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.

项目摘要 海马在整个生命周期中的学习和记忆中都起着出色的作用， 从婴儿期到老年观察到的与发育和可塑性相关的基因表达变化。由于 该地区的结构和电路与许多关键行为函数有关。海马 根据树突 - 轴极性，神经元以密集的层层组织和突触连接 海马内是整个生命周期的结构和功能可塑性的主要部位 与学习，记忆，情绪和压力调节有关的关键功能。许多重要的可塑性有关 转录本位于树突室及其转录，从细胞核中传输，然后 在发育和神经元活性上，树突室内的翻译受到严格的调节。 此外，尽管表征了产后神经发生的功能重要性 啮齿动物齿状回（DG），人DG（HDG）中成人神经发生的无可争辩的证据 在整个生命周期中，难以捉摸及其持久性仍然存在争议。最近，细胞型特异性分子 已经描述了成人和整个寿命的人类海马的特征，使用了单一 核RNA测序（snRNA-seq）;但是，这些资源缺乏空间解决方案 海马并从胞质室中丢失转录组信息。考虑到紧密的相关性 在HPC中的空间结构和功能之间 突触室，分子分析技术，具有解决这些差距的能力 需要知识。因此，我们提出了空间分辨的全转录组基因的产生 整个寿命的HDG中的表达谱，来自人类四个年龄组的神经型供体 寿命（婴儿，青少年，中年和老年人）。数据将作为用户友好的浏览器作为一个 社区资源。专家神经生物学家将对规范子场进行手动注释，而 生物统计学家将应用无监督的聚类算法来识别新型的空间领域。然后我们会 比较整个寿命中的基因表达以识别发育和空间调节的基因 表达。我们将通过执行特定新型基因标记的细胞表达模式 在我们的捐助者队列中的Smfish。这种方法将促进空间基因表达模式的精致注释 在人类海马中，有助于理解神经发育和神经退行性 通过识别与空间定义的细胞群的临床关联，可以针对的疾病 预防和治疗。