Trophic Interactions During Visual System Development

项目摘要/摘要。基础神经科学和临床神经科学的最大挑战之一是理解 神经系统连接的基本组织原则以及识别细胞类型和对分子的反应 塑造发育中的脊椎动物大脑的信号。拟议研究的目标是进一步探索分子和 视觉回路形成的细胞机制，特别是那些影响突触后神经元形态和 视网膜顶盖连接过程中的连接性。在这里，我们将测试分子信号子集相互作用的假设 控制完整、发育中的大脑中的树突状树枝结构和连通性，其中年龄相关的反应 影响有功能的树枝的早期生长和维持。多年来，我们实验室的工作 重点研究了控制视网膜顶盖回路发育的细胞和分子机制。 神经营养因子BDNF和经典轴突引导分子netrin-1在神经元活动中的作用 这是在成功发现视网膜神经节细胞(RGC)轴突路径之后进行的。拟议的研究建立在小说和 重要发现Netrin-1在神经元形态和发育的早期发展中起着不同但关键的作用 中枢神经元的连通性，特别是那些从视网膜节细胞接受输入的神经元。具体地说，网络连接 大鼠视顶盖神经元树突生长的方向性及树枝的分枝和修剪 这种方式与netrin对RGC轴突分支的调节截然不同。在拟议的研究中，实时成像 将使用最先进的功能获得和丧失方法来研究非洲爪哇胚胎中的神经元 慢性和尖锐地操纵Netrin受体信号以证明Netrin及其调控表达 特定受体通过诱导局部和快速形成视网膜顶盖系统中的突触后连接 对中枢神经元树突发育的反应。这些研究还将检验这一假设 网织蛋白功能的发育和活动相关变化影响视觉回路形成和功能 视觉回路的成熟。此外，我们的研究将建立细胞黏附分子唐氏综合症 细胞黏附分子(DSCAM)是树突自我回避所必需的，并与Netrin合作建立 顶盖神经元树突的图案化。通过成像基因修饰的单个神经元的反应 完整、发育中的大脑，我们的研究将促进我们对树突和树突形成的早期机制的理解 脊椎动物大脑中的突触，以及进一步了解形成功能的组织原理 中枢神经系统的连通性。阐明电路发育的早期分子机制 不同的影响突触前和突触后的连接对理解人类 大脑功能改变与早期连接性缺陷有关的神经发育障碍，例如 智力低下和自闭症。

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.