The Development and Organization of Central Synapses in Drosophila

果蝇中央突触的发育和组织

• 批准号: 9379496
• 负责人: Timothy J. Mosca
• 金额: $ 24.9万
• 依托单位: THOMAS JEFFERSON 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 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9379496
• 关键词: Address; Affect; Autistic Disorder; Behavior; 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; Image; Individual; Intellectual functioning disability; Interneurons; Link; Lobe; Maintenance; Memory; Methods; Modeling; Molecular; Molecular Analysis; Molecular Genetics; Neurodevelopmental Disorder; Neurons; Neurophysiology - biologic function; Odors; Olfactory Pathways; Olfactory Receptor Neurons; Organism; Pathologic; Population; Research; Resolution; Role; Series; Signal Transduction; Synapses; System; Work; autism spectrum disorder; base; behavioral response; cognitive function; experimental study; insight; nervous system disorder; neural circuit; neuron component; olfactory receptor; postsynaptic; public health relevance; relating to nervous system; 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取决于神经元之间的突触连接。要开始理解神经功能，必须首先理解突触本身：它们如何组织，其发育和功能所需的分子机制是什么，以及一种来自一种神经元的突触如何与其他神经元类别的突触相互作用？该建议旨在通过确定果蝇中央大脑中突触的组织，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。在果蝇嗅觉系统中，三个神经元类合作，使环境中的气味有强烈的感觉，处理这些气味以及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，可以在单个神经元内或神经元之间研究具有单细胞分辨率和刻板印象的遗传访问系统。我开发了研究嗅觉系统中的突触组织的方法，建立了新的模型中心突触。这些方法揭示了果蝇触角叶中嗅觉神经元中突触组织的新方面。该提案将进一步进一步，为单个嗅觉神经元中的突触提供高分辨率分析。它将确定这些突触何时发展，以及发育中的突触与成熟嗅觉神经元的突触如何不同。这种分析将提供一个基本框架，以解决该病理状况（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检查与智力障碍和自闭症谱系障碍有关的三类分子，Teneurins，Neurexins和Neuroligins。了解这些实体中的每个实体如何为突触组织做出贡献，对于了解这些疾病的基础至关重要。最后，我将研究电路内不同神经元的突触如何相互关联。电路中神经元之间的协调对于其功能和有机行为至关重要。但是，电路如何在突触水平上实现这种协调是未知的。使用新建立的方法，我将询问电路中一个神经元类别的突触会影响其他神经元的突触。具体而言，我将确定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应对电气突触的损失。对这些电路响应基础的机制的进一步研究将推出负责其构建的新分子和组织范式。通过了解各个突触的组织的这些方面以及在突触组之间，我们将不仅可以深入了解神经元功能，还可以了解神经回路如何协调信息以确保在生物体层面上的适当功能。