Molecular principles of neuronal maturation and integration in the adult and aging brain

成人和衰老大脑中神经元成熟和整合的分子原理

• 批准号: 10159316
• 负责人: Paola Arlotta
• 金额: $ 53.35万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159316
• 关键词: Acceleration; Address; Adult; Aging; Argentina; Argentine; Automobile Driving; Behavioral; Bioinformatics; Biological Assay; Birth; Brain; Brain region; Cell Maturation; Cells; Collaborations; Communities; Date of birth; Development; Developmental Delay Disorders; Disease; Environment; Epigenetic Process; Equipment; Exhibits; Exposure to; Gene Expression Profile; Gene Expression Profiling; Generations; Genes; Genetic Transcription; Global Change; Goals; Grant; Hippocampus (Brain); Human Resources; Individual; Institutes; Knowledge; Laboratories; Life; Mediating; Mediator of activation protein; Molecular; Molecular Profiling; Morphology; Mus; Neurons; Phase; Physical Exercise; Population; Postdoctoral Fellow; Process; Proteins; Research; Research Personnel; Role; Signal Transduction; Site; Space Perception; Stimulus; Techniques; Technology; Testing; Training; Work; aged; aging brain; aging hippocampus; dentate gyrus; differential expression; equipment training; experience; graduate student; granule cell; improved; in vivo; international center; knock-down; member; middle age; overexpression; prevent; tool; trait; transcription factor; transcriptome; transcriptome sequencing; transcriptomics; young adult

The hippocampus is a region of the brain that continues to produce new dentate granule cells (GCs) throughout life. Development of adult-born GCs and their integration into preexisting circuits is modulated by environment and by electrical activity of the local circuits, and is altered in the aging brain. To understand how GC integration occurs and how it is modulated by activity and aging, it is crucial to dissect the precise molecular mechanisms underlying these processes. The technology required for addressing these fundamental problems is unavailable in Argentina, but routinely applied in the Arlotta lab at Harvard. Joining efforts to address this specific problem is a natural next step. The overarching goal of this proposal is to exploit the strategies for transcriptional profiling and bioinformatic analysis in brain development validated by the Arlotta lab and the Schinder lab's expertise in functional characterization of adult-born GCs to build an experimental pipeline for the discovery of new molecules controlling circuit plasticity in the adult and aging brain, that includes assays for testing the roles of individual proteins to an unprecedented level of molecular and functional detail. In Aim 1, we propose to generate a pipeline to reveal transcription factors, epigenetic regulators, or effector genes controlling the developmental transitions along GC maturation and integration. The proposed experimental pipeline is similar for all three Aims: (i) FACS-purify birth-dated adult-born GCs at different stages; (ii) transcriptionally profile each population using two complementary forms of RNA sequencing; (iii) bioinformatically identify transcription factors or epigenetic regulators that may control stage progression; and (iv) functionally test candidate molecules through in vivo knock-down or overexpression. Using this same approach, we will then investigate how stage-specific transcriptome dynamics are altered in GCs from the aging hippocampus, to identify and functionally test changes in regulatory molecules that may be responsible for their protracted development (Aim 2). Finally, we will seek to identify molecular mediators of activity-mediated acceleration in GC development in the adult and the aging brain. (Aim 3). This grant will further the aims of the Fogarty International Center in expanding the technical capacities of Dr Schinder's lab, including availability of equipment, training of Argentinian graduate students and postdoctoral fellows, and building collegial networks between members of the Leloir and Harvard research communities. This work will significantly expand the capacity of Leloir to apply state-of-the-art transcriptomic profiling (currently limited, throughout Argentina) to solve new problems related to brain function and disease, locally supported by a bioinformatician who is co-investigator in the project. The workflow proposed will therefore not only enable a new generation of molecular studies in the Schinder lab by implementing the most advanced molecular tools and technologies, but also transfer expertise and know-how through personnel training such that these technologies and approaches will become available for routine use at the Leloir Institute at large.

海马体是大脑中不断产生新的齿状颗粒细胞的区域。