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: 8073981
• 负责人: K Matthew Lattal
• 金额: $ 47.87万
• 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/8073981
• 关键词: Abbreviations; Affect; Animal Model; Applications Grants; Behavior; Behavior Therapy; Behavioral; Behavioral Mechanisms; 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）：药物滥用研究的一个常见发现是，暴露于药物使用发生的环境中可能会引发复发，导致寻求药物行为和随后药物使用的增加。因此，旨在消除吸毒行为的干预措施的一个主要目标必须是消除情境线索诱发导致旧瘾复发的记忆的能力。研究记忆的行为和神经生物学方法已经确定了消退，即切断环境和药物之间的关系，作为消除条件行为的一种方法。然而，基于消除的疗法的一个主要挑战是，消除的行为通常会随着时间的推移或重新接触药物后重新出现。因此，基于消退的行为干预必须关注促进消退发展的方法，以及使消退记忆持久的方法，从而导致对原始背景-药物关联的持续抑制。在分子水平上，记忆和消退的研究证明了基因转录对于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调控涉及多种转录因子和辅因子的协同作用，这些转录因子和辅因子与染色质（一种包装 DNA 的蛋白质复合物）相互作用。染色质修饰是表观遗传基因调控的主要机制，它正在成为参与突触可塑性和记忆存储所需基因表达转录调控的主要分子途径。表观遗传基因调控已被证明是细胞水平和行为水平持续长期变化的基础。重要的是，在成瘾动物模型中，慢性药物暴露会诱导稳定的染色质修饰，从而维持基因表达，这被认为会驱动行为的持续变化。考虑到药物成瘾以及学习和记忆通路所涉及的电路存在大量重叠，本次拨款申请的重点是调节学习和记忆通路，以消除与背景药物相关的记忆。我们将使用行为、药理学和遗传相结合的策略来研究如何增强可卡因诱导的条件性位置偏好消退的发展，从而导致原始背景药物关联的持续抑制。在具体目标 1 中，我们将使用条件位置偏好 (CPP) 程序确定上下文呈现的最佳时间模式，以消除上下文与可卡因的关联。在具体目标 2 中，我们将研究施用全身或海马内药物放松染色质结构的行为和分子后果，从而在可卡因诱导的 CPP 消退过程中增强基因转录。在具体目标 3 中，我们将研究抑制称为 CREB ​​结合蛋白 (CBP) 的染色质修饰酶的效果，该酶通过 CBP 的基因突变和局部缺失来松弛染色质结构，从而在可卡因诱导的 CPP 消退过程中抑制转录。这种新颖的方法有望阐明灭绝的行为和表观遗传机制，并使我们能够确定用于药物干预的进一步分子靶点和大脑系统。 公共卫生相关性：可卡因成瘾是美国的一个主要公共卫生问题。在这个项目中，我们研究了可卡因寻求小鼠模型中的行为和药理学干预措施，这可能有助于扭转可卡因寻求并减少复发。