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Mechanisms and functions of Drosophila motoneuron dendritic shape development

果蝇运动神经元树突形状发育的机制和功能

基本信息

批准号：
8686090
负责人：
STUART J NEWFELD
金额：
$ 22.37万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8686090
关键词：
Adult Affect Afferent Neurons Animals Architecture Behavior Biological Models Brain Calcium Cells Complex Cues Cyclic AMP-Dependent Protein Kinases Databases Defect Dendrites Development Disease Drosophila genus Ensure Fragile X Syndrome Genetic Genetic Models Growth Human Image Individual Knowledge Length Life Mechanoreceptors Mediating Metric Modeling Molecular Morphology Motor Neurons Nature Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurons Neuropil Pattern Phenotype Process Records Controls Regulation Role Shapes Signal Pathway Signal Transduction Simulate Staging Structure Synapses System Test Result Testing Trees base cell type cellular imaging fly genetic manipulation information processing insight neural circuit neuron development novel patch clamp postsynaptic presynaptic research study response success synaptogenesis tool

项目摘要

DESCRIPTION (provided by applicant): The brains of all animals are composed out of individual neurons with cell type specific morphologies. The remarkably diverse dendritic architecture of neurons determines two fundamental aspects of neural circuitry: First, it dictates which presynaptic neurons can contact the postsynaptic dendritic arbor. Second, it affects the summation and computation of synaptic input in the postsynaptic dendritic arbor. Consequently, healthy brain function relies on the correct development of dendritic structure, and dendritic architecture defects have been associated with a number of neurodegenerative diseases, such as Rett- and Fragile-X Syndrome. Identifying the molecular mechanisms that regulate dendritic architecture development and synapse placement on dendritic arbors is imperative to understanding neural circuit development in the healthy and in the diseased brain. Despite recent success in identifying key molecular mechanisms regulating dendritic arbor development, our knowledge on the functional consequences of dendritic architecture mis-regulation for synaptic partner matching and for synaptic input processing in the postsynaptic neuron remains fragmentary. This study aims to unravel molecular mechanisms underlying specific aspects of dendritic architecture development as well as the functional consequences of false regulation. During development dendritic structure is regulated by innate genetic factors, guidance cues, humoral cues, and by neuronal activity. Although some of these signals may be integrated by similar intracellular signaling pathways, different signals can independently affect various dendritic features in the same neuron, such as dendritic branch lengths and numbers, dendritic territory borders, and the correct spacing of dendritic arbors within their territories. During recent years, fundamental new insights into the molecular mechanisms that control dendritic self-avoidance and tiling, and thereby correct dendritic arbor spacing, have come from the Drosophila genetic model system. However, it remains largely unclear how these mechanisms interact with synaptic partner matching during circuit assembly in the central nervous system. Therefore, the proposed experiments will test how dendritic self-avoidance mechanisms interact with central synapse formation during dendritic arbor development of Drosophila motoneurons. A quantitative database on control motoneuron dendritic architecture features will serve as bedrock for testing the roles of key molecules mediating dendritic repulsion by targeted genetic manipulation. In addition, we have identified sensory neurons that synapse onto these motoneurons, allowing one to test for functional interactions between dendritic repulsion and synaptic partner matching during dendritic arbor growth. Furthermore, correct and false dendritic architecture regulation will be related to neuronal function by computational approaches and electrophysiological recordings in control and genetically manipulated animals. We expect to gain novel insight into the regulation of dendritic arbor architecture during development as well as into the functional consequences of dendritic arbor defects in mature neurons.

描述(申请人提供)：所有动物的大脑都是由具有细胞类型特定形态的单个神经元组成的。神经元的树突结构的显著多样性决定了神经电路的两个基本方面：第一，它决定了哪些突触前神经元可以接触突触后树突丛。第二，影响突触后树突支中突触输入的总和和计算。因此，健康的大脑功能依赖于树突状结构的正确发展，树突状结构缺陷与许多神经退行性疾病有关，如Rett-和Fragile-X综合征。确定调节树突结构发育和突触在树枝上放置的分子机制，对于了解健康和疾病大脑中神经回路的发育是至关重要的。尽管最近成功地确定了调控树突发育的关键分子机制，但我们对树突结构错误调控对突触伙伴匹配和突触后神经元中突触输入处理的功能后果的了解仍然不完整。这项研究旨在揭示树突状结构发育的特定方面潜在的分子机制以及虚假调控的功能后果。在发育过程中，树突状结构受先天遗传因素、引导线索、体液线索和神经元活动的调节。虽然其中一些信号可能通过相似的细胞内信号通路整合，但不同的信号可以独立地影响同一神经元中的各种树突特征，如树突分支的长度和数量、树突区域的边界以及树突分支在其区域内的正确间距。近年来，对控制树突自我回避和平铺从而纠正树枝间距的分子机制的基本新见解来自于果蝇遗传模型系统。然而，在中枢神经系统的回路组装过程中，这些机制如何与突触伙伴匹配相互作用在很大程度上仍然不清楚。因此，拟议的实验将测试树突自我回避机制如何在果蝇运动神经元的树枝发育过程中与中央突触形成相互作用。一个关于控制运动神经元树突结构特征的定量数据库将作为测试关键分子通过靶向基因操作调节树突排斥的作用的基础。此外，我们还鉴定了与这些运动神经元突触的感觉神经元，使人们能够测试树突排斥和突触伙伴匹配在树枝生长过程中的功能相互作用。此外，在对照和基因操纵动物中，通过计算方法和电生理记录，正确和错误的树突结构调控将与神经元功能有关。我们期望对发育过程中树突状茎结构的调节以及成熟神经元中树突状茎缺陷的功能后果获得新的见解。