Mouse Cell Type-Specific Brain Mapping in Health and Disease

描述（由申请人提供）： 解剖电路是信息在大脑中传播的基础。因此，全面的布线图是理解电路如何控制复杂的行为和认知过程的基础。然而，只有稀疏的连接数据集存在哺乳动物模式物种，大多数是整理道跟踪文献。这是有问题的，因为不同的实验室有各种各样的方法、目标区域、命名和连接强度评估。相反，在艾伦研究所，我们创建了一个全新的，标准化的，公开和免费提供的数据集（Mouse Connectivity Atlas;：connectivity.brain-map.org），该数据集基于现代顺行轴突追踪和高通量双光子成像方法，以可视化来自约300个区域的整个年轻成年小鼠大脑的区域间和遗传定义的细胞类型特异性投影。小鼠连接图谱数据揭示了健康大脑的一般组织原则，但仍缺少许多细节。例如，投射到单个或多个目标的区域内的神经元的子类并不总是被定义的，皮层输入神经元到特定目标的起源层也不被定义。在细胞类型而不是区域水平上对结构连接模式进行更高分辨率的描述，将使健康和疾病中皮质信息处理和认知的建模和假设更加准确。在剥夺患者认知能力的神经退行性疾病中，如阿尔茨海默病（AD），病理学以类似但不完全复制网络架构的特定模式在选择性脆弱区域传播。因此，考虑特定的皮质投射通路可以为理解、预测和治疗疾病提供更好的结构框架。我们建议通过对来自神经元的全脑轴突通路进行集中解剖追踪来增强小鼠连接图谱，神经元由疾病相关大规模皮质网络内外的投射目标定义。这将通过开发基于病毒的逆行和顺行交叉荧光标记策略以及我们建立的成功的高通量成像和信息学平台来实现。我们将密集地调查和映射由小鼠默认模式样和海马网络中的目标区域定义的细胞类型投影，这些区域参与基本的正常认知任务并且容易受到AD的影响。新的数据将被整合到艾伦研究所的在线资源中，为外部用户提供原始二维图像、带注释的三维投影模型和其他分析工具。我们将专门测试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优先连接到网络内的其他区域的预测。我们还建议使用这个基础数据集作为生成和分析AD小鼠模型的全脑细胞类型结构连接矩阵的指南，这可以促进AD社区对疾病相关网络功能障碍和病理传播的研究。

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.