Molecular Mechanisms of Somatostatin Interneuron Diversity

项目总结 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决定的。 具体地说，生长抑素中间神经元，包括所有皮质中间神经元的三分之一，通过 通过靶向和选择性抑制兴奋性锥体神经元的树突，在大脑皮层内传递信息。 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 各式各样的子类型。许多研究已经表征了生长抑素的独特和异质性。 功能正常的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 在发展过程中产生这种多样性的机制相对未知。最新研究 已经花费了相当大的努力来获得关于神经元间多样性的描述性描述 通过描述皮质中间神经元期间展开的转录和表观遗传事件来实现发育 发展，但这些研究也不能提供一个机械论的解释。 我们的实验室和其他实验室之前已经证明了转录因子Satb1对适当的 皮质生长抑素中间神经元的发育。有趣的是，去除Satb1具有不同的效果 在生长抑素中间神经元群体中，表明它可能有助于不同 生长抑素中间神经元群体的特征。此外，单细胞转录转录测序数据 结果表明，Satb1在不同的生长抑素中间神经元亚型中的表达水平各不相同。因此，在这方面 我提出的假设是，Satb1以一种浓度依赖的方式促进生长抑素的产生 通过控制不同的遗传程序来控制发育过程中的神经元间多样性。我将使用以下工具验证这一假设 小鼠遗传学、表观遗传学和转录图谱以及显微镜的结合。在AIM 1我试图表征不同生长抑素中间神经元亚型的Satb1蛋白水平以及 清除Satb1的表型。在目标2中，我试图了解不同的Satb1水平可以 导致不同的遗传程序。这项研究的成功完成将有助于阐明 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 突出新的令人兴奋的基因调控原则。这些数据以及研究和科学专业知识 通过此Kirschstein-NRSA F30奖学金奖开发的项目将支持我成为 独立调查员。

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.