Mechanisms of maladaptive memory formation and suppression in a preclinical model of the comorbidity between PTSD and addiction

PTSD 与成瘾共病的临床前模型中适应不良记忆形成和抑制的机制

• 批准号: 10613313
• 负责人: K Matthew Lattal
• 金额: $ 1.15万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10613313
• 关键词: ATAC-seq; Abstinence; Acute; Amygdaloid structure; Animals; Behavior; Behavioral; ChIP-seq; Chromatin Structure; Coupled; Cues; Data; Desire for food; Dominant-Negative Mutation; Dopamine; Epigenetic Process; Exposure to; Extinction (Psychology); Fright; Gene Expression; Genes; Genomic DNA; Goals; HDAC3 gene; Histone Deacetylase; Laboratories; Learning; Long-Term Effects; Measures; Medial; Mediating; Memory; Modeling; Molecular; Molecular Profiling; Motivation; NR4A2 gene; Nature; Neurosciences; Patients; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Post-Traumatic Stress Disorders; Pre-Clinical Model; Prefrontal Cortex; Procedures; Process; Rattus; Regulation; Relapse; Rewards; Rodent; Role; Self Administration; Shock; Signal Transduction; Site; Stress; Stressful Event; Substance Use Disorder; Substance abuse problem; Techniques; Time; Trauma; Work; acute stress; addiction; chromatin protein; comorbidity; comparative; conditioned fear; design; drug relapse; drug seeking behavior; drug testing; experience; experimental study; inhibitor; mutant; novel; novel therapeutics; post-trauma; preclinical study; protein complex; response; stress state; stressor; transcription factor; transcriptome sequencing; trauma exposure

Project Summary There is a high comorbidity between substance use disorders (SUDs) and post-traumatic stress disorder (PTSD). A consequence of this comorbidity is that exposure to cues associated with trauma in a patient with PTSD may trigger relapse of drug seeking, even after successful treatment or periods of abstinence. Thus, a major goal of treatment for both PTSD and substance use disorders is to weaken the ability of environmental cues to induce relapse. One way to do this is through extinction techniques, in which the relation between the cue and the drug, or the cue and the traumatic memory, is severed. A major challenge for purely behavioral approaches to substance abuse and PTSD is that successful treatment with extinction often does not persist and relapse occurs with time, changes in context, or exposure to stress. Work in our laboratories has focused on manipulating epigenetic mechanisms to make the learning that occurs during extinction persistent, resulting in long-term weakening of fear responses (in the case of animal approaches to PTSD) and long-term elimination of drug-seeking (in animal approaches to substance abuse). However, our work, and most of the work in the general field of the neuroscience of extinction, comes from preclinical studies of basic mechanisms of extinction within approaches to PTSD (such as fear conditioning) or addiction (such as drug self- administration) in isolation; comparatively little is known about how learned fear and drug seeking interact at behavioral and molecular levels. We have developed a novel model of the comorbidity between PTSD and addiction in rodents that combines behavioral approaches that are well characterized at behavioral, circuit, and molecular levels. In this model, rodents receive exposure to a battery of shocks in one context and are tested for drug-seeking behaviors in a second context. Our preliminary data show that this exposure to a single battery of shocks causes persistent changes (>30 days) in responsivity to a mild stressor and results in increased cue-induced reinstatement of drug-seeking after extensive extinction. Thus, this approach captures a persistent context-independent change in drug-seeking that is not captured in other stress-induced reinstatement procedures and provides a strong basis for investigating, at a basic level, how reward and aversive processes interact across long periods of time and, at a translational level, how a single traumatic experience results in persistent effects on relapse after successful treatment. The three specific aims outlined in this application are designed to (1) elucidate the persistent behavioral and molecular effects of an acute trauma, (2) evaluate the post-trauma effects of pharmacological manipulation of a specific histone deacetylase (HDAC3) in circuits involved in extinction of fear and drug-seeking, and (3) to evaluate the mechanisms through which HDAC3 manipulations alter relapse after trauma. Our focus on epigenetic mechanisms holds significant promise for understanding how persistent changes in behavior are established following trauma, and provides a novel therapeutic avenue.

项目摘要 物质使用障碍(Suds)和创伤后应激障碍有很高的共患率。 (创伤后应激障碍)。这种共病的一个后果是接触与创伤相关的线索的患者 创伤后应激障碍可能会引发寻求药物的复发，即使在成功的治疗或戒毒期之后也是如此。因此，一个 治疗创伤后应激障碍和物质使用障碍的主要目标是削弱环境的能力 诱使复发的线索。一种方法是通过灭绝技术，在这种技术中，物种之间的关系 线索和药物，或者线索和创伤记忆，被切断了。纯粹的行为行为的一个主要挑战 治疗药物滥用和创伤后应激障碍的方法是，成功地治疗绝症往往不会持续下去 复发会随着时间、环境的变化或暴露在压力下而发生。我们实验室的工作集中在 关于操纵表观遗传机制，使灭绝期间发生的学习持久存在，结果 在恐惧反应的长期减弱(在动物应对创伤后应激障碍的情况下)和长期 消除寻求毒品(在动物滥用药物的方法中)。然而，我们的工作，以及大多数 灭绝神经科学一般领域的工作来自对基本机制的临床前研究 在应对创伤后应激障碍(如恐惧条件作用)或成瘾(如吸毒自我)的方法内消退 管理)孤立；相对较少知道获得性恐惧和寻求毒品是如何在 行为和分子水平。我们开发了一种新的创伤后应激障碍和创伤后应激障碍共病模型。 啮齿类动物的成瘾，结合了行为、环路和 分子水平。在这个模型中，啮齿类动物在一种情况下接受一系列电击，并进行测试 在第二个背景下的毒品寻觅行为。我们的初步数据显示，这一暴露于单一 电击导致对轻微应激源的响应性持续变化(&gt；30天)，并导致 在大范围灭绝后，增加线索诱导的寻找毒品的恢复。因此，此方法捕获了 在寻求药物的过程中持续的与情境无关的变化，这在其他压力诱导的变化中没有体现出来 复职程序，并为在基本层面上调查如何奖励和 令人厌恶的过程在很长一段时间内相互作用，在转换水平上，单个创伤 在成功治疗后，经验会对复发产生持久的影响。概述的三个具体目标 在本应用中旨在(1)阐明急性脑脊髓炎的持续行为和分子效应 创伤，(2)评估特异组蛋白脱乙酰酶的药物治疗对创伤后的影响 (HDAC3)参与消除恐惧和寻找毒品的回路，以及(3)评估这些机制 通过HDAC3操作改变创伤后的复发。我们对表观遗传机制的关注 对于理解创伤后行为的持续变化是如何建立的， 并提供了一种新的治疗途径。