Molecular mechanisms of neuronal plasticity

项目摘要 神经元的可塑性使神经元能够改变彼此之间联系的强度，甚至 要么建立联系，要么切断联系。可塑性是构成无数大脑的神经元的基本属性 功能，如学习，可能还有睡眠，但它在自闭症等疾病中也受到错误的调节。制做 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 表达程序是响应神经元活动而快速诱导的。在这第一波浪潮中的许多基因 基因表达编码转录因子，然后转录因子更直接地调节额外的基因 与可塑性有关的。这些依赖活动的程序的组成部分的突变已经被关联 与人类认知障碍和精神疾病的关系，表明了这一途径的重要性。 我们研究了果蝇主要的昼夜节律起搏神经元S-LNV的可塑性，因为 它们的投射形态的变化是可以预测的，每天都会在规定的时间发生。拥有 每个大脑半球只有4个S-LNV，使得他们的投射很容易可视化，而且我们有工具 改变S-LNV中基因表达或神经元活性的果蝇遗传学，以及表达谱。S- LNV的结构变化是由神经元活动驱动的：其投射在黎明时扩大，此时S-LNV最多 容易激动，在黄昏时分S-LNV超极化时收缩。S-LNV使用活性依赖基因 表达以扩大投射，最终激活rac1 GTP酶来调节肌动蛋白。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 程序反对活性依赖基因表达并导致Rho1 GTP酶激活以收回S-LNV 投射。就像活性依赖的基因表达一样，超极化依赖基因的第一步 表达是转录一个编码转录因子的基因-在这个例子中，Toy是Fly Pax6的同源物。 在目标1中，我们建议了解超极化依赖基因的分子机制 在S-LNV中表达，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- 依赖的基因表达在睡眠中很重要，这与突触整体比例下降有关。在……里面 目标2，我们将研究活性依赖基因和超极化依赖基因之间的竞争 可能同时在转录和转录后工作的表达程序，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联系， 我们预测将广泛适用，还将深入了解如何在 分子水平。总体而言，研究S的可塑性应该给出一个整体的、宽泛的可塑性观点。 与神经生物学相关，并可能识别新的疾病风险位点。

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.