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: 10430617
• 负责人: JOSHUA G CORBIN
• 金额: $ 26.78万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10430617
• 关键词: Adhesions; Adult; Aggressive behavior; Amygdaloid structure; Automobile Driving; Behavior; Behavior Control; Behavioral; Biology; Brain; Cell Nucleus; Cell division; Cells; Cerebral cortex; Complex; Cues; Data; Development; Discrimination; Electrophysiology (science); Electroporation; Embryo; Embryonic Development; Emotional; Emotional disorder; 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; Small Nuclear RNA; Social Behavior; Specific qualifier value; Specificity; Structure of terminal stria nuclei of preoptic region; System; Testing; Therapeutic; Time; Transcription Process; Vertebrates; Work; autism spectrum disorder; base; cohort; developmental disease; experimental study; in utero; in vivo; innovation; multiphoton imaging; nerve stem cell; neuroepithelium; neurogenesis; neuronal patterning; novel; postnatal; progenitor; programs; rational design; receptor; segregation; social; social deficits; time use; transcription factor; transcriptome sequencing; 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.

项目概要 驱动胚胎大脑发育的复杂细胞和分子事件正在变得更好 明白了。然而，这些早期过程如何以及在多大程度上与后来的出现相关联？ 神经元身份和控制不同行为的神经元接线的电路特定模式仍然存在 未知。我们之前对杏仁核内侧亚核（MeA）发育的研究，杏仁核是大脑发育的中心枢纽。 处理嗅觉线索对于先天（未习得的）社会行为至关重要，表明两者之间存在直接联系 胚胎模式和后来的亚型神经元身份、输出连接的谱系特异性模式和 先天的行为调节。利用研究 MeA 的优势，MeA 是一种发育硬连线 系统，我们提出的研究的目标是阐明桥梁的细胞和分子机制 胚胎大脑发育及后期功能输出。根据我们之前的数据，我们假设 MeA 神经元亚型身份和亚电路布线模式的成熟特性是 通过随着 VZ/SVZ 谱系分歧而展开的细胞和分子后遗症进行预先配置。我们 建议通过确定以下内容来检验这一假设： 早期 MeA 谱系的细胞机制 多样化（具体目标 1）和 2）将新兴胚胎转录组程序与 获取神经元身份以及电路组装和连接的遗传标识符（具体目标 2）。 这将通过结合 Haydar 实验室在细胞和转录组机制方面的专业知识来实现 早期祖细胞规范和 Corbin 实验室在杏仁核发育和功能的遗传基础上的研究。 我们建议利用创新方法，包括子宫内超声精确引导 MeA 标记 祖细胞池、跟踪神经元出现的多光子成像以及尖端的无监督技术 单核 (sn) RNA-seq 可识别作为 MeA 运作的完整细胞和分子因子 祖细胞产生功能连接的出生后神经元。