粒细胞的发射。除了放大未知来源的特定多感官通道外，UBC还可以有助于与耳鸣相关的病理增强的DCN活性。要了解多感觉整合的发生是必不可少的，必须确定输入的性质，以及UBC如何将信息传输到DCN电路中的其他单元。该提案的目的是测试：（1）将MFS启动的神经元发起的神经元以及它们所代表的感觉方式，以及（2）它们提供的信息如何集成在DCN电路中。在AIM 1中，我将使用尖端的解剖示踪方法来识别支配UBC的MF项目。这将阐明UBC处理的信号的源和感觉方式。将MF投射到DCN的几个候选区域具有本体感受，电机和高级听觉反馈信息，但尚不清楚它们是否支配UBC。我将确定哪个 来源支配UBC以及是否针对UBC子类型。在AIM 2中，我将通过在UBC投影源中表达通道Ropopsin来表征UBC对UBC的MF输入的功能。使用2光子显微镜I将定义DCN中UBC轴突的空间投影模式，并使配对的电生理记录测试如何在UBC和突触后颗粒细胞之间转化MF输入。这项研究将确定DCN电路的主要缺失部分：UBCS过程及其对颗粒细胞系统的影响。 UBCS对此信息的转换很可能在DCN中的多感觉集成和声源定位中起主要作用。由于UBCS在兴奋性信号的扩增中的潜在作用，这项工作可能会提供对耳鸣的见解，Tinnitus是与DCN多动相关的常见疾病。