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.

本申请的长期目标是阐明视网膜内层的机制和功能 在视觉系统的发展和维护中的振荡。该提案是基于存在 两个独立的振荡机制在成人视网膜。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。 这种情况下，但出现在去传入条件下，如感光细胞变性和完全 先天性静止性夜盲症，以确保眼睛和大脑之间的稳定连接。我们有 发现删除连接蛋白36（Cx 36）而不是Cx45基因可以沉默视网膜振荡。我们还 初步测试了感光细胞变性但没有Cx 36表达的小鼠，发现 retinogeniculate预测变得异常。由于视网膜振荡似乎有一个生物学上的 因此，了解这两种机制的机制细节非常重要。因此，目标1将侧重于 描绘了不太了解的氟吡汀不敏感机制的细胞起源。Aim-2将 严格测试振荡在维持离视网膜投射中的作用， 成年动物感光细胞变性后cx 36基因的可诱导失活。为了 了解视网膜振荡是否有其他功能，有必要知道哪些视网膜神经元 振荡以及通过什么机制。因此，Aim-3将调查遗传上的突触输入， 在两种视网膜传入神经阻滞小鼠模型中可识别的RGC，并测试小鼠RGC 并且存在特定于组的电路连接特性 来驱动不同群体中RGC独特的生理光反应。一个富有成果的结果将在 短期内产生一个资源，其中包含许多遗传可识别的RGC类型在小鼠和 长期分配组特异性形态特征，内在膜特性和光反应 特征给他们。这些努力填补了知识空白，赋予视网膜的生物学功能， 研究资助局在维持中央预算方面的表现，并为日后的调查提供稳固的基础 视网膜疾病机制和治疗窗口和/或选择。