Temporal dynamics of Arc (Arg3.1) transcriptional regulation

Arc (Arg3.1) 转录调控的时间动态

基本信息

批准号：
10370358
负责人：
Sulagna Das
金额：
$ 25.2万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10370358
关键词：
Acute Affect Alleles Alzheimer&apos s Disease Area Bacteriophages Behavior Cell Nucleus Cells ChIP-seq Collaborations Complex Coupling Data Dependence Disease Early Gene Transcriptions Elements Ensure Event Feedback Frequencies Gene Expression Gene Expression Regulation Gene Proteins Genes Genetic Transcription Genome Genomics Glutamates Heterogeneity Hippocampus (Brain)Hour Image Immediate-Early Genes Impairment Individual Kinetics Knock-in Mouse Label Learning Letters Link Maintenance Maps Mediating Memory Memory impairment Mental disorders Messenger RNA Molecular Neurons Neurosciences Nuclear Pattern Periodicity Probability Process Protein Biosynthesis Proteins RNA chemical synthesis Regulation Reporter Role Schizophrenia Signal Transduction Slice Synapses Synaptic Transmission Testing Time TimeLine Training Transcriptional Regulation Translating Translations autism spectrum disorder base behavioral response chromatin remodeling cognitive function cognitive performance cognitive process combinatorial dentate gyrus design detection sensitivity experience granule cell improved insight interest knock-down long term memory mRNA Export memory consolidation mouse model nervous system disorder neuronal circuitry neuronal patterning novel optogenetics promoter real-time images receptor response spatial memory spatiotemporal stem temporal measurement transcription factor transcriptomics

项目摘要

Abstract: Deficits in learning and memory are hallmarks of several psychiatric disorders including schizophrenia, autism, and Alzheimer’s. These cognitive processes in both normal and disease states are controlled by spatiotemporally regulated genes in neuronal circuits. Studies have implicated the role of immediate-early genes (IEGs), particularly, Activity-regulated cytoskeletal associated (Arc/Arg3.1) in behavioral responses. Arc has garnered special interest because it affects synaptic transmission, plasticity and long-term memory. The conversion from short-term to long-term memory, a process known as consolidation, requires Arc protein levels to be maintained over several hours to days. However, existing studies indicate very short half-lives of Arc mRNA and protein (less than 60 mins). It is intriguing how short temporal window of Arc expression promotes memory consolidation over long time scales. For IEGs including Arc, the regulation of gene expression initiates at the level of transcription. Therefore, we hypothesize that periodic cycles of transcription in a subset of neurons would enable persistence of Arc levels in the network for stabilizing the memory trace. We propose to identify the molecular mechanisms underlying these transcription cycles. Recently, we have generated a knock-in mouse model where the endogenous Arc gene is fluorescently labeled with bacteriophage-derived stem loops, enabling high detection sensitivity and imaging of individual Arc alleles in single neurons over several hours with unprecedented temporal resolution. By real-time imaging of endogenous Arc gene transcription in cultured neurons and in acute hippocampal slices, we will establish the long- term Arc transcription dynamics and its dependence on patterns of neuronal activity. We will characterize the role of activity and translational feedback in Arc transcriptional regulation at different time scales. This will provide insights into: i) how long term Arc transcriptional regulation impacts memory consolidation and ii) improve design of activity-based reporters to reliably correlate Arc expression and behavior.

抽象的：学习和记忆缺陷是多种精神疾病的标志，包括精神分裂症、自闭症和阿尔茨海默氏症在正常和疾病中都有这些认知过程。研究表明，状态是由神经回路中的时空调节基因控制的。涉及立即早期基因（IEG）的作用，特别是活性调节的细胞骨架 Arc 因其与行为反应相关（Arc/Arg3.1）而引起了特别的兴趣。影响突触传递、可塑性和长期记忆的转换。长期记忆的过程称为巩固，需要 Arc 蛋白水平然而，现有研究表明半衰期非常短。 Arc mRNA 和蛋白质（少于 60 分钟） Arc 的时间窗口有多短，这一点很有趣。对于包括 Arc 在内的 IEG，表达式可促进长期记忆巩固。基因表达的调控始于转录水平。因此，我们致力于这一点。神经元子集中的周期性转录循环将使 Arc 水平持续存在我们建议确定稳定记忆痕迹的分子机制。最近，我们生成了一个基因敲入小鼠模型。其中内源性 Arc 基因被噬菌体衍生的茎环荧光标记，实现单个神经元中单个 Arc 等位基因的高检测灵敏度和成像通过内源性电弧的实时成像，可以在几个小时内实现前所未有的时间分辨率。在培养的神经元和急性海马切片中的基因转录，我们将建立长术语 Arc 转录动力学及其对神经活动模式的依赖性。描述 Arc 转录调控中活性和翻译反馈的作用这将提供以下方面的见解：i) Arc 转录调控的长期时间。影响内存整合，并且 ii）改进基于活动的生产者的设计，以可靠地将表达和行为关联起来。