Investigating Novel Transcriptional Mechanisms for Visual Neural Circuit Development and Function using Zebrafish

使用斑马鱼研究视觉神经回路发育和功能的新型转录机制

• 批准号: 10334879
• 负责人: SADIE A BERGERON
• 金额: $ 29.95万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-20 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10334879
• 关键词: Ablation; Adult; Affect; Auditory system; Axon; Behavior; Behavioral; Bioinformatics; Biological Models; Brain; Cells; Centers of Research Excellence; Clinical; Complex; Core Facility; Data; Defect; Development; Disease; Electroretinography; Embryo; Ephrins; Etiology; Eye; Eye Movements; Functional disorder; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Models; Genetic Predisposition to Disease; Genetic Transcription; Genomics; Glutamates; Goals; Homeobox; Human; Human Genome; Interneurons; Knock-out; Knowledge; Link; Measures; Mediating; Mentors; Microscopy; Modeling; Molecular; Molecular Genetics; Morphology; Motor; Mus; Mutate; Nervous system structure; Neural Pathways; Neurodevelopmental Disorder; Neuronal Differentiation; Neurons; Neurophysiology - biologic function; Orthologous Gene; Patients; Pharmacology; Phenotype; Play; Positioning Attribute; Presynaptic Terminals; Prevention strategy; Reflex action; Reflex control; Reflex eye movement; Reporting; Research; Research Project Grants; Retinal Ganglion Cells; Rodent; Role; Saccades; Schizophrenia; Sensory; Specific qualifier value; Structure; Symptoms; Techniques; Testing; Time; Vertebrates; Vision; Visual; Visual system structure; Work; Zebrafish; axon guidance; base; behavior test; behavioral response; cell type; comorbidity; comparative; diagnostic strategy; experimental study; gene network; genome wide association study; glutamatergic signaling; human disease; in vivo; insight; mRNA Expression; mutant; neural circuit; neurodevelopment; neuromechanism; neurotransmission; novel; programs; protein expression; response; sensory system; superior colliculus Corpora quadrigemina; synaptogenesis; transcription factor; vision development; vision science; visual processing; visual stimulus; visual tracking

Project 003 (486): Investigating Novel Transcriptional Mechanisms for Visual Neural Circuit Development and Function using Zebrafish, Bergeron, PL PROJECT SUMMARY / ABSTRACT Neuroanatomical and behavioral changes associated with neurodevelopmental disorders, such as eye tracking dysfunction in schizophrenia, are caused by unknown genetic mechanisms. Identifying these critical gene networks for sensory motor responsiveness in the visual system is one key to developing targeted early diagnostic and preventative strategies for the symptoms of these disorders that make the world a difficult place to navigate for those afflicted by them. My long-term goal is to characterize causative genetic mechanisms for neurodevelopmental disorders-related phenotypes using zebrafish as a model system. This powerful genetic model provides a unique opportunity as an easily accessible vertebrate with a comparatively “simple” nervous system, rapid neurodevelopment, many orthologues of human disease-related genes, and defined and tractable behavioral responses to visual stimuli. We can begin to study specific classes of neurons based on their molecular identity and function from the moment that they are born in the embryo through adulthood in rapid time compared to other vertebrate models. My previous work and that of others revealed for the first time the molecular identity of key interneurons that mediate sensory processing and reflexive control in the mouse and zebrafish auditory system. These neurons express the transcription factor Genomic Screen Homeobox 1 (Gsx1), and I sought to determine the role that Gsx1 plays in the development of neural circuits for sensory processing across the CNS. Upon examination of targeted gsx1 zebrafish mutants, we found profound defects in neuronal differentiation and axon guidance in the developing visual system. Despite its documented expression in the developing visual system in mouse and zebrafish, no research has been performed to date to examine the role that Gsx1 plays in development and function of visual neural circuits. Given the importance of transcriptional mechanisms for neural circuit development in sensory systems and the proposed ability to target key players in these large gene networks to treat diseases, we seek to fill this gap in knowledge. Aim 1 of this proposal will determine the consequences of mutating gsx1 on innate visually mediated behaviors and cell fate determination in the zebrafish pretectum and the eye. The experiments described in Aim 2 will identify the cellular mechanisms by which Gsx1 regulates arborization of axons in the pretectum that connect the eyes to the brain. We will be able to perform these experiments and analyze and validate the large amount of data that will be generated under the expert guidance of the Visual Function & Morphology Core, as well as the WVU Genomics Core Facility and the Bioinformatics Core Facility. This research will provide insight into the complex genetic etiology of neurodevelopmental disorders in which patients have comorbid defects in sensory processing. In addition, our studies will provide an abundance of data that can be utilized to support future research projects that align well with the development of visual function.

项目003（486）：研究视觉神经回路发展的新型转录机制和 使用斑马鱼，Bergeron，PL的功能 项目摘要 /摘要 与神经发育障碍相关的神经解剖学和行为变化，例如眼睛跟踪 精神分裂症的功能障碍是由未知的遗传机制引起的。识别这些关键基因 视觉系统中感觉运动响应能力的网络是提早开发目标的关键 这些疾病的症状的诊断和预防策略使世界变得困难 为那些受到他们折磨的人导航。我的长期目标是表征警告性的遗传机制 使用斑马鱼作为模型系统，神经发育与疾病相关的表型。这个有力的遗传 模型提供了一个独特的机会，作为一种易于使用的脊椎动物，具有相对“简单”的神经 系统，快速神经发育，与人类疾病相关基因的许多直系同源物，并定义和易于处理 对视觉刺激的行为反应。我们可以根据它们的神经元开始研究特定类别的类别 分子身份和功能从快速到成年的胚胎出生的那一刻起 与其他脊椎动物模型相比。我以前的作品和其他作品首次揭示了 关键中间神经元的分子身份，介质的感觉处理和反射性控制在小鼠和反射性控制中 斑马鱼听觉系统。这些神经元表达转录因子基因组筛选同型1（GSX1）， 我感觉确定GSX1在感官处理的神经回路发展中所扮演的作用 跨过中枢神经系统。在检查靶向GSX1斑马鱼突变体后，我们发现了神经元的深刻缺陷 开发视觉系统中的分化和轴突指导。尽管它在 在小鼠和斑马鱼中开发视觉系统，迄今为止尚未进行研究以检查角色 GSX1在视觉神经回路的发展和功能中发挥作用。鉴于转录的重要性 感官系统中神经电路发展的机制以及拟议的主要参与者的能力 这些大型基因网络用于治疗疾病，我们试图在知识中填补这一空白。该提议的目标1将 确定突变GSX1对先天视觉介导的行为和细胞脂肪测定的后果 在斑马鱼和眼睛中。 AIM 2中描述的实验将确定细胞机制 GSX1通过该调节在大脑保护性眼睛中的轴突的树木化。我们会的 可以执行这些实验并分析和验证将生成的大量数据 在视觉功能和形态核心的专家指导下以及WVU基因组核心设施 以及生物信息学核心设施。这项研究将提供对复杂的遗传病因的见解 神经发育障碍患者在感觉处理中患有合并症。另外，我们的 研究将提供可用于支持未来良好研究项目的数据的抽象 随着视觉功能的发展。