Mechanisms, functions and utility of RGC oscillation in retinal deafferentation mouse models

视网膜传入神经阻滞小鼠模型中 RGC 振荡的机制、功能和效用

• 批准号: 9327552
• 负责人: Ching-Kang Jason Chen
• 金额: $ 39.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9327552
• 关键词: Adult; Affect; Aging; Amacrine Cells; Biological Process; Brain; Cells; Characteristics; Cone; Coupled; Coupling; Deafferentation procedure; Development; Electroretinography; Ensure; Exhibits; Eye; Foundations; Future; Gap Junctions; Genes; Glutamate Receptor; Glutamates; Goals; Immunologic Markers; Individual; Investigation; Ipsilateral; Kinetics; Knock-out; Knowledge; Light; Light Cell; Maintenance; Masks; Mediating; Membrane; Membrane Potentials; Modeling; Morphology; Mus; Night Blindness; Outcome; Photoreceptors; Physiological; Potassium Channel; Predisposition; Property; Resources; Rest; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Retinal Ganglion Cells; Role; Source; Stimulus; Strychnine; Surveys; Synapses; Testing; Tracer; Transgenic Organisms; Visual system structure; aged; base; cell type; connexin 36; flupirtine; genetic manipulation; insight; mature animal; mouse model; novel; patch clamp; photoreceptor degeneration; presynaptic; response; retinal neuron; retinogeniculate; starburst amacrine cell

The long-term goal of this application is to elucidate the mechanisms and functions of inner retina oscillation in development and maintenance of the visual system. The proposal is based on the existence of two independent oscillation mechanisms in adult retina. We hypothesize that these oscillation mechanisms are built-in function of the retina, masked by glutamate released by photoreceptor in normal situation but emergent under deafferentation conditions such as photoreceptor degeneration and complete congenital stationary night blindness to ensure stable connection between the eye and the brain. We have found that deleting connexin 36 (Cx36) but not Cx45 genes can silence retinal oscillation. We have also preliminarily tested mice with photoreceptor degeneration but without Cx36 expression and found that retinogeniculate projections become abnormal. Since retinal oscillation appears to have a biological function, it is important to know mechanistic details of the two mechanisms. Aim-1 will thus focus on delineating the cellular origin of the less understood flupirtine-insensitive mechanism. Aim-2 will stringently test the role of oscillation in maintaining retinofugal projections by genetically manipulating Cx36 gene including inducible inactivation in adult animals after photoreceptor degeneration. In order to understand whether retinal oscillation has other functions, it is necessary to know which retinal neurons oscillate and through what mechanisms. Aim-3 will thus survey synaptic inputs onto genetically identifiable RGCs in two retinal deafferentation mouse models and test the hypotheses that mouse RGCs are more diverse than currently appreciated and that group-specific circuit connection characteristics exist to drive RGCs' unique physiological light responses in different groups. A fruitful outcome will in the short-term generate a resource that contains many genetically identifiable RGC types in mouse and in the long-term assign group-specific morphometric features, intrinsic membrane properties, and light response characteristics to them. These efforts fill knowledge gaps, confer a biological function to retinal oscillation in maintaining RGC central projection, and provide a strong foundation for future inquiries into retinal disease mechanisms and treatment window and/or options.

这项应用的长期目标是阐明视网膜内部的机制和功能 视觉系统的开发和维护中的振荡。这项提议是基于 成人视网膜中两种独立的振荡机制。我们假设这些振荡 机制是视网膜的内在功能，在正常情况下被光感受器释放的谷氨酸所掩盖 情况，但在去传入的情况下出现，如光感受器变性和完全 先天性静止性夜盲，确保眼睛和大脑之间稳定的连接。我们有 研究发现，删除连接蛋白36(Cx36)而不是Cx45基因可以抑制视网膜振荡。我们还有 对光感受器变性但没有Cx36表达的小鼠进行了初步测试，发现 视网膜原化投射变得异常。因为视网膜振荡似乎有生物学上的 功能，重要的是要了解这两种机制的机械细节。因此，AIM-1将专注于 描绘了鲜为人知的氟平不敏感机制的细胞起源。AIM-2将 通过基因操作严格测试振荡在维持视黄醇投射中的作用 Cx36基因包括成年动物感光细胞变性后的可诱导失活。为了 要了解视网膜振荡是否还有其他功能，有必要知道哪些视网膜神经元 振荡和通过什么机制。因此，AIM-3将调查突触在基因上的输入 在两种视网膜去传入小鼠模型中可识别的视网膜节细胞，并检验小鼠视网膜节细胞的假设 比目前所理解的更加多样化，且存在特定于组的电路连接特性 在不同的群体中驱动视网膜节细胞独特的生理性光反应。一个富有成果的结果将在 短期内在小鼠和小鼠体内产生包含许多可遗传识别的RGC类型的资源 长期分配群体特有的形态计量学特征、固有的膜特性和光响应 对他们来说是有特点的。这些努力填补了知识空白，赋予了视网膜生物学功能 维持研资局中央投影的振荡，并为日后的查询提供坚实的基础 视网膜疾病机制和治疗窗口和/或选项。