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 哺乳动物脑干外侧上橄榄核(LSO)的主神经元(PNS)是中枢神经系统的重要组成部分 对双耳线索的处理，用于声音定位，是选择性注意的基础。他们做到了这一点 通过比较同侧耳朵驱动的兴奋性突触输入和由同侧耳朵驱动的抑制性输入 对侧耳。人们越来越认识到，除了它们在耳间强度差异方面的经典作用 (IID)编码，LSO PNS还对耳间时差(ITD)进行编码。这两个功能角色，以及 LSO的定位组织，对LSO神经元的细胞特性提出了不同的要求。我的专业 假设IID和ITD编码存在LSO PN的功能分离。这种功能隔离 可由发射器释放、投射图案、形态、树突整合功能或 突触输入。这项提案将开发核心方法，以利用LSO的这些蜂窝功能。 兴奋性LSO PN偏向高频区，主要以对侧投射为主，同时具有抑制性 细胞偏向于较低的频率并向同侧投射。与以下内容相关的发射响应特征 锁相和ITD编码偏向较低频率区域，潜在地与抑制相关 PNS。我将研究同侧投射抑制性孤束核更适合ITD编码的可能性 而对侧投射兴奋性PN更适合于IID编码。这潜在地提供了一种手段 将这些信息隔离在上游中心。对于理解抑制性和兴奋性 细胞在电路内具有明显的功能作用，是它们相对固有的细胞属性。高效地 为此，我将开发一种转基因小鼠品系，使我能够靶向兴奋性和抑制性细胞。 脑片生理学实验中的类型。我的预期是抑制/ITD编码细胞会有 更低的输入电阻，更快的膜时间常数，更大的直径和更少的树枝晶，以及 相激型，而兴奋性/IID编码将与更综合的膜特性相关。 这些实验将对LSO的细胞组织产生基础性的见解。的功效 动作电位和突触电位在树突中的传播是整合的重要组成部分 神经元的功能和突触可塑性，不能仅从躯体记录中测量。近期 工作揭示了适应ITD编码的树枝状特性。相比之下，几乎什么都不知道。 LSO树枝晶的电学性质或树枝状生理的哪些方面最支持IID编码。这就做 开发使用多光子成像进行无偏双树突状/体细胞斑块记录的方法 来自LSO神经元，它不仅允许分析树突中的局部反应，而且还允许分析信号 传播到躯体的变形。将这一信息与我们对 沿音调轴对单元的不同编码要求，以及潜在地在PN类型之间的不同编码要求将产生新的 洞察细胞特性和电路功能之间的关系。