Mouse Cell Type-Specific Brain Mapping in Health and Disease

健康和疾病中的小鼠细胞类型特异性脑图谱

• 批准号: 9061558
• 负责人: Julie Harris
• 金额: $ 70.97万
• 依托单位: ALLEN INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9061558
• 关键词: 3-Dimensional; APP-PS1; Accounting; Adult; Affect; Alzheimer' s Disease; Area; Atlases; Axon; Back; Behavior; Behavioral; Biological Markers; Brain; Brain Mapping; Brain region; CAV2 gene; Canine Adenoviruses; Cells; Cognition; Cognition Disorders; Communities; Complex; Data; Data Set; Databases; Deposition; Development; Disease; Disease Progression; Foundations; Goals; Health; Hippocampus (Brain); Human; Image; Institutes; Label; Link; Literature; Maps; Measurement; Mediating; Methods; Mining; Modeling; Mus; Neurodegenerative Disorders; Neurons; Nomenclature; One-Step dentin bonding system; Pathology; Pathway interactions; Patients; Pattern; Population; Primates; Process; Projections and Predictions; Proteins; Rattus; Recombinants; Research; Resolution; Resources; Rest; Rodent; Signal Transduction; Source; Specific qualifier value; Surveys; Testing; Tracer; Transgenic Organisms; Travel; Viral; Wild Type Mouse; adeno-associated viral vector; anatomical tracing; base; cell type; cognitive ability; cognitive process; cognitive task; connectome; imaging informatics; imaging modality; information processing; mouse model; network architecture; network dysfunction; peptide A; research study; retrograde transport; tomography; tool; transgenic model of alzheimer disease; two-photon; uptake; young adult

DESCRIPTION (provided by applicant): Anatomical circuitry is the foundation by which information travels within the brain. Therefore, comprehensive wiring diagrams are fundamental for understanding how circuits control complex behavioral and cognitive processes. However, only sparse connectivity datasets exist for mammalian model species, and most are collated from tract tracing literature. This is problematic due to the large variety of methods, targeted areas, nomenclature, and assessment of connection strengths by different labs. Instead, at the Allen Institute, we created an entirely new, standardized, publicly and freely available, dataset (Mouse Connectivity Atlas; ://connectivity.brain-map.org) based on modern anterograde axon tracing and high-throughput 2-photon imaging methods to visualize inter-areal and genetically defined cell type-specific projections across the entire young adult mouse brain from ~300 regions. The Mouse Connectivity Atlas data reveals general organizational principles in healthy brains, but many details are still missing. For example, subclasses of neurons within a region projecting to either single or multiple targets are not always defined, nor are the layers of origin of cortical input neurons to specific targets defined. Higher resolution descriptions of structural connection patterns at the cell type, rather than areal, level will enable more accurate modeling and hypotheses on cortical information processing and cognition in health and disease. In neurodegenerative diseases that rob patients of cognitive abilities, such as Alzheimer's disease (AD), pathology spreads in selectively vulnerable regions in specific patterns that resemble, but do not exactly duplicate, network architecture. Taking into account specific cortical projection pathways could thus provide a better structural framework for understanding, predicting, and treating disease. We propose to enhance the Mouse Connectivity Atlas through focused anatomical tracing of whole-brain axon pathways from neurons defined by their projection targets within and outside of disease- relevant large-scale cortical networks. This will be accomplished through the development of a combined viral- based retrograde and anterograde intersectional fluorescent labeling strategy, and our established, successful high-throughput imaging and informatics platform. We will densely survey and map cell type projections defined by target regions in the mouse default mode-like and hippocampal networks, which participate in essential normal cognitive tasks and are vulnerable to AD. New data will be integrated into Allen Institute online resources, providing external users access to raw 2-D images, annotated 3-D projection models, and other analysis tools. We will specifically test the prediction that anatomical classes of projection neurons within an area belonging to the functionally-defined default mode network preferentially connect to other areas within the network. We also propose to use this foundational dataset as a guide for generating and analyzing a brain- wide cell type structural connectivity matrix for an AD mouse model, which could facilitate research in the AD community on disease-related network dysfunction and propagation of pathology.

描述（由申请人提供）： 解剖回路是信息在大脑内传播的基础。因此，全面的接线图对于理解电路如何控制复杂的行为和认知过程至关重要。但是，哺乳动物模型物种仅存在稀疏的连通性数据集，并且大多数是根据图表的文献整理的。由于不同实验室的各种方法，目标区域，命名法和连接强度评估，这是有问题的。 Instead, at the Allen Institute, we created an entirely new, standardized, publicly and freely available, dataset (Mouse Connectivity Atlas; ://connectivity.brain-map.org) based on modern anterograde axon tracing and high-throughput 2-photon imaging methods to visualize inter-areal and genetically defined cell type-specific projections across the entire young adult mouse brain from ~300 regions.鼠标连通性地图集数据揭示了健康大脑中的一般组织原理，但仍缺少许多细节。例如，投射到单个目标或多个目标的区域内的神经元的子类并不总是定义的，皮质输入神经元的起源层也不总是定义为定义的特定靶标。对细胞类型的结构连接模式的更高分辨率描述，而不是区域，水平将使对健康和疾病中皮质信息处理和认知的更准确的建模和假设。在神经退行性疾病中，使患者具有认知能力，例如阿尔茨海默氏病（AD），病理学以类似但不完全复制的网络体系结构的特定模式中有选择性的脆弱区域扩散。因此，考虑到特定的皮质投影途径可以为理解，预测和治疗疾病提供更好的结构框架。我们建议通过对疾病相关的大型皮质网络内外的投影靶标的神经元的整体轴突途径的重点解剖学追踪来增强小鼠连通性地图集。这将通过开发基于病毒的逆行和同类荧光标签策略以及我们已建立的成功的高通量成像和信息信息平台来实现。我们将密集地调查和映射由鼠标默认模式和海马网络中的目标区域定义的细胞类型投影，这些预测参与了基本的正常认知任务，并且容易受到AD的影响。新数据将集成到Allen Institute在线资源中，从而为外部用户访问RAW 2-D图像，注释的3-D投影模型和其他分析工具。我们将专门测试以下预测，即属于功能定义的默认模式网络的区域内的投射神经元的解剖类别类别优先连接到网络中的其他区域。我们还建议将此基础数据集用作为AD小鼠模型生成和分析脑部宽细胞类型结构连通性矩阵的指南，这可以促进与疾病相关网络功能障碍和病理传播的AD社区中的研究。