A Translational 3D Map of Hippocampal Cell Types To Drive Investigations of Alzheimer's Disease

项目总结/摘要 阿尔茨海默氏病（AD）是一种进行性神经退行性疾病， 它的起源在内侧颞叶海马体是最早和最受影响的大脑区域之一， AD和海马萎缩与行为症状的严重程度有关。而其中也有很多 尽管已经提出了许多理论，但海马神经变性的分子基础仍然不清楚。 这种缺乏了解阻碍了AD药物开发将动物研究转化为人类研究 治疗我相信，一个翻译细胞图谱，桥梁之间的差距差距小鼠和人类AD 需要研究来确定哪些特定的海马细胞类型受到AD的影响。我之前的研究 创建小鼠海马基因表达图谱（HGEA）为这项工作奠定了坚实的基础 （Bienkowski等人，Nature Neuroscience，2018）。HGEA定义了20个不同的遗传细分， 海马和下托的基因表达模式，描绘了每个区域的输入/输出 路径，并展示了每个区域如何有助于全脑网络。总的来说，我发现， 海马基因表达模式与特定的解剖连接模式高度相关。之间 许多新的见解，我发现下托基因表达模式揭示了金字塔的隐藏层， 神经元，并证明了这种层状结构是如何构成类似于神经元的柱状组织的基础的。 大脑皮层总之，HGEA证明了海马体的多尺度组织， 个体遗传细胞类型到调节动物行为的神经元网络。我建立了一些 在老鼠连接组项目网站上的资源和工具，使周围的其他海马科学家 世界可以使用HGEA来指导自己的研究实验。K 01指导研究的资金来源 科学家职业发展奖申请将为我提供所需的培训和专业知识，以便 开发人类版本的HGEA作为理解AD神经变性的翻译资源。建筑 在小鼠HGEA上，拟议的研究使用了一种尖端的空间转录组学方法， 光学透明组织切片（STARmap）揭示多重基因表达模式，构建人类 HGEA可以与MRI数据配准，并研究HGEA定义的神经元细胞类型引起的变化 通过AD小鼠模型（5XFAD小鼠）和患有AD的人类中的海马神经变性。引导 为了这个项目和我的职业发展，我组建了一个世界级的支持导师团队（亚瑟博士 Toga和Berislav Zlokovic）和合作者（卡罗尔米勒博士）为我提供新的培训，以调查 阿尔茨海默病在转基因小鼠模型和人类死后组织中的研究。最终， 这份K 01提案将完成我的职业发展，领导一个转化神经科学实验室 研究神经系统疾病中基因表达、连接和行为的关系。

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a progressive neurodegenerative disease that spreads across the brain from its origin in the medial temporal lobe. The hippocampus is one of the earliest and most affected brain regions in AD and hippocampal atrophy has been linked to the severity of the behavioral symptoms. Although numerous theories have been put forth, the molecular underpinnings of hippocampal neurodegeneration remain unclear. This lack of understanding has stymied AD drug development from translating animal research into human treatment. I believe that a translational cellular atlas that bridges the gap between mouse and human AD research is needed to determine which specific hippocampal cell types are affected by AD. My previous research creating the mouse Hippocampus Gene Expression Atlas (HGEA) lays a strong foundation for this effort (Bienkowski et al., Nature Neuroscience, 2018). The HGEA defines 20 distinct genetic subdivisions of the hippocampus and subiculum based on mapped gene expression patterns, delineates each region’s input/output pathways, and demonstrates how each region contributes to brain-wide networks. Overall, I found that hippocampal gene expression patterns were highly related to specific anatomical connectivity patterns. Among many new insights, I discovered that subiculum gene expression patterns revealed hidden lamina of pyramidal neurons and demonstrated how this laminar architecture underlies a columnar organization similar to the cerebral cortex. Altogether, the HGEA demonstrates the multiscale organization of the hippocampus from individual genetic cell types to neuronal networks regulating animal behavior. I established a number of resources and tools on the Mouse Connectome Project website so that other hippocampal scientists around the world could use the HGEA to guide their own research experiments. The funding of this K01 Mentored Research Scientist Career Development Award application will provide me with training and expertise I need in order to develop a human version of the HGEA as a translational resource to understand AD neurodegeneration. Building on the mouse HGEA, the proposed research uses a cutting-edge spatial transcriptomics approach in thick optically-cleared tissue sections (STARmap) to reveal multiplexed gene expression patterns, build a human HGEA that can be registered to MRI data, and investigate changes to HGEA-defined neuronal cell types caused by hippocampal neurodegeneration within an AD mouse model (5XFAD mice) and humans with AD. To guide this project and my career development, I have assembled a world-class team of supportive mentors (Drs. Arthur Toga and Berislav Zlokovic) and collaborators (Dr. Carol Miller) to provide me with new training to investigate Alzheimer’s disease in both transgenic mouse models and human post-mortem tissue. Ultimately, the funding of this K01 proposal will complete my career development toward leading a translational neuroscience laboratory studying the relationship of gene expression, connectivity, and behavior in neurological disease.