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

项目摘要 大脑老化研究中最基本的问题之一是，与年龄相关的改变是否会影响所有的大脑 或者某些区域以及这些区域内的细胞类型是否更容易受到影响 比其他人衰老。衰老与认知能力下降有关，据报道，衰老会导致多种 重要的细胞过程和多种细胞类型（例如，小胶质细胞、星形胶质细胞、神经元）。大类 已知受影响大脑区域的细胞选择性地易受年龄相关的神经退行性疾病的影响。 疾病，但这种脆弱性背后的具体分子机制尚不清楚。一个基本 了解这种选择性脆弱性的先决条件是了解细胞类型的详细变化， 老化过程中的电路水平。对正常衰老大脑中的脑细胞类型及其连接进行分类， 这是揭示与年龄相关的大脑疾病的机制和治疗机会的基础。 最先进的单细胞技术，特别是单细胞转录组学， 分子信息，空间转录组学，单细胞表观基因组学和单细胞形态学， 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 我建议利用我们完善的组学管道来表征和分类18个月大的细胞类型 雄性和雌性C57 BL/6 J小鼠，并将结果与年轻成年人的广泛脑范围数据集进行比较 （~P56）小鼠已经在当前的BRAIN Initiative Cell Census Network（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元和非神经元细胞进行高水平研究 类/类型在整个小鼠大脑，然后深入的单细胞和空间转录组学研究， 大脑区域显示出与年龄相关的变化和/或易受神经退行性疾病的影响。我们将利用我们的 基于成像的配准过程，将所有数据映射到通用坐标框架（CCF）中， 它允许准确的跨年龄定量比较，这对于发现与年龄有关的变化至关重要。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，以及不同细胞类型的比例和分布的详细空间转录组学图， 具体的分子途径，我们将绘制一个综合的路径，以获得机制的洞察力， 衰老和与年龄相关的疾病病理学中的认知能力下降。

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.