Molecular Mechanisms of Reconsolidation Boundaries

再固结边界的分子机制

• 批准号: 8385018
• 负责人: JONATHAN E PLOSKI
• 金额: $ 19.13万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-10 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8385018
• 关键词: Affect; Age-associated memory impairment; Agonist; Amygdaloid structure; Attenuated; Behavioral; Calcium; Cycloserine; Data; Development; Down-Regulation; Emotional; Emotions; Endocytosis; Figs - dietary; Fright; Funding; Future; Gene Delivery; Hour; Knowledge; Learning; Maintenance; Measures; Mediating; Memory; Mental Health; Mental disorders; Methods; Modeling; Molecular; N-Methyl-D-Aspartate Receptors; NR1 gene; NR2A NMDA receptor; Neurobiology; Neurons; Pathology; Patients; Positioning Attribute; Post-Traumatic Stress Disorders; Process; Psychopathology; Rattus; Receptor Signaling; Research; Research Personnel; Resistance; Signal Transduction; Synapses; System; Testing; Update; Viral; aging brain; attenuation; base; clinically relevant; conditioned fear; conditioning; experience; mutant; overexpression; pre-clinical; preclinical study; receptor; research study; treatment effect

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.

描述（由申请人提供）：心理健康研究的一个核心挑战是开发临床有效的方法来治疗减轻适应不良情绪。一些有前途的未来治疗方法旨在减弱情绪记忆，针对这样的现象：当记忆被重新激活时，它们似乎进入暂时不稳定的状态，这被认为需要通过称为重新巩固的过程来重新稳定。针对重新巩固过程已被认为是许多精神病理学（包括创伤后应激障碍）的潜在治疗方法。对于 PTSD，阻止创伤性记忆的重新巩固可能会减弱这些创伤性记忆，从而减少 PTSD 病理。然而，临床前研究表明，所有情绪记忆都不会受到阻碍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再巩固更新的诱导受到损害，从而使这些记忆对再巩固封锁具有抵抗力。由于 PTSD 患者患有强烈的病理记忆，这些临床前数据表明，除非开发出方法/策略来克服这一关键障碍，否则针对患者的再巩固过程的疗效可能有限。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 比率的变化引起的。此外，我们假设改变 NR2A/B 比率也会对初始学习产生深远的影响——这是部分解释与年龄相关的认知衰退的机制。该项目将研究改变杏仁核神经元内的 NR2A/NR2B 比率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到杏仁核神经元来增加 NMDA 受体亚基 NR2A、NR2B 或突变 NR2 来实现这一目标，无论是在学习学习实验的巴甫洛夫恐惧条件反射之前，还是在专注于再巩固更新的实验的恐惧条件反射之后。我们假设高比例的 NR2A/NR2B 将抑制记忆形成，低比例的 NR2A/NR2B 将促进记忆形成。此外，我们假设过度表达 NR2B 将促进再巩固更新的诱导，而过度表达 NR2A 将抑制再巩固更新。该项目将回答神经生物学的一个重要问题 - NR2A/B 开关对学习和记忆的功能/后果是什么？此外，该项目将是同类项目中第一个确定生物学和可能临床相关的分子解释，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。 公共卫生相关性：恐惧系统的失调与许多精神疾病有关，这强调需要开发更好的治疗方法来治疗病理性恐惧。该项目旨在确定有助于维持病理性恐惧的机制，并为减轻适应不良的恐惧记忆的策略提供基础。