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: 10609480
• 负责人: K Matthew Lattal
• 金额: $ 67.66万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609480
• 关键词: ATAC-seq; Abstinence; Acute; Amygdaloid structure; Animals; Behavior; Behavioral; ChIP-seq; Chromatin; Chromatin Structure; Coupled; Cues; Data; Desire for food; Dominant-Negative Mutation; Dopamine; Epigenetic Process; Exposure to; Extinction; Fright; Gene Expression; Genes; Genomic DNA; Goals; Histone Deacetylase; Histone Deacetylase Inhibitor; Laboratories; Learning; Long-Term Effects; Measures; Medial; Mediating; Memory; Modeling; Molecular; Molecular Profiling; Motivation; NR4A2 gene; Nature; Neurosciences; Patients; Pharmaceutical Preparations; 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; comorbidity; comparative; conditioned fear; design; drug relapse; drug seeking behavior; drug testing; experience; experimental study; learning extinction; mutant; novel; novel therapeutics; pharmacologic; 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.

项目概要 物质使用障碍 (SUD) 和创伤后应激障碍之间存在很高的合并症 （创伤后应激障碍）。这种合并症的一个后果是，患有这种疾病的患者暴露于与创伤相关的线索 即使在成功治疗或戒断一段时间后，创伤后应激障碍也可能引发药物寻求复发。因此，一个 治疗创伤后应激障碍（PTSD）和物质使用障碍的主要目标是削弱环境的能力 诱发复发的线索。做到这一点的一种方法是通过灭绝技术，其中 线索和药物，或者线索和创伤记忆，被切断。纯粹行为的重大挑战 药物滥用和创伤后应激障碍 (PTSD) 的治疗方法之一是，成功的治疗方法通常不会持久 随着时间、环境的变化或压力的增加，复发也会发生。我们实验室的工作重点是 操纵表观遗传机制，使灭绝期间发生的学习持续存在，从而产生 恐惧反应的长期减弱（在动物方法治疗创伤后应激障碍的情况下）和长期 消除寻求药物的行为（在动物方法中滥用药物）。然而，我们的工作以及大部分 灭绝神经科学一般领域的工作来自基本机制的临床前研究 消除创伤后应激障碍（如恐惧调节）或成瘾（如药物自我戒断）的方法 管理）隔离；对于习得性恐惧和药物寻求如何相互作用，人们知之甚少。 行为和分子水平。我们开发了一种关于 PTSD 和 PTSD 之间共病的新模型 啮齿类动物的成瘾结合了在行为、回路和 分子水平。在此模型中，啮齿类动物在某种环境下接受一系列电击并接受测试 在第二种情况下寻找药物的行为。我们的初步数据显示，这种暴露于单一 一系列的电击会导致对轻微压力源的反应发生持续变化（>30天），并导致 在广泛灭绝后，线索诱导的药物寻求恢复增加。因此，这种方法捕获了 药物寻求过程中持续的、与环境无关的变化，这种变化在其他压力引起的情况下没有体现出来 恢复程序，并为在基础层面上调查如何奖励和 厌恶过程在很长一段时间内相互作用，并且在转化层面上，单个创伤如何 经验会对成功治疗后的复发产生持续影响。概述了三个具体目标 在本申请中的目的是（1）阐明急性发作的持续行为和分子影响 创伤，(2) 评估特定组蛋白脱乙酰酶的药理学操作的创伤后效应 (HDAC3) 参与恐惧消退和药物寻求的回路，以及 (3) 评估机制 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仍然存在 对于理解创伤后行为的持续变化是如何建立的具有重要意义， 并提供了一种新颖的治疗途径。