Cell Biological Limitations Constrain Dendritic Branching Morphology and Neuronal Function

细胞生物学限制限制了树突分支形态和神经元功能

• 批准号: 9146993
• 负责人: Jonathon Howard
• 金额: $ 83.25万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-21 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9146993
• 关键词: Address; Architecture; Behavior; Biological; Biological Neural Networks; Calcium; Caliber; Cells; Cellular biology; Characteristics; Conflict (Psychology); Costs and Benefits; Dendrites; Development; Drosophila genus; Electron Microscopy; Goals; Laboratories; Larva; Length; Maps; Measurement; Measures; Mechanoreceptors; Morphology; Nature; Nervous system structure; Neurons; Neurophysiology - biologic function; Neurosciences; Organelles; Output; Process; Proteins; Research; Signal Transduction; Structure; Synapses; System; Testing; Theoretical model; fly; genetic manipulation; information processing; insight; light microscopy; meetings; mutant; research study; sensory input; signal processing; theories; voltage

DESCRIPTION (provided by applicant): The general problem that I will address is how neurons integrate their inputs and compute their outputs. Central to integration and computation is the morphology of neurons, and in particular that of their highly branched dendritic arbors, which receive synaptic input from other neurons or sensory input from the outside world. The connections between axonal and dendritic processes define the nervous system's structure, which is viewed as a prerequisite for understanding neural function; connectomics, the global study of neuronal connectivity, has emerged as a major goal of neuroscience. In this Pioneer proposal, I want to take an orthogonal approach to neuronal morphology. My hypothesis is that the cell biology of the neuron-the transport and turnover of materials-places very strong constraints on both building and maintaining dendrites. Furthermore, I propose that these constraints are so strong that they actually compromise the functioning of neurons: I hypothesize, for example, that the changes in diameters of dendritic processes across branch junctions are dictated by transport constraints and that they actually degrade signal propagation. If this is true, then morphology is a compromise between cell biology and neuronal function, and determining the nature of the tradeoff is likely to provide key insight into connectivity. The morphological rules that I will uncover will provide powerful a prioris for determining connectivit maps, and may help to solve a major problem in connectomics: how well does the connectivity map need to be in order to understand the function? To test this hypothesis, one needs a system in which morphology can be measured precisely (and in the most general sense, which includes protein localization), where it can be manipulated in a controlled way, and where morphology can be correlated with function. The Class IV dendritic arborization mechanoreceptor of Drosophila larvae meets these requirements, and will be the initial focus of study. The experimental goals are: (i) to use light and electron microscopy to discover the full set of branching rules—that is, how diameters, angles, branch lengths, and protein & organelle distributions change over branch points. And: (ii) to use calcium and voltage recordings, together with behavior, to characterize the function of the neuron. The measurements will be done in wild-type flies and in mutants, in which the morphology has been modified using precise genetic manipulations. The theoretical goal is to determine the extent to which the observed anatomical and functional characteristics optimize transport and developmental constraints on the one hand, and signal processing constraints on the other hand. The theory will be done in close coordination with experiments performed in the same laboratory. The nature of the tradeoff between these conflicting costs and benefits will provide tremendous insight into neuronal architecture. This research, via the combination of precise experimental measurement and theoretical modeling, will add inestimably to our understanding of the relationship between form and function in the nervous system. We hope that principles will be found that apply broadly across nervous systems and that the principles will have practical value in the determination of the structure of neural networks.

描述（由应用程序提供）：我要解决的一般问题是神经元如何整合其输入并计算其输出。整合和计算的核心是神经元的形态，尤其是其高度分支的树突状乔木，它们从其他神经元或外界的感觉输入接收突触输入。轴突和树突过程之间的连接定义了神经系统的结构，这被视为理解神经元功能的先决条件。全球神经元连接性研究连接元已经成为神经科学的主要目标。在这个先锋提案中，我想采取一种正交方法来进行神经元形态。我的假设是，神经的细胞生物学 - 材料 - 材料的运输和营业额在建筑物和维护树突上都非常强大。此外，我建议这些约束非常强，以至于它们实际上损害了神经元的功能：例如，我假设，例如，分支连接的树突状过程的直径变化是由传输约束决定的，并且它们实际上降低了信号传播。如果这是真的，那么形态就是细胞生物学和神经元功能之间的妥协，确定权衡的性质可能会提供对连通性的关键见解。我将要发现的形态学规则将为确定连接图的优先级提供功能，并可能有助于解决连接组学的主要问题：连接图映射为了理解该功能需要如何处理？ 为了检验这一假设，需要一个可以精确测量形态的系统（最多也是 一般意义，包括蛋白质定位），可以以受控的方式进行操作，以及 形态可以与功能相关。果蝇幼虫的IV级树突状树皮机制 满足这些要求，并将成为研究的最初重点。实验目标是：（i）使用光和电子 显微镜检查了整个分支规则，即直径，角度，分支长度和蛋白质＆ 细胞器分布在分支点上变化。和：（ii）使用钙和电压记录以及行为， 表征神经元的功能。测量将以野生型蝇和突变体进行，其中 形态已通过精确的遗传操纵进行了修饰。理论目标是确定 观察到的解剖学和功能特征优化了对一个人的运输和发育约束 另一方面，手和信号处理约束。该理论将与实验密切协调 在同一实验室进行。 这些相互矛盾的成本和利益之间权衡的性质将为您提供深刻的见识 神经元建筑。这项研究是通过精确实验测量和理论建模的组合 将不可估量地理解神经系统中形式与功能之间的关系。我们希望 该原则将发现广泛适用于神经系统，并且原则将具有实际价值 神经网络结构的确定。