Molecular Mechanisms of Reconsolidation Boundaries

描述(由申请人提供)：精神健康研究的一个中心挑战是开发临床上有效的方法来治疗减轻适应不良情绪。未来一些有希望的治疗方法旨在减弱情绪记忆，针对的现象是，当记忆重新激活时，它们似乎进入了短暂的不稳定状态，据信需要通过一个称为重新巩固的过程重新稳定。以再巩固过程为靶点已被认为是包括创伤后应激障碍在内的许多精神病理学的潜在治疗方法。对于创伤后应激障碍来说，阻止创伤记忆的重新巩固可能会减弱这些创伤记忆，进而减少创伤后应激障碍的病理变化。然而，临床前研究表明，并不是所有的情感记忆都容易受到阻止重新巩固过程的治疗的影响。例如，强烈重新激活的厌恶记忆的重新巩固更新的诱导受到损害，从而使这些记忆抵抗重新巩固障碍。由于PTSD患者有很强的病理性记忆，这些临床前数据表明，除非开发出克服这一关键障碍的方法/策略，否则针对患者的再巩固过程可能效果有限。我们假设，突触N-甲基-D-天冬氨酸受体亚单位NR2A/NR2B比率的变化导致了再巩固更新的抑制。此外，我们假设，改变NR2A/B比率也会对最初的学习产生深远的影响--这是一种在一定程度上解释与年龄相关的认知下降的机制。这个项目将研究改变杏仁核神经元内NR2A/NR2B的比例如何影响学习和再巩固更新。我们将通过增加NMDA受体亚单位NR2A、NR2B或突变的NR2，通过病毒介导的基因传递到杏仁核神经元来实现这一点，无论是在巴甫洛夫恐惧条件作用之前研究学习的实验之前，还是在专注于再巩固更新的实验的恐惧条件作用之后。我们假设，高NR2A/NR2B比率将抑制记忆形成，而低比率NR2A/NR2B将促进记忆形成。此外，我们假设NR2B的过表达将促进再巩固更新的诱导，而NR2A的过表达将抑制再巩固更新。这个项目将回答神经生物学的一个重要问题--NR2A/B开关在学习和记忆上的功能/后果是什么？此外，这个项目将是同类项目中第一个确定生物学上以及可能具有临床意义的分子解释，以解释为什么某些记忆容易受到针对重新巩固过程的治疗的影响，而其他记忆则不是。 公共卫生相关性：恐惧系统的失调与许多精神疾病有关，这突显了开发更好的病理性恐惧治疗方法的必要性。该项目旨在确定有助于维持病理性恐惧的机制，并为减轻适应不良恐惧记忆的策略提供基础。

DESCRIPTION (provided by applicant): A central challenge for mental health research is to develop clinically effective methods to therapeutically attenuate maladaptive emotions. Some promising future treatments are aimed at attenuating emotional memories, targeting the phenomenon that when memories are reactivated, they appear to enter a transiently destabilized state which is believed to require re-stabilization via a process referred to as reconsolidation. Targeting the reconsolidation process has been proposed to be a potential treatment for many psychopathologies, including PTSD. For PTSD, blocking the reconsolidation of traumatic memories might attenuate these traumatic memories, in turn reducing PTSD pathology. However preclinical studies suggest that all emotional memories are not susceptible to treatments that block the reconsolidation process. For example induction of reconsolidation updating of strong reactivated aversive memories is impaired, consequently making these memories resistant to reconsolidation blockade. Since PTSD patients suffer from strong pathological memories, these preclinical data suggest that targeting the reconsolidation process in patients may have limited efficacy unless methods/strategies are developed to overcome this critical barrier. We hypothesize that inhibition of reconsolidation updating is caused by a change in the synaptic N-methyl D-aspartate receptor subunit NR2A/NR2B ratio. Additionally we hypothesize that altering the NR2A/B ratio can also have profound consequences on initial learning - a mechanism to explain in part age related cognitive decline. This project will examine how changing the NR2A/NR2B ratio within amygdala neurons effects learning and reconsolidation updating. We will accomplish this by increasing NMDA receptor subunits NR2A, NR2B or mutant NR2s via viral mediated gene delivery to amygdala neurons either before Pavlovian fear conditioning for the experiments studying learning or after fear conditioning for the experiments focusing on reconsolidation updating. We hypothesize that a high ratio of NR2A/NR2B will inhibit memory formation and a low ratio of NR2A/NR2B will promote memory formation. Additionally we hypothesize that overexpressing NR2B will promote the induction of reconsolidation updating and the overexpression of NR2A will inhibit reconsolidation updating. This project will answer a significant question of neurobiology - What is the function/consequence of the NR2A/B switch on learning & memory? Additionally this project will be the first of its kind to determine a biologically and possibly clinically relevant molecular explanation to why certain memories are susceptible to treatments that target the reconsolidation process while other memories are not. PUBLIC HEALTH RELEVANCE: Dysregulation of the fear system is associated with many psychiatric disorders underscoring the need for developing better treatments for pathological fear. This project aims to identify the mechanisms that contribute to the maintenance of pathological fear and provide the basis of a strategy for attenuating maladaptive fear memories.