Cellular properties mediating specialization of lateral superior olive principal neuron types for timing and intensity based sound localization

介导外侧上橄榄主要神经元类型专业化的细胞特性，用于基于时间和强度的声音定位

• 批准号: 9919441
• 负责人: Bradley D Winters
• 金额: $ 15.6万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9919441
• 关键词: Action Potentials; Binaural; Brain; Brain Stem; Brain region; Caliber; Cells; Characteristics; Code; Contralateral; Cues; Cyclic Nucleotides; Data; Dendrites; Ear; Equilibrium; Erythrocytes; Event; Fire - disasters; Foundations; Frequencies; GLYT2; Glutamates; Glycine; Grouping; Hearing; In Vitro; Ion Channel; Ipsilateral; Mammals; Measurement; Measures; Mediating; Membrane; Methodology; Modeling; Morphology; Mus; Neurons; Patch-Clamp Techniques; Pattern; Phase; Physiology; Process; Property; Reporter; Resistance; Role; Signal Transduction; Slice; Sodium Channel; Sound Localization; Synapses; Synaptic Potentials; Synaptic plasticity; System; Tail; Testing; Time; Training; Transgenic Mice; Work; attenuation; base; cell type; cyclic-nucleotide gated ion channels; density; electrical property; expectation; experimental study; insight; lateral superior olive; medial superior olive; mouse model; multiphoton imaging; neuronal cell body; prevent; programs; rate of change; response; segregation; selective attention; superior olivary nucleus; vesicular glutamate transporter 2; voltage; voltage clamp

Project abstract Principal neurons (PNs) of the lateral superior olive (LSO) in the brainstem of mammals are a key component in the processing of binaural cues used for sound localization that underlie selective attention. They accomplish this by comparing excitatory synaptic inputs driven by the ipsilateral ear with inhibitory inputs driven by the contralateral ear. It is increasingly appreciated that along with their classical role of interaural intensity difference (IID) coding, LSO PNs also encode interaural time differences (ITDs). These two functional roles, along with the tonotopic organization of the LSO, place different demands on the cellular properties of LSO neurons. My major hypothesis is that there is functional segregation of LSO PNs for IID and ITD coding. This functional segregation may be defined by transmitter released, projection pattern, morphology, dendritic integration functions, or synaptic inputs. This proposal will develop core methodologies to access these cellular features of the LSO. Excitatory LSO PNs are biased to higher frequency regions and largely project contralaterally while inhibitory cells are biased to lower frequencies and project Ipsilaterally. Firing response characteristics associated with phase locking and ITD coding are biased toward lower frequency regions, potentially associating with inhibitory PNs. I will investigate the possibility that ipsilateral projecting inhibitory PNs are better adapted for ITD coding while contralateral projecting excitatory PNs are better adapted for IID coding. This potentially provides a means to segregate this information in upstream centers. Critical for understanding whether inhibitory and excitatory cells have distinct functional roles within the circuit is their relative intrinsic cellular properties. To efficiently investigate this I will develop a transgenic mouse line that will allow me to target excitatory and inhibitory cell types during brain slice physiology experiments. My expectation is that inhibitory/ITD coding cells would have lower input resistances, faster membrane time constants, larger diameter and less complicated dendrites, and phasic firing type, whereas, excitatory/IID coding will be associated with more integrative membrane properties. These experiments will yield foundational insights into the cellular organization of the LSO. Efficacy of propagation of action potentials and synaptic potentials in dendrites is a critical component of integrative functions and synaptic plasticity in neurons which cannot be measured from somatic recordings alone. Recent work has revealed dendritic properties that have adapted for ITD coding. In contrast, almost nothing is known of the electrical properties of LSO dendrites or what aspects of dendritic physiology best support IID coding. I will develop methodologies using multiphoton imaging to make unbiased dual dendritic/somatic patch recordings from LSO neurons which allow for the analysis not only of local responses in the dendrites but also signal transformations with propagation to the soma. Combining this information with our developing understanding of the different coding demands on cells along the tonotopic axis, and potentially between PN types, will yield new insights into the relationship between cellular properties and circuit function.

项目摘要 哺乳动物脑干的横向上橄榄（LSO）的主要神经元（PNS）是关键组成部分 用于选择性关注的声音定位的双耳线索的处理。他们做到了 通过比较由同侧耳朵驱动的兴奋性突触输入与由抑制性输入驱动的 对侧耳朵。越来越多地赞赏的是，随着他们的经典作用 （IID）编码，LSO PNS还编码室内时间差（ITD）。这两个功能角色以及 LSO的吨位组织对LSO神经元的细胞特性提出了不同的需求。我的专业 假设是IID和ITD编码的LSO PNS有功能分离。这个功能分离 可以通过释放的发射机，投影模式，形态，树突整合功能来定义，或 突触输入。该建议将开发核心方法，以访问LSO的这些细胞特征。 兴奋性的LSO PN偏向更高的频率区域，并且在很大程度上会对侧进行抑制 细胞偏向较低的频率和同侧投射。发射响应特征与 相位锁定和ITD编码偏向较低的频率区域，可能与抑制 PNS。我将调查同侧投影抑制性PN的可能性，更好地适应ITD编码 尽管对侧投影兴奋性PN可以更好地适用于IID编码。这有可能提供一种手段 在上游中心隔离这些信息。了解抑制和兴奋是否至关重要 细胞在电路中具有不同的功能作用是它们的相对固有细胞特性。有效 调查这一点，我将开发一个转基因小鼠系，这将使我能够靶向兴奋性和抑制性细胞 大脑切片生理实验期间的类型。我的期望是抑制/ITD编码单元将具有 较低的输入电阻，更快的膜时间常数，较大的直径和较少复杂的树突，并且 阶段性发射类型，而兴奋性/IID编码将与更整合的膜特性相关联。 这些实验将对LSO的细胞组织产生基本见解。功效 树突中的动作电位和突触电位的传播是综合的关键组成部分 神经元的功能和突触可塑性不能仅从体细胞记录中测量。最近的 工作揭示了适用于ITD编码的树突特性。相比之下，几乎什么都不知道 LSO树突的电性能或树突生理学的哪些方面最佳支持IID编码。我会 使用多光子成像制定方法，以制作公正的双树种/体贴片记录 来自LSO神经元，不仅可以分析树突中的局部反应，还可以发出信号 传播到躯体的转变。将这些信息与我们对 对沿吨位轴的细胞以及PN类型之间的细胞的不同编码需求将产生新的 洞悉细胞性质与电路函数之间的关系。