Molecular Mechanisms of Somatostatin Interneuron Diversity

生长抑素中间神经元多样性的分子机制

• 批准号: 10601433
• 负责人: Jinoh Lee
• 金额: $ 4.14万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601433
• 关键词: Address; Adult; Alleles; Antibodies; Award; Binding; Biological Assay; Brain; Categories; Cell Nucleus; Cells; Cellular Assay; Cerebral cortex; Chromatin; Chromatin Remodeling Factor; Complex; Data; Dendrites; Development; Epigenetic Process; Epitopes; Event; Excision; Fellowship; Fluorescent in Situ Hybridization; Gene Expression; Gene Expression Regulation; Generations; Genetic; Genetic Transcription; Genomics; Goals; Heterogeneity; Immunofluorescence Immunologic; Interneurons; Knock-in Mouse; Knowledge; Laboratories; Lead; Maps; Microscopy; Molecular; Mus; National Research Service Awards; Neurons; Neurosciences; Pathology; Perception; Phenotype; Physiological; Play; Population; Property; Proteins; Research; Research Personnel; Role; Route; Running; Sensory; Severities; Shapes; Somatostatin; Testing; Transposase; Work; cell type; conditional knockout; epigenetic profiling; experimental study; falls; genetic approach; genetic profiling; hippocampal pyramidal neuron; insight; mouse genetics; programs; single-cell RNA sequencing; tool; transcription factor; transcriptome sequencing; transcriptomic profiling; transcriptomics

PROJECT SUMMARY The multitude and complexity of cortical functions is shaped by the diversity of cortical interneurons populations. Specifically, somatostatin interneuron, which comprise one-third of all cortical interneurons, route the flow of information within the cortex by targeting and selectively inhibiting the dendrites of excitatory pyramidal neurons. Recent efforts have demonstrated that cortical somatostatin interneurons are themselves further divided into various subtypes. Many studies have characterized the distinct and heterogenous properties of somatostatin interneuron subtypes in the functioning adult brain and their diverse contributions to cortical function, but the mechanisms by which this diversity is generated during development are relatively unknown. Recent studies have devoted considerable effort into obtaining a descriptive account of interneuron diversification during development by profiling the transcriptomic and epigenetic events that unfold during cortical interneuron development, but these studies also fall short of presenting a mechanistic explanation. Our lab and others have previously demonstrated the requirement of the transcription factor Satb1 for the proper development of cortical somatostatin interneurons. Interestingly, removal of Satb1 has heterogeneous effects within the somatostatin interneuron population, suggesting that it may contribute to the generation of diverse features within the somatostatin interneuron population. Moreover, single-cell transcriptomic sequencing data shows that Satb1 is expressed at varying levels across distinct somatostatin interneuron subtypes. Thus, In this proposal, I present the hypothesis that Satb1, in a concentration-dependent manner, contributes to somatostatin interneuron diversity during development by controlling distinct genetic programs. I will test this hypothesis using a combination of intersectional mouse genetics, epigenetic and transcriptomic profiling, and microscopy. In Aim 1 I seek to characterize varying Satb1 protein levels across somatostatin interneuron subtypes and the phenotype of Satb1 removal. In Aim 2 I seek to understand the mechanism by which varying Satb1 levels may lead to distinct genetic programs. Successful completion of this study will help to elucidate fundamental mechanisms by which the brain creates neuronal diversity during development. Furthermore, these studies will highlight new exciting principles for gene regulation. These data along with the research and scientific expertise developed through this Kirschstein-NRSA F30 Fellowship Award will support my long-term goal of becoming an independent investigator.

项目摘要 皮质功能的多样性和复杂性是由皮质中间神经元群体的多样性形成的。 具体地说，生长抑素中间神经元，其中包括三分之一的所有皮层中间神经元，路由的流动， 通过靶向和选择性地抑制兴奋性锥体神经元的树突，在皮质内传递信息。 最近的研究表明，皮质生长抑素中间神经元本身进一步分为 各种亚型。许多研究表明生长抑素具有明显的异质性 功能性成人大脑中的中间神经元亚型及其对皮质功能的不同贡献，但 在发育过程中产生这种多样性的机制相对未知。最近的研究 我投入了相当大的努力，以获得描述性的帐户，中间神经元的多样化， 通过分析皮质中间神经元发育过程中出现的转录组和表观遗传事件， 发展，但这些研究也未能提出一个机械的解释。 我们的实验室和其他实验室先前已经证明了转录因子Satb 1对于适当的转录的需要。 皮质生长抑素中间神经元的发育。有趣的是，Satb 1的去除具有异质性效应， 在生长抑素中间神经元群体中，这表明它可能有助于产生不同的 生长抑素中间神经元群体内的特征。此外，单细胞转录组测序数据 显示Satb 1在不同的生长抑素中间神经元亚型中以不同的水平表达。所以针对本 根据这一提议，我提出了Satb 1以浓度依赖性方式参与生长抑素的假说 通过控制不同的遗传程序来控制发育过程中的interneuron多样性。我将用以下方法来检验这个假设： 交叉小鼠遗传学、表观遗传学和转录组学分析以及显微镜的组合。在Aim中 1我试图描述不同的Satb 1蛋白水平在生长抑素中间神经元亚型和 Satb 1去除的表型。在目标2中，我试图理解不同的Satb 1水平可能 导致不同的遗传程序。成功完成这项研究将有助于阐明基本的 大脑在发育过程中创造神经元多样性的机制。此外，这些研究将 突出了基因调控的新的令人兴奋的原则。这些数据沿着研究和科学专业知识 通过这个Kirschstein-NRSA F30奖学金奖开发将支持我成为一个长期目标， 独立调查员