The Development and Organization of Central Synapses in Drosophila

果蝇中央突触的发育和组织

• 批准号: 8486768
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8486768
• 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（由申请人提供）：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必需的分子机制是什么，来自一种神经元的突触如何与来自其他神经元类别的突触相互作用？该提案旨在通过确定果蝇中央脑中突触的组织，其维持和发育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，三个神经元类合作，使来自环境的气味的强大的感知，这些气味的处理，并将信息传输到更高的大脑中心。因此，嗅觉系统代表了一个机会，研究一个遗传可访问的系统与单细胞的分辨率和单一神经元内或神经元组之间的刻板。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。这项建议将进一步这项工作，提供一个高分辨率的分析突触在单个嗅觉神经元。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的突触有何不同。这样的分析将提供一个基本的框架，以解决病理条件，包括神经发育障碍，如何改变突触组织。此外，我将使用这种新的模型突触来检查三类分子，Teneurins，Neurexins和Neuroligins，它们与智力残疾和自闭症谱系障碍有关。了解这些实体中的每一个是如何对突触组织做出贡献的，对于深入了解这些疾病的基础至关重要。最后，我将研究回路中不同神经元的突触是如何相互关联的。电路中神经元之间的协调对于其功能和生物行为至关重要。但是，神经回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，我将询问在回路中扰动一类神经元的突触如何影响其他神经元的突触。具体来说，我将确定一个电路如何处理一种特定类型的突触增加和减少，以及电路内的化学突触如何对电突触的损失作出反应。对这些电路反应机制的进一步研究将揭示负责其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的组织的这些方面，我们不仅可以深入了解神经元的功能，还可以深入了解神经回路如何协调信息，以确保生物体水平的正常功能。