Chromatin Remodeling in the Prefrontal Cortex in Cocaine Addiction

可卡因成瘾中前额皮质的染色质重塑

基本信息

批准号：
8037810
负责人：
Tod Edward Kippin
金额：
$ 18.37万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA BARBARA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2012-08-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8037810
关键词：
Abstinence Acetylation Adult Behavior Behavioral Behavioral Model Brain Brain Pathology Brain region Catheters Chemosensitization Chromatin Structure Cocaine Cocaine Dependence Cognitive Collaborations DNA DNA Methylation DNA Methyltransferase DNA Modification Methylases Deacetylation Development Disease Dopamine Receptor Dorsal Employment Ensure Environment Enzymes Epigenetic Process Gene Expression Gene Targeting Genes Genetic Genetic Transcription Genomics Glutamates Goals Histone Deacetylase Histones Intake Laboratories Longitudinal Studies Maintenance Maps Mass Spectrum Analysis Medial Mediating Messenger RNA Methylation Modeling Molecular Molecular Target Nature Neurobiology Neuronal Plasticity Neurosciences Pattern Pharmaceutical Preparations Play Prefrontal Cortex Principal Investigator Process Proteins Rattus Regulation Relapse Resolution Role Saline Self Administration Self-Administered Signal Transduction Structure Syndrome Techniques The Sun Time Tissues Withdrawal addiction base chromatin immunoprecipitation chromatin modification chromatin remodeling cocaine exposure cognitive function drug seeking behavior genome-wide genome-wide analysis histone acetyltransferase histone modification interest neural circuit neuropeptide Y promoter public health relevance research study response sodium bisulfite transcription factor

项目摘要

DESCRIPTION (provided by applicant): A hallmark of addiction is excessive drug-seeking behavior which is believed to be mediated by pathological changes in a number of brain structures, including the prefrontal cortex, involving drug-induced alterations in gene expression. Chromatin remodeling or epigenetic regulation is a key determinant of gene expression that has recently been implicated in drug-induced neuroplasticity. The present project will develop a collaborative effort been the Principal Investigator (Kippin), whose expertise is in behavioral neuroscience, and the co-Principal Investigator (Sun), whose expertise is in epigenetics, to explore chromatin remodeling produced during a rat cocaine self-administration model of addiction. Specifically, this study is based on a rat model of cocaine self-administration (via a i.v. catheter) with either short or prolonged daily access with the latter condition leading to a time-dependent escalation of cocaine intake and subsequent relapse vulnerability which is similar to the pattern observed in cocaine addiction. Based on the results of a high-throughput, genome-wide analysis of DNA methylation using a MeDIP-CHIP assay in the dorsal medial prefrontal cortex produced by prolonged access to cocaine self- administration, the present application will verify methylation in genes of interest, determine the consequences for expression of those genes (at mRNA and protein levels), determine changes in the epigenetic machinery produced by cocaine exposure, and determine the enduring nature of these changes across 2 months of cocaine withdrawal. The long-term goals of this project are to establish the utility of high-throughput DNA methylation and other techniques to identify molecular targets involved in addiction as well as establish a collaboration between our laboratories to map changes in chromatin remodeling (both DNA methylation and histone modifications) in neural circuits mediating motivational and cognitive processes that are disrupted in addiction. These studies will provide a more detailed understanding of the role of chromatin remodeling to the brain pathology associated with the addiction process. PUBLIC HEALTH RELEVANCE: Changes in gene expression are widely implicated in the pathological function of brain structures during the addiction processes. The present project will determine the contribution of chromatin remodeling, specifically DNA methylation, to gene expression changes within the prefrontal cortex that are produced in a rat model of excessive cocaine intake. These experiments will establish a framework for studying the long-term changes in genetic function at the chromatin modification level in addiction through the employment of high-throughput molecular techniques combined with diseases relevant behavioral models in order to inform our understanding of addiction-related brain pathology.

描述（由申请人提供）：成瘾的一个标志是过度寻求药物的行为，这种行为被认为是由包括前额叶皮层在内的许多大脑结构的病理变化介导的，涉及药物诱导的基因表达改变。染色质重塑或表观遗传调控是基因表达的关键决定因素，最近与药物诱导的神经可塑性有关。本项目将由首席研究员 (Kippin) 和副首席研究员 (Sun) 共同努力，前者的专长是行为神经科学，后者的专长是表观遗传学，以探索大鼠可卡因自吸过程中产生的染色质重塑。成瘾管理模型。具体来说，这项研究基于可卡因自我给药（通过静脉导管）的大鼠模型，每日短期或长期服用可卡因，后一种情况会导致可卡因摄入量随时间推移而增加，并导致随后的复发易感性，这类似于可卡因成瘾中观察到的模式。基于使用 MeDIP-CHIP 测定在长期使用可卡因自我施用产生的背侧内侧前额叶皮层中对 DNA 甲基化进行高通量、全基因组分析的结果，本申请将验证感兴趣基因的甲基化，确定这些基因表达的后果（在 mRNA 和蛋白质水平），确定可卡因暴露产生的表观遗传机制的变化，并确定这些变化在可卡因戒断 2 个月内的持久性质。该项目的长期目标是利用高通量 DNA 甲基化和其他技术来识别与成瘾有关的分子靶标，并在我们的实验室之间建立合作，以绘制染色质重塑（DNA 甲基化和组蛋白）的变化图谱。调节在成瘾中被破坏的动机和认知过程的神经回路中的改变）。这些研究将更详细地了解染色质重塑对与成瘾过程相关的大脑病理学的作用。公共卫生相关性：成瘾过程中基因表达的变化与大脑结构的病理功能广泛相关。本项目将确定染色质重塑（特别是 DNA 甲基化）对过量可卡因摄入大鼠模型中产生的前额皮质内基因表达变化的贡献。这些实验将建立一个框架，通过采用高通量分子技术结合疾病相关的行为模型来研究成瘾中染色质修饰水平的遗传功能的长期变化，以帮助我们了解成瘾相关的大脑病理学。