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 推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出现的 神经元身份和控制不同行为的神经元连接的电路特定模式仍然存在 未知。我们以前对杏仁核内侧亚核(Mea)发育的研究，杏仁核内侧亚核是 处理先天(非后天)社会行为所必需的嗅觉线索，表明 胚胎模式和后来的神经元亚型识别，特定血统的输出连接模式和 天生的行为规则。利用学习MEA的优势，一种发展上的硬连接 系统，我们提出的研究的目标是阐明连接 胚胎大脑发育，功能输出较晚。根据我们之前的数据，我们假设 MEA神经元亚型同一性和亚回路配线模式的成熟特性是 通过细胞和分子后遗症预先配置，这些后遗症随着VZ/SVZ血统的分歧而展开。我们 建议通过确定：早期MEA血统背后的细胞机制来检验这一假说 多样化(具体目标1)和2)将新出现的胚胎转录计划与 获取神经元特性以及电路组装和连接的遗传识别符(具体目标2)。 这将通过结合海达尔实验室在细胞和转录机制方面的专业知识来实现。 研究了早期祖细胞的规范和科尔宾实验室在杏仁核发育和功能的遗传基础。 我们建议使用创新的方法，包括宫内超声精确引导标记mea。 祖细胞池、多光子成像以在神经元出现时跟踪它们，以及尖端无人监督 单核(SN)RNA-SEQ用于鉴定作为mea起作用的细胞和分子因子的全部谱系 祖细胞产生功能相连的出生后神经元。