Transcriptional Control of Synaptic Plasticity by Class IIa HDACs

IIa 类 HDAC 对突触可塑性的转录控制

基本信息

批准号：
10605220
负责人：
Anton Maximov
金额：
$ 68.76万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10605220
关键词：
Acute Address Affect Amygdaloid structure Animals Architecture Area Ataxia Telangiectasia Basic Science Binding Proteins Biological Brain Brain Mapping Brain imaging Brain region Caenorhabditis elegans Cell Nucleus Cells Chromatin Code Cytoplasm Development Drosophila genus ERG gene Electron Microscopy Electrophysiology (science)Environment Face Genes Genetic Genetic Techniques Genetic Transcription Glutamates Goals HDAC4 gene HDAC5 gene Hippocampus Histone Deacetylase Homologous Gene Human Image Individual Interneurons Learning Link Maps Mass Spectrum Analysis Mediating Memory Mental Retardation Microscopy Modeling Molecular Mus Mutant Strains Mice Nervous System Neuronal Plasticity Neurons Nuclear Nuclear Import Organelles Parkinson Disease Pathway interactions Pattern Pharmaceutical Preparations Physiological Play Protein Isoforms Proteins Reporter Repression Research Role Scanning Electron Microscopy Sensory Signal Transduction Slice Structure Synapses Synaptic plasticity Syndrome Testing Time Transcription Repressor Transcriptional Regulation Uncertainty awake blood-brain barrier crossing calcium indicator cell type chemical genetics conditional knockout connectome deep sequencing effective therapy entorhinal cortex experience fear memory gain of function gene induction genetic approach genetic manipulation human disease in vivo in vivo imaging insight memory acquisition memory consolidation memory encoding nervous system disorder neural neural circuit novel patch clamp pharmacologic programs recruit response sensory input sensory stimulus small molecule spatiotemporal tool transcription factor two-photon

项目摘要

The goal of this project is to elucidate the molecular mechanisms of experience-dependent plasticity of neural circuits essential for learning and memory. We focus on class IIa histone deacetylases (HDACs), transcriptional repressors that shuttle between the nucleus and cytoplasm. We and our colleagues have previously demonstrated that the class IIa HDAC isoform, HDAC4, regulates memory in mice, drosophila and C.elegans. In conjunction with these findings, HDAC4 has been linked to several neurological disorders in humans. In the initial project period, we discovered that HDAC4 and its close homolog, HDAC5, restrict the transcriptional response to sensory input. These observations support the hypothesis that plasticity- and memory-related genes are dynamically repressed in the brain in any environment. Here, we propose to determine how class IIa HDACs operate at circuit, cellular and molecular levels, and how their nuclear signaling impacts neurons in the mouse hippocampus. Moreover, we will exploit class II HDACs as tools for rapid chemical-genetic control of transcription in behaving animals. Our aims are: 1) To determine how class IIa HDAC operate at a circuit level by using immunofluorescent microscopy, activity-based tagging of memory engrams cells, and in vivo 2-photon imaging of repressors and calcium indicators; 2) To identify nuclear effectors of class IIa HDACs in specific genetically-defined neuron types by deep sequencing and mass spectrometry; 3) To define the consequences of class IIa HDACs signaling on circuit structure and function. This will be accomplished by combining electron microscopy, whole-brain imaging, and electrophysiology; and 4) To leverage chemical-genetic manipulation of class IIa HDAC signaling for mapping of brain areas where activity-dependent transcription promotes memory coding. Taken together, these studies will explain how neuronal chromatin-binding proteins associated with human disease function in the normal brain, and will provide novel insights into the basic mechanisms underlying network plasticity and memory storage.

该项目的目标是阐明神经经验依赖性可塑性的分子机制学习和记忆所必需的电路。我们专注于 IIa 类组蛋白脱乙酰酶 (HDAC)、转录在细胞核和细胞质之间穿梭的阻遏蛋白。我们和我们的同事之前曾证明 IIa 类 HDAC 同工型 HDAC4 调节小鼠、果蝇和线虫的记忆。结合这些发现，HDAC4 与人类的多种神经系统疾病有关。在项目初期，我们发现HDAC4及其密切同源物HDAC5限制转录对感官输入的反应。这些观察结果支持了这样的假设：可塑性和记忆相关基因在任何环境下大脑中都会受到动态抑制。在这里，我们建议确定 IIa 类 HDAC 如何在电路、细胞和分子水平上运作，以及它们的核信号如何影响小鼠的神经元海马体。此外，我们将利用 II 类 HDAC 作为快速化学遗传控制转录的工具在行为动物中。我们的目标是：1) 使用免疫荧光确定 IIa 类 HDAC 如何在电路水平上运行显微镜、基于活动的记忆印迹细胞标记以及阻遏物和细胞的体内 2 光子成像钙指标； 2) 鉴定特定基因定义的神经元类型中 IIa 类 HDAC 的核效应子通过深度测序和质谱分析； 3) 定义 IIa 类 HDAC 信号传导的后果电路结构和功能。这将通过结合电子显微镜、全脑成像、和电生理学； 4) 利用 IIa 类 HDAC 信号传导的化学遗传操作绘制大脑区域图，其中活动依赖性转录促进记忆编码。总而言之，这些研究将解释神经元染色质结合蛋白如何与人类相关正常大脑中的疾病功能，将为了解其基本机制提供新的见解网络可塑性和记忆存储。