Cellular diversity underlying timing- and intensity-based sound localization in the superior olivary complex

上橄榄复合体中基于时间和强度的声音定位的细胞多样性

• 批准号: 10817312
• 负责人: Bradley D Winters
• 金额: $ 20.28万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10817312
• 关键词: Action Potentials; Attention; Auditory; Auditory Perceptual Disorders; Bilateral; Biophysics; Brain; Brain Stem; Calcium; Calcium Channel; Cells; Child; Code; Complement; Complex; Comprehension; Computer Models; Contralateral; Coupling; Data; Dendrites; Disease; Disparate; Ear; Electrophysiology (science); Environment; Equilibrium; Exhibits; Gene Expression; Image; In Situ Hybridization; Ion Channel; Ipsilateral; Kinetics; Knowledge; Location; Mammals; Methodology; Morphology; Mus; Neurons; Patch-Clamp Techniques; Pattern; Phase; Physiology; Play; Population; Process; Property; Reporter; Reporter Genes; Reporting; Role; Signal Transduction; Slice; Sodium; Sodium Channel; Sound Localization; Source; Speech; Stimulus; Supporting Cell; Synapses; System; Testing; Thinking; Time; Transgenic Organisms; Update; attenuation; cell type; density; design; differential expression; experimental study; imaging modality; improved; information organization; information processing; innovation; insight; lateral superior olive; models and simulation; neurophysiology; patch clamp; patch sequencing; response; segregation; sound; synergism; transcriptome; transcriptomics; transmission process; two-photon; voltage

Project abstract The superior olivary complex (SOC) in the brainstem of mammals integrates information from the two ears to localize sound sources and enable selective auditory attention. The lateral superior olive (LSO) plays a critical role in these functions. Principal neurons (PNs) of the lateral superior olive (LSO) compare excitatory inputs driven by the ipsilateral ear with inhibitory inputs driven by the contralateral ear. The cellular properties of LSO PNs are fundamental to how they encode and transmit information; however, critical cellular mechanisms are not yet resolved. The classical view of the LSO is that it extracts ongoing interaural level differences (ILDs). Recent reports challenge this thinking, suggesting the major function of LSO is encoding interaural time differences (ITDs) for brief sounds or amplitude modulations. Currently it is not clear whether the LSO is primarily performing one of these functions or both, however, these roles place disparate demands on the cellular properties of LSO neurons. Furthermore, there is cellular diversity among LSO PNs that is not fully explored. Our overarching hypothesis is that there are LSO PN populations adapted for ILD and ITD coding and that their intrinsic properties, transmitter systems, and projection patterns provide a means to organize this information in higher centers. This project will yield foundational insights into the cellular organization of the SOC which may be disrupted in poorly understood disease states such as auditory processing disorder. There are inhibitory (I) and excitatory (E) LSO PNs that exhibit different projection patterns. A major gap in our knowledge is that intrinsic cellular differences between these I/E cell types has not been examined. We will target I/E cells for ex vivo experiments using established reporter mouse lines. Aim 1 will examine the intrinsic properties of I/E LSO PNs using ex vivo patch-clamp and two-photon imaging in brain slices from transgenic reporter mice, in situ hybridization, tract tracing, and transcriptomic approaches. Synaptic drive and integrative properties of LSO neurons could accentuate or offset intrinsic differences. In Aim 2 we will examine the number, strength, and short-term dynamics of synaptic inputs onto I/E cell types. Biophysically-based computational models that facilitate the systematic study of synaptic differences and firing types on ILD/ITD coding strategies will complement our ex vivo experiments. How signals propagate in dendrites is a critical component of integrative functions in neurons. Almost nothing is known of the dendritic physiology of LSO neurons. In Aim 3 we will use dual dendritic/somatic patch-clamp technique in targeted LSO neuron types to analyze local responses as well as signal transformations that occur with propagation. Higher throughput two-photon calcium imaging methods will also be used to assess signal propagation. Together these experiments will expand our view of the functional role of LSO cell types and sound localization coding strategies. This proposal is conceptually innovative in its treatment of the LSO as a diverse group with cellular properties tuned for multiple functional roles and methodologically innovative in our use of transcriptomics and dendritic patch-clamp.

项目摘要 哺乳动物脑干的上级橄榄络合物（SOC）将两只耳朵的信息整合到 本地化声音来源并引起选择性听觉的关注。横向上级橄榄（LSO）发挥着关键 在这些功能中的作用。横向上橄榄（LSO）的主神经元（PNS）比较兴奋性输入 由同侧耳朵驱动，并由对侧耳朵驱动。 LSO的细胞特性 PNS是它们如何编码和传输信息的基础；但是，关键的细胞机制不是 尚未解决。 LSO的经典观点是它提取了正在进行的跨层间差异（ILD）。最近的 报告挑战了这一思维，表明LSO的主要功能是编码室内时间差异 （ITD）用于简短的声音或振幅调制。目前尚不清楚LSO是否主要执行 但是，这些功能之一或两者兼有，这些角色对LSO的细胞性质提出了不同的需求 神经元。此外，LSO PNS之间存在细胞多样性。我们的总体 假设是有适用于ILD和ITD编码的LSO PN种群 属性，发射器系统和投影模式提供了一种在较高中组织此信息的方法 中心。该项目将对SOC的细胞组织产生基本见解，这可能是 在知识渊博的疾病状态（例如听觉加工障碍）中被破坏。 有抑制性（i）和兴奋性（e）LSO PN，它们表现出不同的投影模式。一个主要差距 我们的知识是，尚未检查这些I/E细胞类型之间的固有细胞差异。我们将 靶向I/E细胞，用于使用已建立的报告鼠标线的体内实验。 AIM 1将检查固有的 I/E LSO PNS的特性，使用离体贴片夹和转基因中的脑切片中的两光片成像 记者小鼠，原位杂交，道跟踪和转录组方法。突触驱动和综合驱动器 LSO神经元的特性可以突出或抵消固有差异。在AIM 2中，我们将检查数字， 突触输入I/E细胞类型的突触输入的强度和短期动力学。基于生物物理的计算 促进ILD/ITD编码策略的突触差异和发射类型的系统研究的模型 将补充我们的离体实验。信号如何在树突中传播是 神经元中的综合功能。 LSO神经元的树突生理学几乎一无所知。在目标3中我们 将在靶向LSO神经元类型中使用双重树突/体细节钳技术来分析局部反应 以及传播发生的信号转换。较高的吞吐量两光子钙成像 方法还将用于评估信号传播。这些实验将共同扩大我们对 LSO细胞类型和声音定位编码策略的功能作用。该建议在概念上是 在将LSO作为多元化群体的治疗中，具有多种功能作用的细胞特性的创新性 以及我们对转录组学和树突状贴剂钳的使用方面的创新。