Profiling the human dentate gyrus across the lifespan with spatially-resolved transcriptomics

利用空间分辨转录组学分析人类齿状回的整个生命周期

• 批准号: 10724575
• 负责人: Stephanie Carinne Hicks
• 金额: $ 50.94万
• 依托单位: LIEBER INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10724575
• 关键词: Acceleration; Address; Adult; Age; Aging; Algorithms; Axon; Behavioral; Biological Process; Brain; Brain region; Cell Nucleus; Cells; Clinical; Cognition; Cognitive; Communities; Data; Dementia; Dendrites; Dendritic Spines; Development; Disease; Elderly; Event; Fluorescent in Situ Hybridization; Future; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic Transcription; Genomics; Growth and Development function; Hippocampus; Histology; Human; Image; Impairment; In Situ Hybridization; Infant; Knowledge; Learning; Life; Link; Long-Term Depression; Long-Term Potentiation; Longevity; Maintenance; Manuals; Maps; Measurement; Mediating; Memory; Messenger RNA; Methods; Molecular; Molecular Profiling; Moods; Neuroanatomy; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Neuropil; Nuclear; Output; Parahippocampal Gyrus; Pattern; Play; Population; Positioning Attribute; Prevention; Process; Pyramidal Cells; Regulation; Resolution; Resources; Rodent; Role; Sampling; Site; Source; Spottings; Stress; Structure; Synapses; Synaptic Transmission; Synaptic plasticity; Technology; Teenagers; Tissue-Specific Gene Expression; Tissues; Transcript; Translations; adult neurogenesis; age group; age related; age related cognitive disorder; cell type; cognitive ability; cognitive function; cognitive performance; cohort; density; dentate gyrus; differential expression; functional plasticity; granule cell; human old age (65+); infancy; interest; long term memory; middle age; neurodevelopment; neurogenesis; novel; novel marker; postnatal; single molecule; single nucleus RNA-sequencing; transcriptome; transcriptomics; user-friendly

PROJECT SUMMARY The hippocampus plays a well-established role in learning and memory across the lifespan, with developmental and plasticity-related gene expression changes observed from infancy through old age. Due to its structure and circuitry, the region has been linked to a number of critical behavioral functions. Hippocampal neurons are organized in densely packed layers according to dendrite-axon polarity, and synaptic connections within the hippocampus are major sites of structural and functional plasticity across the lifespan that regulate critical functions related to learning, memory, mood and stress regulation. Many important plasticity-related transcripts are localized to the dendritic compartment, and their transcription, transport out of the nucleus, and translation within the dendritic compartment is tightly regulated, both developmentally and by neuronal activity. Additionally, despite extensive characterization of the functional importance of postnatal neurogenesis in rodent dentate gyrus (DG), indisputable evidence of adult neurogenesis in the human DG (hDG) remains elusive and its persistence throughout the lifespan remains controversial. Recently, cell-type specific molecular profiles of the human hippocampus in adults and across the lifespan have been described, using single- nucleus RNA sequencing (snRNA-seq); however, these resources lack spatial resolution within the hippocampus and lose transcriptomic information from the cytosolic compartment. Given the tight correlation between spatial structure and function in HPC, and the particular importance of transcripts localized to the synaptic compartment, molecular profiling technologies with the capacity to address these gaps in our knowledge are needed. Thus, we propose the generation of spatially-resolved, transcriptome-wide gene expression profiles in hDG across the lifespan, from neurotypical donors in four age groups across the human lifespan (infant, teen, middle-age, and elderly). Data will be compiled into a user-friendly browser as a community resource. Expert neurobiologists will perform manual annotations of canonical subfields, while biostatisticians will apply unsupervised clustering algorithms to identify novel spatial domains. We will then compare gene expression across the lifespan to identify developmentally- and spatially-regulated gene expression. We will validate the cellular expression patterns of specific novel gene markers by performing smFISH in our donor cohort. This approach will facilitate refined annotation of spatial gene expression patterns in the human hippocampus, and contribute to understanding neurodevelopmental and neurodegenerative disorders by identifying clinical associations with spatially-defined cell populations that can be targeted for prevention and treatment.

项目概要 海马体在整个生命周期的学习和记忆中发挥着明确的作用， 从婴儿期到老年观察到的发育和可塑性相关基因表达变化。由于 该区域的结构和电路与许多关键的行为功能有关。海马 神经元根据树突轴突极性和突触连接组织成密集的层 海马体内是整个生命周期中结构和功能可塑性的主要部位，负责调节 与学习、记忆、情绪和压力调节相关的关键功能。许多重要的可塑性相关 转录物定位于树突区室，它们的转录、转运出细胞核，以及 树突区室内的翻译受到发育和神经元活动的严格调控。 此外，尽管对出生后神经发生的功能重要性进行了广泛的描述 啮齿动物齿状回（DG），人类 DG（hDG）中成人神经发生的无可争议的证据 难以捉摸，其在整个生命周期中的持续性仍然存在争议。最近，细胞类型特异性分子 已经描述了成人和整个生命周期中人类海马体的概况，使用单 核RNA测序（snRNA-seq）；然而，这些资源缺乏空间分辨率 海马体并丢失来自胞质室的转录组信息。鉴于紧密相关性 HPC 中的空间结构和功能之间的关系，以及本地化转录本的特殊重要性 突触室、分子分析技术能够解决我们的这些差距 需要知识。因此，我们建议生成空间分辨的、转录组范围的基因 hDG 在整个生命周期中的表达谱，来自人类四个年龄组的神经典型供体 寿命（婴儿、青少年、中年和老年人）。数据将被编译到用户友好的浏览器中作为 社区资源。专家神经生物学家将对规范子领域进行手动注释，同时 生物统计学家将应用无监督聚类算法来识别新的空间域。我们随后将 比较整个生命周期的基因表达，以确定发育和空间调控的基因 表达。我们将通过执行来验证特定新基因标记的细胞表达模式 我们的捐赠者队列中的 smFISH。这种方法将有助于空间基因表达模式的精细注释 在人类海马体中，有助于理解神经发育和神经退行性疾病 通过识别与空间定义的细胞群的临床关联来治疗疾病 预防和治疗。

项目成果

Spatially-resolved transcriptomics of human dentate gyrus across postnatal lifespan reveals heterogeneity in markers for proliferation, extracellular matrix, and neuroinflammation.

人类齿状回在出生后寿命期间的空间分辨转录组学揭示了增殖、细胞外基质和神经炎症标记物的异质性。

• 发表时间: 2023-12-04
• 作者: Ramnauth, Anthony D;Tippani, Madhavi;Divecha, Heena R;Papariello, Alexis R;Miller, Ryan A;Pattie, Elizabeth A;Kleinman, Joel E;Maynard, Kristen R;Collado;Hyde, Thomas M;Martinowich, Keri;Hicks, Stephanie C;Page, Stephanie C
• 通讯作者: Page, Stephanie C