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.

该应用的长期目标是阐明视网膜内层的机制和功能 视觉系统发育和维护的振荡。该提案是基于现有 成人视网膜中两种独立振荡机制的研究。我们假设这些振荡 机制是视网膜的内在功能，正常情况下被光感受器释放的谷氨酸所掩盖 情况但在传入阻滞条件下出现，例如光感受器变性和完全性变性 先天性静止性夜盲症，保证眼睛和大脑之间的稳定连接。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 初步测试了光感受器变性但无Cx36表达的小鼠，发现 视网膜原代投射变得异常。由于视网膜振荡似乎具有生物 功能，了解这两种机制的机制细节很重要。因此，Aim-1 将重点关注 描述了不太了解的氟吡汀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网膜离断投射中的作用 Cx36 基因包括成年动物光感受器变性后的诱导失活。为了 了解视网膜振荡是否还有其他功能，就需要知道视网膜神经元有哪些 振荡以及通过什么机制。因此，Aim-3 将调查基因上的突触输入 在两种视网膜传入神经阻滞小鼠模型中可识别 RGC，并测试小鼠 RGC 的假设 比目前理解的更加多样化，并且存在特定于组的电路连接特性 驱动不同群体的 RGC 独特的生理光反应。将会取得丰硕的成果 短期生成包含小鼠和小鼠体内许多可遗传识别的 RGC 类型的资源 长期指定群体特定的形态特征、内在膜特性和光响应 他们的特点。这些努力填补了知识空白，赋予视网膜生物学功能 维持RGC中心投影的振荡，为未来的查询提供坚实的基础 视网膜疾病机制和治疗窗口和/或选择。