Pharmacologically Enhancing the Modification of Strong Modification Resistant Memories

从药理学上增强强修改抗性记忆的修改

• 批准号: 10505551
• 负责人: JONATHAN E PLOSKI
• 金额: $ 38.19万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10505551
• 关键词: Pharmacologically; Enhancing; Modification; Strong; Resistant

Therapeutic methods designed to attenuate maladaptive emotional memories are not satisfactorily effective. Disruption of the reconsolidation process has been proposed to be a powerful method to attenuate strong memories in psychopathologies such as PTSD, but numerous studies indicate that strong memories are resistant to becoming destabilized following reactivation. Because of this, viable treatments to therapeutically attenuate maladaptive memories by taking advantage of the phenomenon of reconsolidation updating have yet to be fully developed. Here, we present preliminary data detailing the ability of the FDA-approved drug simvastatin (SV) to enhance the retrieval-dependent destabilization of a strong fear memory. Our proposed experiments will investigate the potential clinical utility of SV, as well as determine the mechanism of action by which SV renders typically modification-resistant circuits modifiable. This work has broad applicability because it investigates both the mechanisms gating induction of plasticity in difficult-to-modify circuits and potential therapeutic methods to intervene on these states. Aim 1: Our preliminary data indicate that 5 days of SV treatment prior to fear memory retrieval enhances destabilization of a strong fear memory. Therefore, we propose to assess the ability of SV to enhance destabilization of a strong fear memory by using an animal model of PTSD in conjunction with FDA- approved reconsolidation disruptors. Aim 2: SV has been reported to enhance GluN2B surface localization via inhibition of its phosphorylation-driven endocytosis. To determine if inhibition of this process is sufficient to enhance destabilization of a strong fear memory, we generated lenti viruses to express GluN2B(E1479Q) within α-CaMKII positive BLA neurons in a doxycycline-dependent manner. This allows us to increase surface expression of GluN2B after the memory has consolidated by manipulating the same phosphorylation-driven endocytosis pathway that SV is reported to affect. We show that expression of GluN2B(E1479Q) in the mouse BLA is sufficient to enhance destabilization of a strong fear memory, supporting the hypothesis that SV enhances plasticity by enhancing synaptic localization of GluN2B. Therefore, we propose a suite of biochemical and electrophysiological analyses to determine precisely how SV alters BLA GluN2B trafficking, neurotransmission, and plasticity. Aim 3: In this aim, we will determine whether SV exerts its mechanism of action through inhibition of HMG-CoA reductase (HMGCR) pharmacologically by utilizing other statins, and genetically by conditionally and acutely knocking out HMGCR in Floxed-HMGCR mice. Investigating the mechanism of action of SV may lead to discoveries that not only have the potential to affect current therapeutic practice for PTSD, but also for other disorders for which their etiologies involve modification-resistant neuronal circuits (e.g., depression and chronic pain). By advancing our understanding of circuit stability and our ability to modify previously modification- resistant traces, our proposed experiments may lead to the development of novel therapeutic strategies to attenuate pathological symptoms and improve the health of patients suffering from a variety of disorders.

旨在减弱适应不良情绪记忆的治疗方法效果并不令人满意。 破坏再固结过程已被认为是一种强有力的方法， 但许多研究表明，强烈的记忆是有抵抗力的， 重新激活后变得不稳定。正因为如此，可行的治疗，以治疗衰减 利用再巩固更新现象的适应不良记忆尚未完全被 开发在这里，我们提供了初步的数据，详细说明了FDA批准的药物辛伐他汀（SV）的能力， 增强强烈恐惧记忆的提取依赖性不稳定。我们提出的实验将 研究SV的潜在临床效用，以及确定SV使 通常是可修改的抗修改电路。这项工作具有广泛的适用性，因为它调查了 在难以修改的回路中门控诱导可塑性的机制和潜在的治疗方法， 干预这些国家。目的1：我们的初步数据表明，5天的SV治疗前的恐惧记忆， 提取增强了强烈的恐惧记忆的不稳定性。因此，我们建议评估SV的能力， 与FDA联合使用创伤后应激障碍动物模型，增强强烈恐惧记忆的不稳定性- 批准的重新整合破坏者。目的2：已经报道SV通过以下途径增强GluN 2B表面定位： 抑制其磷酸化驱动的内吞作用。为了确定该过程的抑制是否足以 为了增强强烈恐惧记忆的不稳定性，我们产生了慢病毒来表达GluN 2B（E1479 Q）， α-CaMK Ⅱ阳性BLA神经元呈强力霉素依赖性。这使我们能够增加表面 GluN 2B的表达后，记忆已经巩固通过操纵相同的磷酸化驱动， 据报道SV影响的内吞途径。我们发现GluN 2B（E1479 Q）在小鼠中的表达 BLA足以增强强烈恐惧记忆的不稳定性，支持SV增强恐惧记忆的假设。 可塑性通过增强GluN 2B的突触定位。因此，我们提出了一套生物化学和 电生理学分析，以精确确定SV如何改变BLA GluN 2B运输，神经传递， 和可塑性。目的3：在这个目的中，我们将确定SV是否通过抑制来发挥其作用机制 HMG-CoA还原酶（HMGCR）通过利用其他他汀类药物而被抑制， 并在Floxed-HMGCR小鼠中急性敲除HMGCR。研究SV的作用机制可能 这些发现不仅有可能影响目前PTSD的治疗实践， 其病因涉及抗修饰神经元回路的其它病症（例如，抑郁和 慢性疼痛）。通过提高我们对电路稳定性的理解和我们修改先前修改的能力- 耐药痕迹，我们提出的实验可能会导致新的治疗策略的发展， 减轻病理症状并改善患有各种疾病的患者的健康。