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 的函数 项目概要/摘要 与神经发育障碍相关的神经解剖学和行为变化，例如眼球追踪 精神分裂症的功能障碍是由未知的遗传机制引起的。 视觉系统中感觉运动反应网络是早期开发有针对性的关键 针对这些使世界变得困难的疾病症状的诊断和预防策略 为那些受其困扰的人导航，我的长期目标是确定其致病遗传机制。 使用斑马鱼作为模型系统来研究神经发育障碍相关的表型。 该模型提供了一个独特的机会，作为一种易于接近的脊椎动物，具有相对“简单”的神经 系统，快速神经发育，人类疾病相关基因的许多直系同源物，以及明确且易于处理的 我们可以根据神经元的特定类别开始研究它们对视觉刺激的行为反应。 从胚胎出生到成年的那一刻起，分子特性和功能迅速 与其他脊椎动物模型相比，我之前的工作和其他人的工作首次揭示了这一点。 介导小鼠感觉处理和反射控制的关键中间神经元的分子身份 斑马鱼听觉系统这些神经元表达转录因子基因组筛选同源盒 1 (Gsx1)， 我试图确定 Gsx1 在感觉处理神经回路发展中所扮演的角色 在对目标 gsx1 斑马鱼突变体进行检查后，我们发现了神经元的严重缺陷。 发育中的视觉系统中的分化和轴突引导，尽管其在视觉系统中的表达有记录。 在小鼠和斑马鱼中发育视觉系统，迄今为止尚未进行任何研究来检验其作用 鉴于转录的重要性，Gsx1 在视觉神经回路的发育和功能中发挥着重要作用。 感觉系统中神经回路发育的机制以及针对关键参与者的拟议能力 通过这些大型基因网络来治疗疾病，我们将寻求填补这一知识空白。该提案的目标 1 将是。 确定 gsx1 突变对先天视觉介导行为和细胞命运决定的影响 目标 2 中描述的实验将确定斑马鱼前盖层和眼睛的细胞机制。 Gsx1 通过它调节连接眼睛和大脑的前顶盖轴突的树状化。 能够执行这些实验并分析和验证将生成的大量数据 在视觉功能和形态学核心以及西弗吉尼亚大学基因组学核心设施的专家指导下 这项研究将深入了解复杂的遗传病因学。 神经发育障碍，患者在感觉处理方面存在共病。 研究将提供大量数据，可用于支持未来的研究项目 随着视功能的发育。