Cellular and transcriptomic programs linking amygdala progenitors to mature neuronal identity

将杏仁核祖细胞与成熟神经元身份联系起来的细胞和转录组程序

• 批准号: 10751113
• 负责人: JOSHUA G CORBIN
• 金额: $ 10.26万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-11 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10751113
• 关键词: Adhesions; Adult; Aggressive behavior; Amygdaloid structure; Automobile Driving; Behavior; Behavior Control; Behavioral; Biology; Brain; Cell division; Cells; Cerebral cortex; Complex; Cues; Data; Development; Discrimination; Early identification; Electrophysiology (science); Electroporation; Embryo; Embryonic Development; Emotional; Emotional disorder; Endowment; Event; Exhibits; Experimental Models; FOXP2 gene; Gene Expression; Genes; Genetic; Goals; Human; Hypothalamic structure; Instinct; Intervention; Ion Channel; Knowledge; Label; Link; Medial; Mental disorders; Molecular; Molecular Profiling; Morphology; Neurons; Neurotransmitters; Olfactory Pathways; Output; Partner in relationship; Pattern; Phenotype; Process; Proliferating; Property; Regulation; Social Behavior; Specific qualifier value; Specificity; Structure of terminal stria nuclei of preoptic region; System; Testing; Therapeutic; Transcription Process; Vertebrates; Work; autism spectrum disorder; cohort; developmental disease; experimental study; in utero; in vivo; inhibitory neuron; innovation; multiphoton imaging; nerve stem cell; neuroepithelium; neurogenesis; neuronal patterning; neuropathology; novel; postmitotic; postnatal; progenitor; programs; rational design; receptor; segregation; single nucleus RNA-sequencing; social; social deficits; time use; transcription factor; transcriptomics; ultrasound

Project Summary The complex cellular and molecular events driving embryonic brain development are becoming better understood. However, how and to what extent these early processes are linked to the later emergence of neuronal identity and circuit specific patterns of neuronal wiring controlling diverse behaviors remains unknown. Our previous studies of development of medial subnucleus of the amygdala (MeA), a central hub for processing olfactory cues essential for innate (unlearned) social behavior, suggests a direct link between embryonic patterning and later subtype neuronal identity, lineage-specific patterns of output connectivity and innate behavioral regulation. Leveraging the advantages of studying the MeA, a developmentally hard-wired system, the goal of our proposed studies is elucidate the cellular and molecular mechanisms that bridge embryonic brain development with later functional outputs. Based on our previous data, we hypothesize that the mature properties of MeA neuronal subtype identity and subcircuit wiring patterns are preconfigured via cellular and molecular sequalae that unfold as lineages diverge in the VZ/SVZ. We propose to test this hypothesis by determining: the cellular mechanisms underlying early MeA lineage diversification (Specific Aim 1) and 2) linking emerging embryonic transcriptomic programs with the acquisition of genetic identifiers of neuronal identity and circuit assembly and connectivity (Specific Aim 2). This will be achieved by combining the expertise of the Haydar lab in cellular and transcriptomic mechanisms of early progenitor specification and the Corbin lab in the genetic basis of amygdala development and function. We propose to utilize innovative approaches including in utero ultrasound precision guided labeling of MeA progenitor pools, multiphoton imaging to follow neurons as they emerge, and cutting-edge unsupervised single-nuclei (sn) RNA-seq to identify the full repertoire of cellular and molecular factors operating as MeA progenitors generate functionally connected postnatal neurons.

项目摘要 复杂的细胞和分子事件驱动胚胎脑发育变得更好 理解。但是，这些早期过程如何以及在何种程度上与后来的出现有关 神经元的身份和电路特定模式控制着多种行为的神经元接线 未知。我们先前关于杏仁核内侧亚核（MEA）的发展的研究， 处理嗅觉提示对于先天（未经学习的）社会行为必不可少的 胚胎图案和后来的亚型神经元身份，输出连接的特定谱系特定模式和 先天的行为调节。利用研究MEA的优势，这是一种发育坚硬的连线 系统，我们提出的研究的目的是阐明桥接的细胞和分子机制 胚胎脑发育具有后来的功能输出。根据我们以前的数据，我们假设 MEA神经元亚型身份和子电路接线模式的成熟特性是 通过谱系在VZ/SVZ中差异而展开的细胞和分子序列。我们 建议通过确定：早期MEA谱系的细胞机制来检验这一假设 多元化（特定目的1）和2）将新兴的胚胎转录程序程序与 获得神经元身份和电路组装和连通性的遗传标识符的获取（特定目标2）。 这将通过结合海达尔实验室在细胞和转录组机制中的专业知识来实现​​这一目标 在杏仁核发育和功能的遗传基础上，早期祖细胞规范和Corbin实验室的规范。 我们建议利用创新方法，包括在子宫超声精确指导下的MEA标签 祖细胞池，多光子成像以在神经元出现时跟随神经元和尖端的无监督 单核（SN）RNA-seq，以确定作为MEA的细胞和分子因子的完整曲目 祖细胞产生功能连接的产后神经元。