Trophic Interactions During Visual System Development

视觉系统发育过程中的营养相互作用

• 批准号: 8579031
• 负责人: SUSANA COHEN-CORY
• 金额: $ 36.8万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2015-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8579031
• 关键词: Acute; Affect; Age; Autistic Disorder; Axon; Behavior; Biological Assay; Brain; Brain-Derived Neurotrophic Factor; Cell Adhesion Molecules; Cells; Clinical; Complement Receptor; Complex; Cues; Dendrites; Development; Down Syndrome Cell Adhesion Molecule; Embryo; Employee Strikes; Event; Funding; Goals; Grant; Growth; Human; Image; Individual; Knowledge; Laboratories; Lateral; Life; Maintenance; Mental Retardation; Molecular; Morphology; Nervous system structure; Neuraxis; Neurodevelopmental Disorder; Neurons; Neurosciences; Optics; Pattern; Play; Process; Proteins; Receptor Signaling; Recruitment Activity; Regulation; Retina; Retinal; Retinal Ganglion Cells; Role; Shapes; Signal Transduction; Staging; Structure; Swimming; Synapses; System; Tadpoles; Tectum Mesencephali; Testing; Time; Time Study; Visual; Visual system structure; Work; Xenopus; Xenopus laevis; age related; axon guidance; cell type; dark rearing; human NTN1 protein; in vivo; insight; loss of function; mind control; netrin receptor; netrin-1; neuron development; neurotrophic factor; novel; postsynaptic; presynaptic; receptor; receptor expression; research study; response; retinotectal; synaptogenesis; vision development

Project Summary/Abstract. One of the great challenges in basic and clinical neuroscience is to understand fundamental organizing principles during nervous system wiring and to identify cell types and responses to molecular signals that sculpt the developing vertebrate brain. The goal of the proposed studies is to further explore molecular and cellular mechanisms of visual circuit formation, particularly those that influence postsynaptic neuronal morphology and connectivity during retinotectal wiring. Here, we will test the hypothesis that a subset of molecular signals interact to control dendritic arbor structure and connectivity in the intact, developing brain, where age-dependent responses influence both early growth and maintenance of a functional dendritic arbor. Over the years, the work of our laboratory has focused on the cellular and molecular mechanisms that control retinotectal circuit development by focusing on the role that the neurotrophic factor BDNF and the classical axon guidance molecules netrin-1, play during wiring events that follow successful retinal ganglion cell (RGC) axon pathfinding. The proposed studies build on the novel and important finding that netrin-1 plays a differential, but key role in the early development of neuronal morphology and connectivity of central neurons, particularly of those neurons that receive input from RGCs. Specifically, netrin influences the directionality of dendrite growth and the branching and pruning of optic tectal neuron dendritic arbors in a manner that is quite different from netrin regulation of RGC axon branching. In the proposed studies real-time imaging of neurons in developing Xenopus laevis embryos and state-of-the-art gain- and loss-of-function approaches will be used chronically and acutely manipulate netrin receptor signaling to demonstrate that regulated expression of netrin and its specific receptors shape postsynaptic connectivity in the retinotectal system by inducing both localized and rapid responses on developing dendrites of central neurons. These studies will also examine the hypothesis that developmental and activity related changes in netrin function impact visual circuit formation and the functional maturation of the visual circuit. Furthermore, our studies will establish that the cell adhesion molecule Down syndrome cell adhesion molecule (DSCAM) is required for dendrite self-avoidance and collaborates with netrin to establish the patterning of tectal neuron dendritic arbors. By imaging responses of genetically modified individual neurons in the intact, developing brain, our studies will advance our understanding of the early mechanisms that sculpt dendrites and synapses in the vertebrate brain, and further our knowledge of the organizing principles that shape functional connectivity in the central nervous system. Elucidating early molecular mechanisms of circuit development that differentially impact pre- and postsynaptic connectivity has broader implications for understanding human neurodevelopmental disorders in which altered brain function is associated with deficits in early connectivity, such as mental retardation and autism.

项目摘要/摘要。基本和临床神经科学的巨大挑战之一是了解 神经系统接线期间的基本组织原理，并确定细胞类型和对分子的响应 雕刻发育中的脊椎动物大脑的信号。拟议研究的目的是进一步探索分子和 视觉电路形成的细胞机制，尤其是那些影响突触后神经元形态和 视网膜直肠接线期间的连通性。在这里，我们将检验以下假设：一部分分子信号相互作用 在完整，发展的大脑中控制树突状植物结构和连通性，其中依赖年龄的反应 影响功能性树突状乔木的早期生长和维持。多年来，我们实验室的工作 专注于通过专注于控制视网膜直肠发育的细胞和分子机制 神经营养因子BDNF和经典轴突指导分子Netrin-1在接线事件中发挥作用 遵循成功的视网膜神经节细胞（RGC）轴突路径。拟议的研究以小说为基础 Netrin-1在神经元形态的早期发展和 中枢神经元的连通性，特别是从RGC接收输入的神经元的连通性。具体来说，网络 影响树突生长的方向性以及视觉神经元树突状arbor的分支和修剪 一种与RGC轴突分支的Netrin调节完全不同的方式。在拟议的研究中实时成像 将使用神经元开发Xenopus laevis胚胎和最先进的功能丧失方法 长期和敏锐地操纵Netrin受体信号传导，以证明Netrin及其ITS的调节表达 特定的受体通过诱导局部和快速来塑造视网膜直肠系统中突触后连通性 关于发展中央神经元树突的反应。这些研究还将研究以下假设 Netrin功能的发展和活动相关的变化影响视觉电路的形成和功能 视觉电路的成熟。此外，我们的研究将确定细胞粘附分子唐氏综合症 细胞粘附分子（DSCAM）是树突自我避免并与Netrin合作以建立netrin所必需的 构图直肠神经元树突状轴。通过成像对转基因神经元的反应 完整的大脑，我们的研究将提高我们对雕刻树突和雕刻早期机制的理解 脊椎动物大脑中的突触，并进一步我们对塑造功能性的组织原理的了解 中枢神经系统中的连通性。阐明电路发展的早期分子机制 差异影响突触前和后连通性对理解人类具有更大的影响 神经发育障碍，其中脑功能改变与早期连通性的缺陷有关，例如 智力低下和自闭症。