Relating structure to function: Development of dendritic arborisations underlying orientation selectivity in the vertebrate visual system

将结构与功能联系起来：脊椎动物视觉系统中方向选择性的树突状树枝化的发展

• 批准号: BB/R000972/1
• 负责人: Robert Hindges
• 金额: $ 72.86万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR000972%2F1
• 关键词: Relating; structure; function; Development; dendritic

Structure and function in the nervous system are closely related, but it is not clear how structure-function relationships develop. One example where the structural diversity of cells is clearly evident is the vertebrate retina. It consists of over 70 different types of neurons with the function to transform light information into electrochemical signals and send them to the brain. Interestingly, visual information is pre-processed already in the retina and split into different channels, such as motion, colour or edges. This is done through the formation of distinct networks between different retinal cells, for example amacrine cells and retinal ganglion cells. Amacrine cells are the most diverse (and least studied) class of neurons in the retina, with many distinct shapes. Although some progress has been made in uncovering factors that influence shape, complexity and connectivity of neurons, our knowledge about the exact mechanisms is limited and many processes are still unclear. This project will use two specific types of amacrine cells in the retina -previously identified by us- that have a striking correspondence between morphology and function as a model to study how such neuronal structure-function relationships in the brain are generated. These cells form many processes or arbours (called dendrites) that are in the shape of elongated structures, similar to elliptic areas. We found that these ellipses are arranged radially in the eye, meaning along the axis from the middle of the retina to the outside. Our results demonstrated that these cells are crucial for detection of oriented visual stimuli, a key element in visual information. However, it is not clear a) what are the developmental steps to form these elliptic cellular structures, b) what influences the generation of this cellular shape and c) how this shape is related to their connected cells in the retina. Using the zebrafish model system, we will follow the structural development of these specific amacrine cells and identify the individual steps until they are functionally mature. To do so, we will use genetic tools already available in our laboratory to label these cells specifically and image them in live animals under the microscope. In a second set of experiments, we will investigate how different parameters will influence the development of our amacrine cells. For this we will alter activity in these neurons (for example keep the fish in the dark to abolish visual input), change the expression of certain genes in them or alter the cellular composition of the retina and then follow the structural development as before. This will answer some important questions about the mechanisms to control cellular structure. Finally, to identify which other cells connect to these specific amacrine cells and map their points of contact (synapses), we will use a state-of-the-art technology based on electron microscopy to create very detailed 3D models of the cellular structures in the retina. This will allow us to identify how the particular amacrine structure is arranged in relation to the structure of other cells and thus the underlying mechanisms for their specific function. Our work will be an important step forward towards better understanding how structure-function relationships develop in the nervous system.

神经系统的结构和功能密切相关，但结构与功能关系如何发展尚不清楚。细胞结构多样性明显的一个例子是脊椎动物的视网膜。它由 70 多种不同类型的神经元组成，具有将光信息转化为电化学信号并将其发送到大脑的功能。有趣的是，视觉信息已经在视网膜中进行了预处理，并分成不同的通道，例如运动、颜色或边缘。这是通过在不同视网膜细胞（例如无长突细胞和视网膜神经节细胞）之间形成不同的网络来完成的。无长突细胞是视网膜中最多样化（也是研究最少）的神经元类别，具有许多不同的形状。尽管在揭示影响神经元形状、复杂性和连接性的因素方面已经取得了一些进展，但我们对确切机制的了解有限，许多过程仍不清楚。该项目将使用我们之前识别出的视网膜中两种特定类型的无长突细胞，它们在形态和功能之间具有惊人的对应关系，作为模型来研究大脑中这种神经元结构-功能关系是如何产生的。这些细胞形成许多突起或乔木（称为树突），其形状为细长结构，类似于椭圆形区域。我们发现这些椭圆在眼睛中呈放射状排列，即沿着从视网膜中部到外侧的轴线。我们的结果表明，这些细胞对于检测定向视觉刺激至关重要，定向视觉刺激是视觉信息的关键要素。然而，目前尚不清楚：a）形成这些椭圆形细胞结构的发育步骤是什么，b）什么影响这种细胞形状的生成，以及c）这种形状与视网膜中相连的细胞有何关系。使用斑马鱼模型系统，我们将跟踪这些特定无长突细胞的结构发育并确定各个步骤，直到它们功能成熟。为此，我们将使用实验室已有的遗传工具来专门标记这些细胞，并在显微镜下对活体动物进行成像。在第二组实验中，我们将研究不同的参数将如何影响无长突细胞的发育。为此，我们将改变这些神经元的活动（例如，将鱼置于黑暗中以消除视觉输入），改变其中某些基因的表达或改变视网膜的细胞组成，然后像以前一样跟踪结构发育。这将回答有关控制细胞结构的机制的一些重要问题。最后，为了确定哪些其他细胞连接到这些特定的无长突细胞并绘制它们的接触点（突触），我们将使用基于电子显微镜的最先进技术来创建视网膜细胞结构的非常详细的 3D 模型。这将使我们能够确定特定的无长突结构相对于其他细胞的结构如何排列，从而确定其特定功能的潜在机制。我们的工作将是朝着更好地理解神经系统中结构与功能关系如何发展的方向迈出的重要一步。