Molecular and anatomical characterization of cell types in the aging mouse brain

项目摘要 脑老化研究中最基本的问题之一是，与年龄相关的变化是否会影响所有大脑 同样地，或者是否某些区域以及这些区域内的细胞类型更容易受到影响 比其他人更容易变老。衰老与认知能力下降有关，而且据报道会导致多种变化。 在重要的细胞过程和各种类型的细胞(如小胶质细胞、星形胶质细胞、神经元)中均有表达。大班级 已知受影响的大脑区域的细胞选择性易受年龄相关的神经退行性变的影响 疾病，但这种脆弱性背后的具体分子机制尚不清楚。必需品 了解这种选择性漏洞的前提是了解细胞类型和 老化过程中的电路电平。编目正常衰老大脑中的脑细胞类型及其连接性 为揭示年龄相关性脑部疾病的机制和治疗机会奠定了基础。 最先进的单细胞技术，特别是具有高维度的单细胞转录组学 分子信息，还有空间转录学，单细胞表观基因组学和单细胞形态， 以前所未有的规模和分辨率提供有关脑细胞类型的变革性信息。我们 建议利用我们完善的组学流水线来鉴定和分类18个月大的细胞类型 雄性和雌性C57BL/6J小鼠，并将结果与年轻成人的广泛脑部数据集进行比较 (~P56)小鼠已经在目前的大脑倡议细胞普查网络(BICCN)中产生。我们将使用 单核转录组学和表观基因组学对神经细胞和非神经细胞的高水平研究 类/类型，然后深入单细胞和空间转录研究 显示与年龄相关的变化和/或易患神经退行性疾病的大脑区域。我们将利用我们的 基于成像的注册过程，将所有数据映射到通用坐标框架(CCF)，该框架 允许准确的跨年龄定量比较，这对于揭示与年龄相关的变化至关重要。通过 在同一大脑中同时进行单细胞基因表达和染色质可及性测量 区域，以及不同类型细胞的比例和分布的详细空间转录图谱 具体的分子途径，我们将绘制一条完整的路径，以获得潜在的机制洞察 认知功能减退与衰老相关疾病病理。

Project Summary One of the most fundamental questions in brain aging research is whether age-related alterations affect all brain regions equally, or whether some regions, and cell types within those regions, are more vulnerable to the effects of aging than others. Aging is associated with cognitive decline, and is reported to cause alterations in a variety of important cellular processes and in a variety of cell types (e.g., microglia, astrocytes, neurons). Broad classes of cells in affected brain regions are known to be selectively vulnerable to age-related neurodegenerative diseases, but the specific molecular mechanisms underlying this vulnerability are unclear. An essential prerequisite to understanding this selective vulnerability is to understand the detailed changes at cell type and circuit levels during the aging process. Cataloging brain cell types and their connectivity in normal aging brain is foundational to uncovering the mechanisms and therapeutic opportunities for age-related brain disorders. State-of-the-art single-cell technologies, in particular single-cell transcriptomics with its high dimensional molecular information, but also spatial transcriptomics, single-cell epigenomics and single-cell morphology, are providing transformative information about brain cell types at an unprecedented scale and resolution. We propose to utilize our well-established omics pipelines to characterize and classify cell types in 18 months old male and female C57BL/6J mice and compare the results with the extensive brain-wide datasets in young adult (~P56) mice already being generated in the current BRAIN Initiative Cell Census Network (BICCN). We will use single-nucleus transcriptomics and epigenomics to obtain a high-level survey of neuronal and non-neuronal cell classes/types across the entire mouse brain, and then an in-depth single-cell and spatial transcriptomic study in brain areas showing age-related changes and/or vulnerable to neurodegenerative diseases. We will utilize our imaging–based registration process to map all data into the Common Coordinate Framework (CCF), which allows accurate cross-age quantitative comparisons that will be crucial for uncovering age-related changes. By conducting concurrent single-cell gene expression and chromatin accessibility measurements in the same brain regions, and a detailed spatial transcriptomic map of the proportion and distribution of different cell types and specific molecular pathways, we will chart an integrated path towards gaining mechanistic insight underlying the cognitive decline in aging and age-related disease pathology.