Influence of retinal ganglion cells on visual neuron identity in superior colliculus

视网膜神经节细胞对上丘视觉神经元特性的影响

• 批准号: 10739368
• 负责人: Jason Triplett
• 金额: $ 50.05万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739368
• 关键词: Acer; Address; Affect; Anatomy; Bite; Blindness; Brain; Cell Nucleus; Cell Separation; Cells; Chromosome Mapping; Color; Complement; Complex; Comprehension; Data; Dedications; Development; Disease; Drama; Electrophysiology (science); Genes; Human; Individual; Injury; Intrinsic drive; Knock-in Mouse; Maintenance; Maps; Mediating; Modeling; Molecular; Molecular Profiling; Morphology; Mus; Neurons; Play; Process; Reporter; Retinal Ganglion Cells; Role; Shapes; Specific qualifier value; Structure; Techniques; Testing; Transgenic Mice; Trauma; Visual; Visual Cortex; Visual System; Work; design; driving force; experimental study; ganglion cell; in vivo; islet; migration; molecular marker; molecular subtypes; mouse model; nerve stem cell; neurogenesis; novel; response; sight restoration; single nucleus RNA-sequencing; superior colliculus Corpora quadrigemina; tool; transcriptome; transcriptomics; visual processing

ABSTRACT The human brain is capable of making astoundingly complex computa8ons thanks in large part to the diversity of specialized neurons that are op8mized to processes discrete bits of informa8on. For example, in the visual system, different subtypes of neurons are tuned to dis8nct aspect of the visual scene, such as mo8on, color or contrast. Decades of elegant work has defined the subclasses in many ways, using func8onal, morphological, and molecular criteria. However, we have a poor understanding of how such diversity arises in the developing visual system, crea8ng a roadblock to the development of regenera8ve strategies to restore vision aCer loss due to disease or trauma8c injury. To address this gap, we will focus on the mouse superior colliculus (SC) in this proposal, which we posit is a tractable model to begin to tackle this complex problem. Previous studies have iden8fied transcrip8on factors required for SC neurogenesis and paKerning, leading to the view that intrinsic gene8c mechanisms underlie fate specifica8on in the SC. However, very few molecules have been iden8fied to have this role in comparison to other visual regions (e.g. re8na or visual cortex); and, our previous and preliminary data challenge this no8on, revealing a poten8al role for re8nal ganglion cells (RGCs) innerva8ng the SC in fate specifica8on. To test this exci8ng possibility, we will take complementary gain- and loss-of-func8on approaches, leveraging unique gene8c tools that allow us to rearrange the organiza8on of RGC inputs to the SC and follow gene8cally-defined neuronal popula8ons in different contexts. Furthermore, by combining morphological analyses of individual neurons, single nucleus RNA sequencing, and cell-specific in vivo optogene8cs with visual tuning analysis, we will comprehensively test our hypothesis. In Aim 1, we will directly determine the role of re8nal input by examining neuronal morphology of (Aim 1A) and the transcrip8onally-defined cellular diversity (Aim 1B) of SC neurons from control and enucleated mice. In Aim 2, we will leverage a unique mouse model in which the projec8ons of Islet2+ and Islet2- RGCs are segregated into different domains in the SC. Previously, we showed that visual func8on was divergent in these regions, sugges8ng poten8al switching of neuronal iden8ty. To test this possibility, we will determine the visual tuning proper8es (Aim 2A), morphology (Aim 2B), and transcriptome (Aim 2C) of gene8cally- defined SC neuron popula8ons in Islet2+- and Islet2--RGC innervated regions of the SC. Taken together, these experiments will significantly advance our understanding of the mechanisms by which cellular diversity is generated in the SC and uncover a poten8ally paradigm-shiCing role for extrinsic synap8c inputs in shaping neuronal iden8ty.

抽象的 人的大脑能够使惊人的复杂计算8子在很大程度上要归功于 专门的神经元被OP8化为处理Informa8on的离散位。例如，在视觉系统中， 神经元的不同亚型被调整为视觉场景的DIS8NCT方面，例如MO8ON，颜色或对比度。几十年 优雅的作品使用func8onal，形态和分子标准在许多方面定义了子类。 但是，我们对发展中的视觉系统中如何产生这种多样性有糟糕的了解，crea8ng a 开发Regenera8ve策略的障碍，以恢复由于疾病或创伤8C损伤而导致的视力宏cer丧失。到 解决此差距，我们将重点介绍该提案中的鼠标超级胶囊（SC），我们是一个可牵引的模型 开始解决这个复杂的问题。先前的研究具有SC所需的IDEN8转录8ON因子 神经发生和破坏，导致认为固有的基因8C机制是SC中的命运特定的基础。 但是，与其他视觉区域相比，很少有分子具有这种作用（例如RE8NA或 Visual Cortex）;而且，我们以前的和初步的数据挑战了这个NO8ON，揭示了Re8nal Ganglion的POTEN8AL角色 细胞（RGC）Intrionva8ng在命运特定CA8ON中的SC。为了测试此优惠的可能性，我们将采取完全的收益和 遗产方法丧失方法，利用独特的基因8C工具，使我们能够将RGC输入的组织8ON重新排列到 SC并遵循不同背景下的基因8cy固定的神经元popula8on。此外，通过组合 单个神经元，单核RNA测序和带有细胞特异性的体内optogene8c的形态分析 视觉调整分析，我们将全面检验我们的假设。在AIM 1中，我们将直接确定 通过检查（AIM 1A）和转录的神经元形态（AIM 1B）通过检查RE8的输入（AIM 1B） 来自对照和枚举小鼠的SC神经元。在AIM 2中，我们将利用独特的鼠标模型 Islet2+和Islet2- rGC的ProJec8ons在SC中被隔离为不同的域。以前，我们显示了视觉 func8on在这些地区有分歧，表明神经元IDEN8TY的8NG POTEN8型转换。为了测试这种可能性，我们 将确定视觉调整符合8E（AIM 2A），形态（AIM 2B）和转录组（AIM 2C）基因8cly- Islet2+ - 和Islet2--RGC神经支配区域中定义的SC神经元popula8ons。总的来说，这些 实验将显着促进我们对细胞多样性产生的机制的理解 SC和揭示了塑造神经元IDEN8TY的外部突触输入的POTEN8ly范式舒适作用。