3D Digital Modeling of the Developing Drosophila Brain

描述(申请人提供)：大脑包含大量神经元，其连接由轴突和树突形成，是控制行为的电路的结构基础。电路的分析是非常重要的。所有精细运动控制、记忆形成和认知的行为，只有在大脑内部处理这些功能的电路已知的情况下才能被理解。同样，对精神疾病机制及其药物治疗的洞察需要详细了解大脑回路。例如，最近的发现表明，自闭症或精神分裂症等疾病可以通过前额叶皮质微循环的异常来理解。在这笔赠款中，我们建议开发和利用生物信息学工具，使我们能够解决果蝇大脑中的电路。果蝇的中央大脑是由大约100对血统组成的，每个血统来自一个神经母细胞。同一血统的神经元形成的过程在大脑的不同间隔内扩散。因此，谱系代表了大脑宏观回路最合适的结构/发育单位。重建所有谱系的投影意味着已经在神经元群体的水平上生成了果蝇大脑回路的准确地图(“宏观回路”)。我们建议生成这张地图，以神经生物学社区可以访问的标准化电子格式呈现。此外，我们将在单个突触水平上重建电路(“微电路”)，这需要电子显微镜(EM)。我们已经开发了自动记录、注册和导航大型EM图像数据集所需的软件。我们将进一步改进并使用这些工具来生成数字EM数据集，该数据集首次涵盖具有大量结构复杂神经元的动物的整个大脑。我们的软件使我们能够高效地重建大脑不同部位遇到的神经网络。我们期待着能够学习到神经网络的结构原理，具有普遍的应用价值。 与公共健康相关：果蝇是研究神经回路如何发展和功能来控制行为的重要模型。果蝇的大脑是由一组不变的谱系组成的，每个谱系都来自唯一的神经干细胞(神经母细胞)，并形成大脑的一个遗传和结构单位。我们将使用生物信息学工具生成一份全面的果蝇大脑谱系及其联系的数字图谱，供神经生物界广泛使用，以绘制和分析神经元和电路。

DESCRIPTION (provided by applicant): Brains contain large number of neurons whose connections, formed by axonal and dendritic processes, are the structural underpinning of electrical circuits that control behavior. The analysis of circuits is of great importance. All acts of fine motor control, memory formation and cognition can only be understood if the circuitry within the brain compartments dealing with these functions is known. Likewise, the insight into psychiatric disease mechanisms and their pharmacological treatment requires brain circuitry to be known in detail. For example, recent findings suggest that diseases like autism or schizophrenia can be understood in terms of abnormalities in the micro- circuitry of the prefrontal cortex. We propose in this grant to develop and utilize bioinformatics tools that enable us to address circuitry in the Drosophila brain. The Drosophila central brain is formed by a stereotyped set of approximately 100 paired lineages, each one derived from one neuroblast. Neurons of one lineage form processes that spread within discrete compartments of the brain. Lineages thereby represent the most appropriate structural/developmental units of brain macro-circuitry. Reconstructing the projection of all lineages means to have generated an accurate map of Drosophila brain circuitry at the level of neuron populations ("macro-circuitry"). We propose to generate this map, presented in a standardized electronic format that is accessible to the neurobiology community. In addition, we will reconstruct circuitry at the level of individual synapses ("micro-circuitry"), which requires electron microscopy (EM). We have developed the software required for the automated recording, registration and navigation of large EM image data sets. We will further improve and use these tools to generate a digital EM dataset that, for the first time, encompasses the entire brain of an animal with a sizeable number of structurally complex neurons. Our software allows us to efficiently reconstruct the neural networks encountered in different parts of the brain. We anticipate that we will be able to learn structural principles about neural network that have general application. PUBLIC HEALTH RELEVANCE: Drosophila serves as an important model to study how neural circuits develop and function to control behavior. The Drosophila brain is formed by an invariant set of lineages, each of which is derived from a unique neural stem cell (neuroblast) and forms a genetic and structural unit of the brain. We will use bioinformatics tools to generate a comprehensive digital atlas of the Drosophila brain lineages and their connections, which can be used by the neurobiology community at large to map and analyze neurons and circuits.