The Development and Organization of Central Synapses in Drosophila

果蝇中央突触的发育和组织

• 批准号: 8643708
• 负责人: Timothy J. Mosca
• 金额: $ 9万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8643708
• 关键词: Address; Affect; Autistic Disorder; Behavior; Behavioral; Binding; Biology; Bipolar Disorder; Brain; Cell surface; Cells; Chemical Synapse; Cognition; Development; Disease; Drosophila genus; Drosophila melanogaster; Electrical Synapse; Ensure; Environment; Excision; Future; Genes; Genetic; Grant; Homeostasis; Homologous Gene; Image; Individual; Intellectual functioning disability; Interneurons; Link; Lobe; Maintenance; Memory; Methods; Modeling; Molecular; Molecular Analysis; Molecular Genetics; Network-based; Neurodevelopmental Disorder; Neuronal Plasticity; Neurons; Neurophysiology - biologic function; Odors; Olfactory Receptor Neurons; Organism; Population; Process; Research; Resolution; Role; Series; Signal Transduction; Synapses; System; Work; autism spectrum disorder; base; cognitive function; insight; nervous system disorder; neural circuit; neuron component; olfactory receptor; postsynaptic; presynaptic; public health relevance; research study; response; stereotypy; synaptic function; synaptogenesis; transmission process

DESCRIPTION (provided by applicant): All aspects of memory, behavior, and cognition rely on the synaptic connections between neurons. To begin to understand neural function, the synapses themselves must first be understood: how are they organized, what are the molecular mechanisms necessary for their development and function, and how do synapses from one type of neuron interact with the synapses from other neuronal classes? This proposal aims to address these questions by determining the organization of synapses in the central brain of Drosophila melanogaster, the molecules necessary for their maintenance and development, and how synapses of different neurons interact. In the Drosophila olfactory system, three neuronal classes cooperate to enable robust sensing of odors from the environment, processing of these odors, and transmission of the information to higher brain centers. The olfactory system thus represents an opportunity to study a genetically accessible system with single-cell resolution and stereotypy within single neurons or between groups of neurons. I have developed methods to study synapse organization in the olfactory system, establishing a new model central synapse. These methods have revealed new aspects of synaptic organization in olfactory neurons in the Drosophila antennal lobe. This proposal will further this work, providing a high-resolution analysis of synapses in single olfactory neurons. It will determine when these synapses develop and how the developing synapse differs from that of the mature olfactory neuron. Such analyses will provide an essential framework from which to address how pathological conditions, including neurodevelopmental disorders, can alter synapse organization. Further, I will use this new model synapse to examine three classes of molecules, the Teneurins, Neurexins and Neuroligins, which are linked to intellectual disabilities and autism spectrum disorders. Understanding how each of these entities contributes to synapse organization is essential for gaining insight into the bases of these disorders. Finally, I will investigate how the synapses of different neurons within a circuit are interrelated. Coordination among neurons in a circuit is essential for its function and organismal behavior. But how a circuit achieves this coordination on a synaptic level is largely unknown. Using newly established methods, I will ask how perturbing the synapses of one neuronal class within a circuit affect synapses of the other neurons. Specifically, I will determine how a circuit deals wih synapse increase and reduction in one specific type, and how chemical synapses within a circuit respond to the loss of electrical synapses. Further study of the mechanisms underlying these circuit responses will unveil new molecules and organizational paradigms responsible for their construction. By understanding these aspects of organization for individual synapses and between groups of synapses, we will gain considerable insight into not just neuronal function, but into how a neural circuit coordinates information to ensure proper function at the organism level.

描述(申请人提供)：记忆、行为和认知的所有方面都依赖于神经元之间的突触连接。要开始了解神经功能，首先必须了解突触本身：它们是如何组织的，它们的发育和功能所需的分子机制是什么，以及一种类型的神经元的突触如何与其他神经元类别的突触相互作用？这项提议旨在通过确定果蝇中央大脑中突触的组织、维持和发育它们所需的分子以及不同神经元的突触如何相互作用来解决这些问题。在果蝇的嗅觉系统中，三个神经元类别相互协作，以实现对来自环境的气味的强大感知，处理这些气味，并将信息传输到高级大脑中心。因此，嗅觉系统代表着一个机会，可以研究在单个神经元内或在神经元组之间具有单细胞分辨率和刻板印象的遗传可及系统。我开发了研究嗅觉系统中突触组织的方法，建立了一个新的中央突触模型。这些方法揭示了果蝇触角叶嗅觉神经元突触组织的新方面。这项提议将进一步推动这项工作，为单一嗅觉神经元中的突触提供高分辨率分析。它将决定这些突触何时发育，以及发育中的突触与成熟的嗅觉神经元有何不同。这些分析将提供一个基本的框架，以解决包括神经发育障碍在内的病理条件如何改变突触组织。此外，我将使用这个新的突触模型来研究三类分子，Teneurins，Neurexins和Neurexins，它们与智力残疾和自闭症谱系障碍有关。了解这些实体如何对突触组织做出贡献，对于深入了解这些疾病的基础是至关重要的。最后，我将研究电路中不同神经元的突触是如何相互关联的。回路中神经元之间的协调对其功能和生物行为是必不可少的。但电路如何在突触水平上实现这种协调在很大程度上是未知的。使用新建立的方法，我会问，扰乱电路中一个神经元类别的突触如何影响其他神经元的突触。具体地说，我将确定一个电路如何处理一种特定类型的突触的增加和减少，以及一个电路中的化学突触如何应对电突触的丢失。进一步研究这些回路反应背后的机制将揭示负责它们构建的新分子和组织范式。通过了解单个突触和突触组之间组织的这些方面，我们不仅将深入了解神经元的功能，而且将深入了解神经电路如何协调信息以确保在有机体水平上的正确功能。