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

项目摘要/摘要 阿尔茨海默病(AD)是一种进行性神经退行性疾病，从 它起源于内侧颞叶。海马体是最早也是受影响最严重的脑区之一 AD和海马区萎缩与行为症状的严重程度有关。虽然数量众多 尽管已有理论提出，但海马神经变性的分子基础仍不清楚。 这种理解的缺乏阻碍了AD药物开发将动物研究转化为人类 治疗。我相信一种翻译的细胞图谱弥合了小鼠和人类AD之间的差距 需要研究来确定哪些特定的海马细胞类型会受到AD的影响。我之前的研究 创建小鼠海马区基因表达图谱(HGEA)为这一努力奠定了坚实的基础 (Bienkowski等人，自然神经科学，2018年)。HGEA定义了20个不同的遗传亚类 根据绘制的基因表达模式，海马体和下丘脑描绘出每个区域的输入/输出 路径，并展示了每个区域如何对全脑网络做出贡献。总体而言，我发现 海马区基因表达模式与特定的解剖连接模式高度相关。其中 许多新的见解，我发现下丘脑的基因表达模式揭示了隐藏的锥体板层 并演示了这种层状结构如何构成类似于 大脑皮层。总而言之，HGEA展示了海马体的多尺度组织 个体遗传细胞类型到控制动物行为的神经网络。我建立了一些 Mouse Connectome Project网站上的资源和工具，以便其他海马区科学家 世界可以使用HGEA来指导他们自己的研究实验。这项K01指导研究的资助 科学家职业发展奖的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，作为了解AD神经退行性变的翻译资源。建房 在小鼠HGEA上，拟议的研究使用了THICH中的尖端空间转录方法 光学透明组织切片(星图)以揭示多路基因表达模式，构建人类 可以注册到MRI数据的HGEA，并调查HGEA定义的神经细胞类型造成的变化 通过AD小鼠模型(5XFAD小鼠)和患有AD的人类的海马神经退行性变。去指导 在这个项目和我的职业发展中，我组建了一个世界级的支持性导师团队(Dr.Arthur 托加和贝里斯拉夫·兹洛科维奇)和合作者(卡罗尔·米勒博士)为我提供了新的调查培训 在转基因小鼠模型和人类死后组织中都存在阿尔茨海默病。归根结底，资金 这份K01提案将完成我的职业发展，领导一家翻译神经科学实验室 研究神经系统疾病中基因表达、连通性和行为的关系。

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.