Molecular mechanisms of neuronal plasticity

神经元可塑性的分子机制

• 批准号: 10356134
• 负责人: JUSTIN BLAU
• 金额: $ 42.54万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10356134
• 关键词: Actins; Brain; Cerebral hemisphere; Cognition Disorders; Development; Disease; Drosophila genus; Ensure; Gene Expression; Genes; Genetic; Genetic Transcription; Genomics; Goals; Guanosine Triphosphate Phosphohydrolases; Human; Learning; Mammals; Mental disorders; Molecular; Morphology; Mutation; Neurobiology; Neuronal Plasticity; Neurons; Pathway interactions; Property; Schizophrenia; Sleep; Specific qualifier value; Synapses; Testing; Time; Toy; Translations; Work; addiction; autism spectrum disorder; base; circadian pacemaker; disorder risk; fly; insight; novel; programs; response; risk variant; tool; transcription factor

Project Summary Neuronal plasticity allows neurons to change the strength of their connections with each other and even to make or break connections. Plasticity is a fundamental property of neurons that underlies numerous brain functions such as learning and probably sleep, but it is also misregulated in diseases such as autism. Making stable changes in neuronal connections requires transcription and translation and an activity-dependent gene expression program is rapidly induced in response to neuronal activity. Many of the genes in this first wave of gene expression encode transcription factors that then regulate additional genes that are more directly involved in plasticity. Mutations in components of these activity-dependent programs have been associated with human cognitive disorders and psychiatric diseases, showing the importance of this pathway. We study plasticity in s-LNvs, the principal Drosophila circadian pacemaker neurons, which are ideal since changes in the morphology of their projections are predictable and happen at defined times each day. Having only 4 s-LNvs per brain hemisphere makes their projections easy to visualize, and we have the tools of Drosophila genetics to alter gene expression or neuronal activity in s-LNvs, along with expression profiles. s- LNv structural changes are driven by neuronal activity: their projections expand at dawn when s-LNvs are most excitable, and retract around dusk when s-LNvs become hyperpolarized. s-LNvs use activity-dependent gene expression to expand projections, ultimately activating Rac1 GTPase to regulate actin. We have identified a second transcriptional program that is activated by neuronal hyperpolarization and/or neuronal inactivity. This program opposes activity-dependent gene expression and leads to Rho1 GTPase activation to retract s-LNv projections. Just like activity-dependent gene expression, the first step in hyperpolarization-dependent gene expression is to transcribe a gene encoding a transcription factor – in this case Toy, a fly Pax6 orthologue. In Goal 1, we propose to understand the molecular mechanism of hyperpolarization-dependent gene expression in s-LNvs, and test if this program functions in mammals. We will also test if hyperpolarization- dependent gene expression is important in sleep, which is associated with overall synaptic downscaling. In Goal 2, we will study competition between the activity-dependent and hyperpolarization-dependent gene expression programs that likely works both transcriptionally and post-transcriptionally to ensure one program dominates. In Goal 3, we will develop a genomic-based approach to identify connections between neurons that we predict will be broadly applicable, and also to give insights into how new connections are specified at the molecular level. Overall, studying plasticity in s-LNvs should give a holistic view of plasticity that is broadly relevant across neurobiology and could identify new disease risk loci.

项目概要 神经元可塑性允许神经元改变彼此之间的连接强度，甚至 建立或断开连接。可塑性是众多大脑神经元的基本属性 学习和睡眠等功能，但在自闭症等疾病中它也受到了错误的调节。制作 神经元连接的稳定变化需要转录和翻译以及活动依赖性基因 表达程序响应神经元活动而快速诱导。第一波浪潮中的许多基因 基因表达编码转录因子，然后调节更直接的其他基因 涉及可塑性。这些活动依赖性程序的组成部分的突变与 与人类认知障碍和精神疾病的关系，显示了该途径的重要性。 我们研究了 s-LNvs 的可塑性，s-LNvs 是果蝇主要的昼夜节律起搏神经元，它是理想的，因为 他们的投影形态的变化是可以预测的，并且会在每天规定的时间发生。拥有 每个大脑半球只有 4 个 s-LNv，使得它们的投影易于可视化，并且我们拥有以下工具 果蝇遗传学改变 s-LNv 中的基因表达或神经元活动以及表达谱。 s- LNv 结构变化是由神经元活动驱动的：它们的投射在黎明时扩展，此时 s-LNv 最为活跃。 兴奋，并在黄昏时分当 s-LNv 变得超极化时收缩。 s-LNvs 使用活性依赖性基因 表达以扩大投射，最终激活 Rac1 GTPase 来调节肌动蛋白。我们已经确定了一个 第二个转录程序由神经元超极化和/或神经元不活动激活。这 程序反对活性依赖性基因表达并导致 Rho1 GTPase 激活以缩回 s-LNv 预测。就像活性依赖性基因表达一样，超极化依赖性基因的第一步 表达是转录编码转录因子的基因——在本例中为Toy，是果蝇Pax6直系同源物。 在目标1中，我们建议了解超极化依赖性基因的分子机制 s-LNvs 中的表达，并测试该程序是否在哺乳动物中发挥作用。我们还将测试超极化是否- 依赖性基因表达在睡眠中很重要，这与整体突触缩小有关。在 目标2，我们将研究活性依赖性基因和超极化依赖性基因之间的竞争 表达程序可能同时在转录和转录后发挥作用，以确保一个程序 占主导地位。在目标 3 中，我们将开发一种基于基因组的方法来识别神经元之间的连接， 我们预测将广泛适用，并且还可以深入了解如何在 分子水平。总的来说，研究 s-LNvs 的可塑性应该给出一个广泛的可塑性的整体观点。 与神经生物学相关，可以识别新的疾病风险位点。