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

• 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
• 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

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）：成瘾的标志是过度寻求药物的行为，被认为是由许多脑结构（包括前额叶皮层）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节是基因表达的关键决定因素，最近与药物诱导的神经塑性有关。本项目将制定合作的努力，是主要研究者（Kippin），其专业知识是行为神经科学的专业知识，而联合主管研究者（SUN）的专业知识是表观遗传学，旨在探索在大鼠可卡因自我递增模型中产生的染色质重塑。具体而言，这项研究基于可卡因自我给药的大鼠模型（通过静脉内导管），每天短或延长访问，后者的条件导致可卡因摄入的时间依赖性升级以及随后的复发性脆弱性，与在可卡因成瘾中观察到的模式相似。 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确定可卡因戒断2个月的这些变化的持久性质。该项目的长期目标是建立高通量DNA甲基化和其他技术的实用性，以确定成瘾中涉及的分子靶标，并在我们的实验室之间建立合作，以绘制介导动机和认知过程中的神经电路中的染色质重塑（DNA甲基化和组蛋白修饰）的变化。这些研究将为与成瘾过程相关的脑病理学的作用提供更详细的了解。 公共卫生相关性：基因表达的变化广泛与成瘾过程中大脑结构的病理功能有关。本项目将确定染色质重塑，特别是DNA甲基化对前额叶皮层内基因表达变化的贡献，这些变化是在过度可卡因摄入的大鼠模型中产生的。这些实验将建立一个框架，通过使用高通量分子技术与疾病相关行为模型的高通量分子技术在成瘾中研究遗传功能的长期变化，以告知我们对成瘾相关的脑病理学的理解。

项目成果

Prenatal Stress Alters Progestogens to Mediate Susceptibility to Sex-Typical, Stress-Sensitive Disorders, such as Drug Abuse: A Review.

• DOI: 10.3389/fpsyt.2011.00052
• 发表时间: 2011
• 期刊: Frontiers in psychiatry
• 影响因子: 4.7
• 作者: Frye CA;Paris JJ;Osborne DM;Campbell JC;Kippin TE
• 通讯作者: Kippin TE

Stimulation of adult neural stem cells with a novel glycolipid biosurfactant.

用新型糖脂生物表面活性剂刺激成体神经干细胞。

• DOI: 10.1007/s13760-013-0232-4
• 发表时间: 2013
• 期刊: Acta neurologica Belgica
• 影响因子: 2.7
• 作者: Stipcevic,Tamara;Knight,ChristopherP;Kippin,TodE
• 通讯作者: Kippin,TodE