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

基本信息

批准号：
10377454
负责人：
JONATHAN E PLOSKI
金额：
$ 40.59万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10377454
关键词：
Acute Affect Agonist Amygdaloid structure Animal Model Animals Anisomycin Attenuated Biochemical Blood - brain barrier anatomy Cells Clinical Data Development Disease Doxycycline Electrophysiology (science)Emotional Endocytosis Endocytosis Pathway Enhancers Etiology Exhibits Extinction (Psychology)FDA approved Fright Future Gene Expression Glutamates Health Hour Hydroxymethylglutaryl-CoA reductase Impairment In Vitro Investigation Journals Knock-out Laboratories Lateral Lead Lentivirus LoxP-flanked allele Maintenance Measures Mediating Memory Mental Depression Mental disorders Methods Midazolam Mifepristone Modeling Modification Molecular Mus N-Methyl-D-Aspartate Receptors Neurons Neurosciences Pathologic Patients Pharmaceutical Preparations Pharmacology Phase Phosphorylation Post-Traumatic Stress Disorders Process Propranolol Psychopathology RAS genes Recovery Reporting Research Research Personnel Resistance Retrieval Simvastatin Stress Surface Symptoms Synapses Synaptic Membranes System TFAP2A gene Testing Therapeutic Training Update Viral Western Blotting Work calmodulin-dependent protein kinase II chronic pain clinical care conditioned fear design excitatory neuron experimental study farnesyl pyrophosphate fear memory glutamatergic signaling hippocampal pyramidal neuron improved memory consolidation memory retrieval neurobiological mechanism neuronal circuitry neurotransmission novel therapeutic intervention presynaptic prevent receptor mediated endocytosis trafficking transcriptome sequencing voltage clamp

项目摘要

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.

旨在减轻适应不良情绪记忆的治疗方法效果并不令人满意。扰乱再巩固过程已被认为是削弱强效的有效方法。创伤后应激障碍（PTSD）等精神病理学中的记忆，但大量研究表明，强烈的记忆具有抵抗力因此，需要采取可行的治疗方法来减弱治疗效果。利用再巩固更新现象产生的适应不良记忆尚未完全得到解决在此，我们提供初步数据，详细说明 FDA 批准的药物辛伐他汀 (SV) 的能力。我们提出的实验将增强强烈恐惧记忆的检索依赖性不稳定。研究 SV 的潜在临床效用，并确定 SV 的作用机制这项工作具有广泛的适用性，因为它研究了这两种电路。难以修改的电路中可塑性诱导的门控机制和潜在的治疗方法目标 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。因此，我们建议评估 SV 的能力。通过与 FDA 联合使用 PTSD 动物模型，增强强烈恐惧记忆的不稳定目标 2：据报道 SV 可通过增强 GluN2B 表面定位。抑制其磷酸化驱动的内吞作用以确定抑制该过程是否足以增强强烈恐惧记忆的不稳定，我们生成了慢病毒来表达 GluN2B(E1479Q) α-CaMKII 阳性 BLA 神经元以强力霉素依赖性方式增加表面。通过操纵相同的磷酸化驱动来巩固记忆后 GluN2B 的表达据报道 SV 影响内吞途径，我们显示 GluN2B(E1479Q) 在小鼠中的表达。 BLA 足以增强强烈恐惧记忆的不稳定，支持 SV 增强的假设通过增强 GluN2B 的突触定位来提高可塑性，因此，我们提出了一套生化和电生理分析可准确确定 SV 如何改变 BLA GluN2B 运输、神经传递、目标3：在这个目标中，我们将确定SV是否通过抑制发挥其作用机制。 HMG-CoA 还原酶 (HMGCR) 在药理学上通过利用其他他汀类药物，并在遗传上有条件地并在 Floxed-HMGCR 小鼠中急性敲除 HMGCR，研究 SV 的作用机制。这些发现不仅有可能影响当前 PTSD 的治疗实践，而且还可能影响其病因涉及修饰抵抗性神经回路的其他疾病（例如抑郁症和抑郁症）通过增进我们对回路稳定性的理解以及我们修改先前修改的能力- 抗药性痕迹，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。