Molecular mechanisms of neuronal plasticity

神经元可塑性的分子机制

• 批准号: 10592864
• 负责人: JUSTIN BLAU
• 金额: $ 1.17万
• 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/10592864
• 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.

项目摘要 神经元的可塑性使神经元能够改变彼此之间连接的强度， 建立或破坏连接。可塑性是神经元的一个基本特性， 它的功能，如学习和可能的睡眠，但它也是失调的疾病，如自闭症。使 神经元连接的稳定变化需要转录和翻译以及活性依赖基因 表达程序响应于神经元活性而被快速诱导。在第一波基因突变中， 基因表达编码转录因子，然后调节其他基因， 与可塑性有关。这些活动依赖性程序的组成部分中的突变与 与人类认知障碍和精神疾病的关系，显示了这一途径的重要性。 我们研究了果蝇昼夜节律起搏神经元s-LNvs的可塑性， 它们的投影形态的变化是可预测的，并且每天在限定的时间发生。具有 每个大脑半球只有4个s-LNvs，这使得它们的投射很容易可视化，我们有工具， 果蝇遗传学改变基因表达或神经元活性的s-LNvs，沿着表达谱。- - LNv结构变化由神经元活动驱动：它们的投射在黎明时扩大，此时s-LNv最多 兴奋，并收回黄昏时，s-LNvs变得超极化。s-LNvs使用活性依赖性基因 表达以扩大投射，最终激活Rac 1 GTdR以调节肌动蛋白。我们已经确定了一 由神经元超极化和/或神经元不活动激活的第二转录程序。这 一个程序对抗活性依赖性基因表达，并导致Rho 1 GTdR激活以收缩s-LNv 预测。就像活性依赖的基因表达一样，超极化依赖基因表达的第一步， 表达是转录一个编码转录因子的基因-在这种情况下，玩具，一个苍蝇Pax 6直向同源物。 在目标1中，我们提出了理解超极化依赖基因的分子机制， 在s-LNvs中表达，并测试该程序是否在哺乳动物中起作用。我们还要测试超极化- 依赖性基因表达在睡眠中是重要的，这与整体突触降尺度有关。在 目标二，研究活性依赖基因和超极化依赖基因之间的竞争 表达程序可能在转录和转录后都起作用，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，并深入了解新的连接是如何指定的， 分子水平。总的来说，研究s-LNvs中的可塑性应该给出一个全面的可塑性观点， 它与神经生物学相关，可以识别新的疾病风险位点。