Molecular Mechanisms of Reconsolidation Boundaries

描述（由申请人提供）：心理健康研究的核心挑战是开发临床有效的治疗方法来减轻适应不良情绪。一些有希望的未来治疗方法旨在减弱情绪记忆，针对这样一种现象：当记忆被重新激活时，它们似乎进入了一种短暂的不稳定状态，这种状态被认为需要通过一个被称为“再巩固”的过程来重新稳定。靶向再巩固过程被认为是治疗包括创伤后应激障碍在内的许多精神病理的潜在方法。对于创伤后应激障碍，阻断创伤记忆的重新巩固可能会削弱这些创伤记忆，从而减少创伤后应激障碍的病理。然而，临床前研究表明，所有的情绪记忆都不容易受到阻止再巩固过程的治疗的影响。例如，强烈的再激活的厌恶记忆的再巩固更新的诱导受到损害，从而使这些记忆抵抗再巩固封锁。由于创伤后应激障碍患者具有强烈的病理性记忆，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。我们假设再巩固更新的抑制是由突触n -甲基d -天冬氨酸受体亚基NR2A/NR2B比值的变化引起的。此外，我们假设NR2A/B比例的改变也会对初始学习产生深远的影响——这是一种部分解释与年龄相关的认知衰退的机制。本项目将研究改变杏仁核神经元内NR2A/NR2B比例如何影响学习和再巩固更新。我们将通过病毒介导的基因传递增加NMDA受体亚基NR2A、NR2B或突变NR2s到杏仁核神经元，在学习实验的巴普洛夫恐惧条件反射之前或在重新巩固更新实验的恐惧条件反射之后。我们假设NR2A/NR2B比例高会抑制记忆的形成，而NR2A/NR2B比例低会促进记忆的形成。此外，我们假设NR2B过表达会促进再巩固更新的诱导，而NR2A过表达会抑制再巩固更新。这个项目将回答神经生物学的一个重要问题——NR2A/B开关在学习和记忆中的功能/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和可能临床上相关的分子解释，以解释为什么某些记忆容易受到针对再巩固过程的治疗的影响，而其他记忆则不然。

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.