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上有效的方法来减轻适应不良的情绪。一些有希望的未来治疗方法旨在减弱情感记忆，以一种现象为目标，即当记忆重新激活时，它们似乎进入了瞬时不稳定的状态，据信这需要通过称为重新溶解的过程进行重新稳定。针对重新溶解过程的靶向已被认为是包括PTSD在内的许多心理病理学的潜在治疗方法。对于PTSD，阻止创伤记忆的重新整合可能会减轻这些创伤记忆，进而减少PTSD病理学。但是，临床前研究表明，所有情绪记忆都不容易受到阻止重新溶解过程的治疗。例如，诱导强烈重新激活的厌恶记忆的重新溶解更新受到损害，因此使这些记忆具有抵抗重新溶解阻塞的能力。由于PTSD患者患有强烈的病理记忆，因此这些临床前数据表明，除非开发了克服这种关键障碍的方法/策略，否则针对患者重新溶解过程的靶向效果可能有限。我们假设抑制重新溶解更新是由突触N-甲基D-天冬氨酸受体亚基NR2A/NR2B比的变化引起的。另外，我们假设改变NR2A/B比也可能对初始学习产生深远的影响 - 一种与部分相关的认知下降的机制。该项目将研究如何改变杏仁核神经元内的NR2A/NR2B比率。我们将通过病毒介导的基因将NR2A，NR2B或突变型NR2增加到杏仁核神经元的递送，以便在研究学习的实验或恐惧调节后，以使重新溶解更新的实验进行恐惧调节之前，我们将通过病毒介导的基因递送到杏仁核神经元来实现这一目标。我们假设NR2A/NR2B的高比例将抑制记忆的形成，而NR2A/NR2B的低比率将促进记忆形成。此外，我们假设过表达NR2B将促进重新溶解更新的诱导，而NR2A的过表达将抑制重新溶解更新。该项目将回答神经生物学的重要问题 - NR2A/B转换在学习和记忆中的功能/结果是什么？此外，该项目将是第一个确定生物学和可能与临床相关的分子解释，以说明为什么某些记忆易受针对重新溶解过程而虽然没有其他记忆的治疗方法。 公共卫生相关性：恐惧系统的失调与许多精神疾病有关，强调了为病理恐惧开发更好治疗方法的必要性。该项目旨在确定有助于维持病理恐惧的机制，并为减弱适应不良的恐惧记忆的策略提供基础。