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：学习和记忆缺陷是几种精神疾病的标志精神分裂症，自闭症和阿尔茨海默氏症。正常和疾病中的这些认知过程状态受神经元回路中的空间调节基因的控制。研究有实施了直接 - 早期基因（IEG）的作用，特别是活性调节的细胞骨架行为响应中的相关（ARC/ARG3.1）。 ARC引起了特别的兴趣，因为它影响突触传播，可塑性和长期记忆。短期转换对于长期记忆，一种称为巩固的过程，需要ARC蛋白水平为维持数小时到几天。但是，现有研究表明半衰期很短电弧mRNA和蛋白质（小于60分钟）。这很有趣表达在长时间范围内促进记忆巩固。对于包括弧在内的IEG，基因表达的调节在转录水平上引发。因此，我们假设神经元子集中转录的周期性周期将使弧水平持续稳定内存跟踪的网络。我们建议确定分子机制这些转录周期的基础。最近，我们生成了一个敲击鼠标模型其中内源性弧基因用细菌衍生的茎环将荧光标记在单个神经元中实现高检测灵敏度和单个弧等位基因的成像几个小时，没有前所未有的临时分辨率。通过内源性弧的实时成像培养神经元和急性海马切片中的基因转录，我们将建立长期的术语ARC转录动力学及其对神经元活性模式的依赖性。我们将表征活动和翻译反馈在ARC转录调控中的作用不同的时间尺度。这将为以下深刻的见解：i）长期弧转录法规多长时间影响记忆合并和ii）改进基于活动的记者的设计相关的弧表达和行为。