Behavioral and Epigenetic Mechanisms in Extinction of Cocaine-Induced Memories

描述（由申请人提供）：药物滥用研究的一个共同发现是，暴露于药物使用发生的环境中会引发复发，导致寻求药物行为和随后的药物使用增加。因此，旨在消除药物寻求的干预措施的主要目标必须是消除导致复发的情境线索引发记忆的能力。行为学和神经生物学研究记忆的方法已经确定了消失，即情境和药物之间的关系被切断，作为消除条件行为的一种方式。然而，基于消失疗法的一个主要挑战是，消失的行为往往会随着时间的推移或在再次接触药物后恢复。因此，基于灭绝的行为干预必须关注如何增强灭绝的发展，以及如何使灭绝记忆持久，从而持续抑制原始情境-药物关联。在分子水平上，记忆和灭绝的研究已经证明了基因转录对长期记忆储存的必要性。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助因子的协同作用，这些转录因子和辅助因子与染色质相互作用，染色质是一种包装DNA的蛋白质复合物。染色质修饰是表观遗传基因调控的主要机制，是参与突触可塑性和记忆储存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，在成瘾的动物模型中，慢性药物暴露诱导稳定的染色质修饰，从而维持基因表达，这被认为是驱动行为持续变化的原因。考虑到涉及药物成瘾和学习记忆通路的电路中存在大量重叠，本资助申请的重点是调节学习和记忆通路，以消除与情境药物相关的记忆。我们将使用行为学、药理学和遗传学相结合的策略来研究如何促进可卡因诱导的条件位置偏好的消失，从而导致原始情境-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）程序确定情境呈现的最佳时间模式，以消除情境-可卡因关联。在Specific Aim 2中，我们将研究全身或海马内药物管理的行为和分子后果，这些药物可以放松染色质结构，从而在可卡因诱导的CPP消失过程中增强基因转录。在特异性目标3中，我们将通过基因突变和CBP的局灶性缺失来研究抑制染色质修饰酶creb结合蛋白（CBP）的影响，从而抑制可卡因诱导的CPP消失过程中的转录。CBP可以放松染色质结构。这种新方法有望阐明灭绝的行为和表观遗传机制，并将使我们能够确定进一步的分子靶点和脑系统进行药物干预。

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.