Pharmacologically Enhancing the Modification of Strong Modification Resistant Memories

旨在减弱不适应情绪记忆的治疗方法并不令人满意地有效。 中断再巩固过程已被认为是削弱强势的有力方法 在创伤后应激障碍等精神疾病中的记忆，但大量研究表明，强记忆具有抵抗力 重新启动后变得不稳定。正因为如此，可行的治疗方法可以从治疗上减轻 利用再巩固更新现象实现的非适应性记忆尚未完全实现 发展起来的。在这里，我们提供了FDA批准的药物辛伐他汀(SV)的初步数据 增强强烈恐惧记忆中依赖提取的不稳定性。我们提议的实验将 研究SV的潜在临床应用，以及确定SV的作用机制 通常是可修改的抗修改电路。这项工作具有广泛的适用性，因为它研究了 难修饰回路可塑性诱导的门控机制及可能的治疗方法 对这些州进行干预。目的1：我们的初步数据表明，在恐惧记忆之前进行5天的SV治疗 重现增强了强烈恐惧记忆的不稳定性。因此，我们建议评估SV的能力 通过与FDA联合使用创伤后应激障碍的动物模型来增强强烈恐惧记忆的不稳定性- 经批准的再整合破坏者。目的2：据报道，SV通过以下途径增强GluN2B表面定位 抑制其磷酸化驱动的内吞作用。为了确定抑制这一过程是否足以 增强强烈恐惧记忆的不稳定性，我们产生了Lenti病毒来表达GluN2B(E1479Q) α-CaMKII阳性神经元呈多西环素依赖性。这使我们可以增加表面积 GluN2B在记忆巩固后通过操纵相同磷酸化驱动的表达 据报道，SV影响的内吞作用途径。我们发现GluN2B(E1479Q)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增强的假设 增强GluN2B突触定位的可塑性。因此，我们提出了一套生化和 电生理分析以准确确定SV如何改变BLA GluN2B运输，神经传递， 和可塑性。目的3：在这个目标中，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)利用其他他汀类药物的药理作用和有条件的遗传学作用 并在氟化的HMGCR小鼠中强烈地敲除HMGCR。研究SV的作用机制可能是 导致的发现，不仅有可能影响目前的创伤后应激障碍的治疗实践，而且 其病因涉及耐修饰神经元回路的其他障碍(例如，抑郁症和 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- ，我们提议的实验可能会导致开发新的治疗策略 减轻病理症状，改善患有各种疾病的患者的健康。

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.