Behavioral and Epigenetic Mechanisms in Extinction of Cocaine-Induced Memories

可卡因诱发记忆消退的行为和表观遗传机制

• 批准号: 7688577
• 负责人: K Matthew Lattal
• 金额: $ 47.12万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7688577
• 关键词: Abbreviations; Affect; Animal Model; Applications Grants; Behavior; Behavior Therapy; Behavioral; Binding; Brain; Brain region; CREB-binding protein; CREB1 gene; Chromatin; Chromatin Structure; Chronic; Cocaine; Cocaine Dependence; Conditioned Stimulus; Cues; Cyclic AMP-Responsive DNA-Binding Protein; DNA Packaging; Data; Dependovirus; Development; Drug Addiction; Drug Exposure; Drug abuse; Drug usage; Effectiveness; Enzymes; Epigenetic Process; Essential Drugs; Ethanol; Exposure to; Extinction (Psychology); FDA approved; Fright; Gene Expression; Gene Expression Regulation; Gene Mutation; Genetic; Genetic Transcription; Goals; Hippocampus (Brain); Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Intervention; Learning; Memory; Methods; Modification; Molecular; Molecular Target; Mus; Mutant Strains Mice; Neurobiology; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacological Treatment; Point Mutation; Procedures; Process; Public Health; Regulation; Relapse; Research; Role; Sodium Butyrate; Synaptic plasticity; System; Therapeutic Agents; Time; Transcriptional Regulation; Trichostatin A; United States; addiction; base; chromatin modification; chromatin remodeling; cocaine use; cofactor; conditioned fear; design; drug craving; drug seeking behavior; histone acetyltransferase; histone modification; human CREBBP protein; long term memory; memory process; mouse model; novel strategies; preference; protein complex; public health relevance; receptor function; recombinase; research study; therapy design; transcription factor

DESCRIPTION (provided by applicant): A common finding from studies of drug abuse is that exposure to the context in which drug use occurs can trigger relapse, resulting in an increase in drug-seeking behavior and subsequent drug use. A major goal of interventions designed to eliminate drug seeking therefore must be to eliminate the ability of contextual cues to elicit memories that result in relapse. Behavioral and neurobiological approaches to memory have identified extinction, in which the relation between the context and the drug is severed, as a way to eliminate conditioned behavior. A major challenge for extinction-based therapies, however, is that extinguished behavior often returns with time or after re-exposure to the drug. Thus, extinction-based behavioral interventions must focus on ways to enhance the development of extinction, as well as methods to make the extinction memory long- lasting, causing persistent suppression of the original context-drug association. At a molecular level, studies of memory and extinction have demonstrated the necessity of gene transcription for long-term memory storage. Our research has found that regulation of gene transcription necessary for long-term memory formation involves the concerted action of multiple transcription factors and cofactors that interact with chromatin, a protein complex that packages DNA. Chromatin modification is a main mechanism of epigenetic gene regulation, which is emerging as a major molecular pathway involved in the transcriptional regulation of gene expression required for synaptic plasticity and memory storage. Epigenetic gene regulation has been shown to underlie persistent long-term changes at the cellular level as well as the behavioral level. Importantly, in animal models of addiction, chronic drug exposure induces stable chromatin modification resulting in maintained gene expression, which is thought to drive persistent changes in behavior. Considering the substantial overlap in the circuitry involved in drug addiction and learning and memory pathways, the focus of this grant application is to modulate learning and memory pathways in order to extinguish context-drug associated memories. We will use a combined behavioral, pharmacological, and genetic strategy to examine ways to enhance the development of extinction of cocaine-induced conditioned place preferences to cause persistent suppression of the original context-drug association. In Specific Aim 1, we will determine the best temporal pattern of context presentations to extinguish context-cocaine associations using the conditioned place preference (CPP) procedure. In Specific Aim 2, we will examine the behavioral and molecular consequences of administration of systemic or intra-hippocampal drugs that relax chromatin structure, thereby enhancing gene transcription during extinction of cocaine-induced CPP. In Specific Aim 3, we will examine the effects of inhibiting a chromatin modifying enzyme called CREB-binding protein (CBP), which relaxes chromatin structure, through genetic mutations and focal deletions of CBP, thereby inhibiting transcription during extinction of cocaine-induced CPP. This novel approach promises to elucidate behavioral and epigenetic mechanisms of extinction and will allow us to identify further molecular targets and brain systems for pharmacological interventions. PUBLIC HEALTH RELEVANCE: Cocaine addiction is a major public health problem in the United States. In this project, we examine behavioral and pharmacological interventions in a mouse model of cocaine seeking that may help reverse cocaine seeking and reduce relapse.

描述（由申请人提供）：对药物滥用研究的共同发现是，暴露于药物使用的情况可能会引发复发，从而导致寻求药物行为的增加和随后的药物使用。因此，旨在消除药物寻求药物的干预措施的主要目标必须是消除上下文提示引起记忆的能力，从而导致复发。行为和神经生物学方法的记忆方法已经鉴定出灭绝，其中上下文与药物之间的关系被切断，以消除条件行为。但是，基于灭绝的疗法的一个主要挑战是，熄灭的行为通常会随着时间或重新暴露在药物后的时间而恢复。因此，基于灭绝的行为干预措施必须集中于增强灭绝开发的方法，以及使灭绝记忆持续持久的方法，从而导致对原始上下文 - 停毒关联的持续抑制。在分子水平上，对记忆和灭绝的研究证明了基因转录需要长期记忆存储的必要性。我们的研究发现，长期记忆形成所需的基因转录的调节涉及多种转录因子和与染色质相互作用的辅助因子的协同作用，这些转录因子是一种包装DNA的蛋白质复合物。染色质修饰是表观遗传基因调节的主要机制，它是参与突触可塑性和记忆存储所需的基因表达转录调控的主要分子途径。表观遗传基因调节已显示出在细胞水平和行为水平上持续的长期变化的基础。重要的是，在成瘾的动物模型中，慢性药物暴露会诱导稳定的染色质修饰，从而导致基因表达，这被认为驱动行为持续变化。考虑到涉及药物成瘾，学习和记忆路径的电路中的实质重叠，该赠款应用的重点是调节学习和记忆途径，以消除上下文与药物相关的记忆。我们将使用合并的行为，药理和遗传策略来研究加强可卡因诱导的条件偏好偏见的灭绝的方法，以引起对原始上下文毒品关联的持续抑制。在特定目标1中，我们将使用条件的位置偏好（CPP）程序确定上下文演示的最佳时间模式。在特定的目标2中，我们将检查释放染色质结构的全身或海马内药物的行为和分子后果，从而增强可卡因诱导的CPP的基因转录。在特定的目标3中，我们将检查抑制称为CREB结合蛋白（CBP）的染色质修饰酶的影响，该酶通过CBP的遗传突变和局部缺失，从而放松染色质结构，从而抑制可卡因诱导的CPP灭绝期间的转录。这种新颖的方法有望阐明灭绝的行为和表观遗传机制，并使我们能够确定进一步的分子靶标和大脑系统进行药理学干预措施。 公共卫生相关性：可卡因成瘾是美国的主要公共卫生问题。在该项目中，我们在可卡因寻求的小鼠模型中检查了行为和药理干预措施，该模型可能有助于逆转可卡因寻求并减少复发。