Common Epigenetic Mechanisms in Cocaine Addiction and Conditioned Fear

可卡因成瘾和条件性恐惧的常见表观遗传机制

• 批准号: 7643528
• 负责人: Timothy W Bredy
• 金额: $ 15.12万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-20 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7643528
• 关键词: Adult; Amygdaloid structure; Animal Model; Animals; Anxiety; Anxiety Disorders; Arts; Attenuated; Auditory; Behavior; Behavior Therapy; Behavioral; Brain; Brain region; Candidate Disease Gene; Cocaine; Cocaine Dependence; Cues; DNA; DNA Methylation; DNA Methylation Inhibition; DNA Modification Methylases; DNA Sequence; Development; Disease; Environment; Environmental Risk Factor; Epigenetic Process; Etiology; Event; Extinction (Psychology); Fright; Gene Expression; Gene Expression Regulation; Genes; Genomics; Hippocampal Formation; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Individual; Infusion procedures; Inherited; Intervention; Learning; Maps; Mass Spectrum Analysis; Memory; Mental Health; Mental disorders; Methylation; Modeling; Morbidity - disease rate; Phobic anxiety disorder; Play; Post-Traumatic Stress Disorders; Prefrontal Cortex; Prejudice; Prevalence; Procedures; Process; Psychotherapy; Reaction; Recovery; Relapse; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Role; Self Administration; Site; Sodium; Technology; Therapeutic; Therapeutic Intervention; Time; Tissues; Training; Variant; addiction; base; chromatin immunoprecipitation; classical conditioning; conditioned fear; craving; demethylation; drug of abuse; genome wide association study; genome-wide; genome-wide analysis; histone modification; improved; inhibitor/antagonist; learning extinction; neuropsychiatry; prevent; programs; promoter; public health relevance; research study; trait

DESCRIPTION (provided by applicant): Many neuropsychiatric diseases involve associative learning. The most obvious of these are the addictions (in which neutral cues in the environment come to evoke strong craving for drugs of abuse) and anxiety disorders (e.g., post-traumatic stress disorder, PTSD, in which neutral cues in the environment of the traumatic event come to evoke strong fear reactions). Epigenetics refers to the process by which cellular traits are established and inherited without a change in DNA sequence. These mechanisms of cellular memory also orchestrate the activity of genes in the adult brain, and recent findings suggest a role for epigenetic factors in the etiology of psychiatric disease. Thus, given the prevalence and co-morbidity of cocaine addiction and fear-related anxiety, and the increasing appreciation that environmental factors play a major role in determining mental health ("DNA is not destiny"), a deeper understanding of common epigenetic mechanisms associated with learning in coordinated models of addiction and fear is both timely and relevant. Aim 1 will employ a genome-wide approach using state-of-the-art technology to investigate epigenetic mechanisms regulating gene expression during the acquisition and extinction of cocaine-seeking behavior in a self-administration model of cocaine addiction, and of fear-related learning in a parallel model of auditory conditioned fear. Aim 2 will validate candidate genes by using ChIP and bisulphite mapping to examine histone modifications and DNA methylation around, and within, individual gene promoters, and correlate them with gene expression in brain regions supporting both forms of learning. These effects will be examined at different time points post-training in an effort to elucidate their role in spontaneous incubation and relapse. Aim 3 will study whether manipulations that induce local histone hyperacetylation, histone demethylation or inhibition of DNA methylation, during cocaine-self administration and fear training will prejudice animals toward incubation, while the same manipulation during extinction will prevent relapse of cocaine-seeking and of conditioned fear. These studies aim to elucidate common epigenetic factors contributing to psychiatric disease, and to explore the epigenome as a therapeutic point of intervention for cocaine addiction, PTSD and phobia. PUBLIC HEALTH RELEVANCE: Using analagous procedures, we will study the importance of common epigenetic mechanisms in animal models of cocaine addiction and fear-related anxiety disorders. These studies may yield improved therapeutic intervention strategies based on facilitating extinction learning through the use of specialized pharmacological adjuncts during psychotherapy for co-morbid psychiatric disorders.

描述(申请人提供)：许多神经精神疾病涉及联想学习。其中最明显的是上瘾(环境中的中性线索引起对滥用药物的强烈渴望)和焦虑症(例如，创伤后应激障碍，创伤后应激障碍，创伤事件环境中的中性线索引起强烈的恐惧反应)。表观遗传学是指在不改变DNA序列的情况下建立和遗传细胞特征的过程。这些细胞记忆的机制也协调了成人大脑中的基因活动，最近的发现表明，表观遗传因素在精神疾病的病因学中发挥了作用。因此，鉴于可卡因成瘾和恐惧相关焦虑的流行和并存，以及人们越来越认识到环境因素在决定心理健康方面发挥着重要作用(DNA不是命运)，更深入地了解与成瘾和恐惧协调模型中的学习相关的常见表观遗传机制是及时和相关的。目标1将使用最先进的技术，采用全基因组方法，在可卡因成瘾的自我给药模型中研究可卡因寻求行为获得和消失过程中基因表达的表观遗传调节机制，以及在听觉条件恐惧的平行模型中研究与恐惧相关的学习。目的2将通过使用芯片和亚硫酸氢盐作图来验证候选基因，以检查单个基因启动子周围和内部的组蛋白修饰和DNA甲基化，并将它们与支持这两种学习形式的大脑区域的基因表达相关联。这些影响将在训练后的不同时间点进行检查，以努力阐明它们在自发潜伏期和复发中的作用。目的3将研究在可卡因自身给药和恐惧训练过程中，引起局部组蛋白超乙酰化、组蛋白去甲基化或抑制DNA甲基化的操作是否会使动物倾向于孵化，而在灭绝过程中同样的操作将防止寻求可卡因和条件性恐惧的复发。这些研究旨在阐明导致精神疾病的常见表观遗传因素，并探索表观基因组作为治疗可卡因成瘾、创伤后应激障碍和恐惧症的干预点。 公共卫生相关性：使用类似的程序，我们将研究常见表观遗传机制在可卡因成瘾和恐惧相关焦虑症动物模型中的重要性。这些研究可能产生改进的治疗干预策略，其基础是通过在心理治疗期间使用专门的药理辅助手段来促进消亡学习，以治疗共病的精神障碍。

项目成果

Exposure to histone deacetylase inhibitors during Pavlovian conditioning enhances subsequent cue-induced reinstatement of operant behavior.

在巴甫洛夫调节过程中暴露于组蛋白脱乙酰酶抑制剂会增强随后的提示诱导的操作行为的恢复。

• DOI: 10.1097/fbp.0b013e32836104ea
• 发表时间: 2013
• 期刊: Behavioural pharmacology
• 影响因子: 1.6
• 作者: Ploense,KyleL;Kerstetter,KerryA;Wade,MatthewA;Woodward,NicholasC;Maliniak,Dan;Reyes,Michael;Uchizono,RussellS;Bredy,TimothyW;Kippin,TodE
• 通讯作者: Kippin,TodE

p300/CBP-associated factor selectively regulates the extinction of conditioned fear.

p300/CBP 相关因子选择性调节条件性恐惧的消失。

• DOI: 10.1523/jneurosci.0178-12.2012
• 发表时间: 2012-08-29
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Wei W;Coelho CM;Li X;Marek R;Yan S;Anderson S;Meyers D;Mukherjee C;Sbardella G;Castellano S;Milite C;Rotili D;Mai A;Cole PA;Sah P;Kobor MS;Bredy TW
• 通讯作者: Bredy TW