Cell Biological Limitations Constrain Dendritic Branching Morphology and Neuronal Function

描述（由申请人提供）：我将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，特别是它们高度分支的树突，它们接收来自其他神经元的突触输入或来自外部世界的感觉输入。轴突和树突过程之间的联系决定了神经系统的结构，这被认为是理解神经功能的先决条件；神经连接组学（Connectomics）是一门研究神经元连通性的全球性学科，它已成为神经科学的一个主要目标。在这个先锋的提案中，我想用正交的方法来研究神经元形态学。我的假设是，神经元的细胞生物学——物质的运输和周转——对树突的形成和维持都有很强的限制。此外，我提出，这些限制是如此之强，以至于它们实际上损害了神经元的功能：例如，我假设，跨分支连接的树突过程直径的变化是由传输限制决定的，它们实际上降低了信号的传播。如果这是真的，那么形态学是细胞生物学和神经元功能之间的一种妥协，确定这种权衡的本质可能会为连接性提供关键的见解。我将揭示的形态学规则将为确定连接图提供强大的优先级，并可能有助于解决连接组学中的一个主要问题：连接图需要多好才能理解功能？

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.