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 人脑能够进行极其复杂的计算，这在很大程度上要归功于 经过优化处理离散信息的专门神经元。例如，在视觉系统中， 不同亚型的神经元被调整为视觉场景的不同方面，例如颜色、颜色或对比度。几十年 优雅的作品使用功能、形态和分子标准以多种方式定义了子类。 然而，我们对这种多样性如何在发育中的视觉系统中产生、如何产生的了解甚少。 开发再生策略以恢复因疾病或外伤造成的视力丧失的障碍。到 为了解决这一差距，我们将在本提案中重点关注小鼠上丘（SC），我们认为这是一个易于处理的模型 开始解决这个复杂的问题。先前的研究已经确定了 SC 所需的转录因子 神经发生和发育，导致人们认为内在的基因机制是 SC 中命运特异性的基础。 然而，与其他视觉区域（例如 re8na 或 视觉皮层）；而且，我们之前的初步数据对这一结论提出了挑战，揭示了肾神经节的潜在作用 细胞（RGC）在命运特异性方面支配 SC。为了测试这种令人兴奋的可能性，我们将采用互补增益和 功能丧失方法，利用独特的gene8c工具，使我们能够重新安排RGC输入的组织 SC 并遵循不同环境中基因定义的神经元群。此外，通过结合 单个神经元的形态学分析、单核 RNA 测序和细胞特异性体内 optogene8cs 视觉调整分析，我们将全面检验我们的假设。在目标 1 中，我们将直接确定角色 通过检查神经元形态（目标 1A）和转录定义的细胞多样性（目标 1B）来确定肾输入 来自对照小鼠和去核小鼠的 SC 神经元。在目标 2 中，我们将利用一种独特的小鼠模型，其中 Islet2+ 和 Islet2- RGC 的投射在 SC 中被分离到不同的域中。之前，我们展示了视觉 这些区域的功能存在差异，表明神经元身份的潜在转换。为了测试这种可能性，我们 将确定基因的视觉调谐特性（目标 2A）、形态学（目标 2B）和转录组（目标 2C） 在 SC 的 Islet2+- 和 Islet2--RGC 神经支配区域中定义了 SC 神经元群。综合起来，这些 实验将极大地增进我们对细胞多样性产生机制的理解 SC 并揭示了外在突触输入在塑造神经元身份中的潜在范式转换作用。