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: 10404657
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404657
• 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; Fogarty International Center; 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; 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.

海马是大脑的一个区域，继续产生新的牙齿颗粒细胞（GCS） 一生。成人出生的GC的开发及其整合到已经存在的电路中。 环境和通过局部电路的电活动，并在衰老的大脑中改变。了解如何 GC集成发生及其如何通过活动和衰老调节，至关重要的是剖析精确 这些过程为基础的分子机制。解决这些问题所需的技术 阿根廷没有基本问题，但通常在哈佛大学的阿洛塔实验室中应用。加入 解决这个特定问题的努力是自然的下一步。该提议的总体目标是利用 由大脑发育中的转录分析和生物信息学分析的策略由 Arlotta Lab和Schinder实验室在成人GC的功能表征方面的专业知识以建立一个 在成人和衰老中发现新分子可控制电路可塑性的实验管道 大脑，其中包括测试单个蛋白质的作用的测定法 和功能细节。在AIM 1中，我们建议生成一条管道来揭示转录因子，表观遗传因素 控制沿GC成熟和整合的发育转变的调节剂或效应基因。 所提出的实验管道对于所有三个目的都是相似的：（i）FACS纯化出生日期的GCS 不同的阶段； （ii）使用两种互补形式的RNA在转录上介绍了每个种群 测序； （iii）生物信息识别可能控制阶段的转录因子或表观遗传调节剂 进展； （iv）通过体内敲低或过表达在功能上测试候选分子。 然后，我们将使用相同的方法研究特定阶段的转录组动力学如何改变 来自衰老海马的GC，以识别并在功能上测试可能是调节分子的变化 负责其旷日持久的发展（AIM 2）。最后，我们将寻求确定 活性介导的成人和大脑衰老大脑的GC发育的加速度。 （目标3）。这笔赠款将 此外 包括设备的可用性，阿根廷研究生和博士后研究员的培训以及 Leloir和哈佛研究社区成员之间建立大学网络。这项工作将 显着扩大了Leloir应用最新转录组分析的能力（目前有限， 在整个阿根廷）解决与大脑功能和疾病有关的新问题，由 生物信息学家是该项目的共同研究者。因此，提出的工作流不仅将启用 通过实施最先进的分子工具，在Schinder实验室中的新一代分子研究 和技术，但也通过人事培训转移专业知识和知识，以便这些 技术和方法将在整个Leloir Institute进行常规使用。

项目成果

Molecular logic of cellular diversification in the mouse cerebral cortex.

• DOI: 10.1038/s41586-021-03670-5
• 发表时间: 2021-07
• 期刊: Nature
• 影响因子: 64.8

Experience-Dependent Structural Plasticity of Adult-Born Neurons in the Aging Hippocampus.

衰老海马体中成年神经元的经验依赖性结构可塑性。

• DOI: 10.3389/fnins.2019.00739
• 发表时间: 2019
• 期刊: Frontiers in neuroscience
• 影响因子: 4.3
• 作者: Trinchero,MarielaF;Herrero,Magalí;Monzón-Salinas,MCristina;Schinder,AlejandroF
• 通讯作者: Schinder,AlejandroF

Dynamic interplay between GABAergic networks and developing neurons in the adult hippocampus.

• DOI: 10.1016/j.conb.2021.03.008
• 发表时间: 2021-08
• 期刊: Current opinion in neurobiology
• 影响因子: 5.7
• 作者: Trinchero MF;Giacomini D;Schinder AF
• 通讯作者: Schinder AF

Optogenetic axon guidance in embryonic zebrafish.

• DOI: 10.1016/j.xpro.2021.100947
• 发表时间: 2021-12-17
• 期刊: STAR protocols
• 作者: Harris JM;Yu-Der Wang A;Arlotta P
• 通讯作者: Arlotta P

Neuroligin-2 controls the establishment of fast GABAergic transmission in adult-born granule cells.

Neuroligin-2 控制成年颗粒细胞中快速 GABA 能传输的建立。

• DOI: 10.1002/hipo.23505
• 发表时间: 2023
• 期刊: Hippocampus
• 影响因子: 3.5
• 作者: Groisman,AyelénI;Aguilar-Arredondo,Andrea;Giacomini,Damiana;Schinder,AlejandroF
• 通讯作者: Schinder,AlejandroF