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

项目摘要 物质使用障碍与创伤后应激障碍之间存在高度的共病性 （PTSD）。这种并发症的一个后果是，暴露于与创伤相关的线索， PTSD可能会引发药物寻求的复发，即使在成功治疗或禁欲期之后。因此 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， 诱发复发的线索其中一种方法是通过灭绝技术， 线索和药物，或者线索和创伤记忆，被切断了。对于纯粹的行为学来说， 药物滥用和创伤后应激障碍的治疗方法是，成功的治疗与灭绝往往不会持续下去 复发会随着时间、环境的变化或压力的暴露而发生。我们实验室的工作重点是 操纵表观遗传机制，使灭绝过程中发生的学习持续下去， 在长期减弱恐惧反应（在动物的情况下，创伤后应激障碍）和长期 消除药物寻求（以动物方式滥用药物）。然而，我们的工作，以及大多数 在灭绝神经科学的一般领域的工作，来自基本机制的临床前研究 在创伤后应激障碍（如恐惧条件反射）或成瘾（如药物自我， 管理）隔离;相对较少的是了解如何学习恐惧和药物寻求相互作用， 行为和分子水平。我们开发了一种新的PTSD和 啮齿类动物的成瘾，结合了行为方法，这些方法在行为、回路和 分子水平。在这个模型中，啮齿动物在一种情况下接受一系列电击， 在第二种情况下寻找毒品的行为我们的初步数据显示， 一系列冲击会导致对轻度压力源的反应力发生持续变化（>30天），并导致 在广泛灭绝后，增加线索诱导的药物寻求恢复。因此，这种方法捕获了 药物寻求中持续的背景独立变化，在其他压力诱导的 恢复程序，并提供了强有力的基础，调查，在基本层面上，如何奖励和 厌恶的过程在很长一段时间内相互作用，在翻译水平上， 成功治疗后，经验会对复发产生持续影响。概述的三个具体目标 在本申请中，设计用于（1）阐明急性脑缺血的持续行为和分子效应， 创伤，（2）评估特定组蛋白去乙酰化酶的药理学操作的创伤后效应 （HDAC 3）在参与消除恐惧和药物寻求的回路中的作用，以及（3）评估机制 HDAC 3操纵通过其改变创伤后的复发。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， 提供了一种新的治疗途径。

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.