Memory Destabilization and Cocaine-Cue Induced Reinstatement in Rat

大鼠记忆不稳定和可卡因诱导的恢复

• 批准号: 10441536
• 负责人: Jane R Taylor
• 金额: $ 33.08万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441536
• 关键词: Anisomycin; Behavior; Behavior Control; Behavioral; Chronic; Cocaine; Cocaine Dependence; Corpus striatum structure; Cues; Data; Development; Disease; Dopamine; Dose; Drug usage; Expectancy; Exposure to; Female; Human; Measures; Memory; Methods; Midbrain structure; Modeling; Neurobiology; Neurons; Outcome; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Population; Prevention strategy; Process; Protein Synthesis Inhibitors; Publishing; Rattus; Relapse; Research; Retrieval; Role; Signal Transduction; Stimulus; Techniques; Therapeutic; Time; addiction; attenuation; base; cocaine relapse; cocaine self-administration; craving; design; disorder later incidence prevention; dopaminergic neuron; drug abstinence; drug seeking behavior; expectation; experience; experimental study; garcinol; histone acetyltransferase; inhibitor; innovation; male; memory retrieval; novel; novel strategies; optogenetics; prevent; relating to nervous system; therapeutic target; tool; translational study

Drug-associated conditioned stimuli (CS), or cues, contribute to both the progression and persistence of addiction. We hypothesize, as have others, that blocking reconsolidation of cocaine-cue memories could prevent cue-induced relapse. Reconsolidation is a process whereby reactivation of a memory renders it labile and vulnerable to disruption. Our published data, and that of others, confirm that limbic-striatal dopamine (DA)- dependent and several plasticity-regulated signaling mechanisms are involved in cocaine-cue reconsolidation processes. In this new proposal we hypothesize that violation of cocaine-cue expectancy renders a memory labile by triggering memory destabilization, thereby making cocaine-cue memories more sensitive to subsequent disruption by amnestic agents. The ability to induce the destabilization of cocaine-cue memories may be a key factor in enabling the use of targeted pharmacotherapies to block cocaine-cue memory reconsolidation and treat maladaptive memories. We propose to investigate directly the role of expectancy in reconsolidation of cocaine-cue memories and their impact on subsequent relapse-like behaviors by varying the difference between what is expected and experienced during reactivation and by photo stimulation of midbrain DA-containing VTA neurons to neutralize or induce prediction error (PE)-like signals. In Aim 1 we will reactivate cocaine memories by violating expectations of a) US (i.e., cocaine) magnitude and b) CS-US temporal contiguity. These manipulations should generate PE-like signals at the time of memory retrieval. According to our hypothesis and preliminary data, both positive and negative PE-like signals should induce destabilization and make the cue memory susceptible to blockade (i.e., reconsolidation) by an amnestic agent to reduce subsequent relapse to drug-seeking behavior. Relapse-like behaviors will include cue-induced and drug-primed reinstatement, and other measures, in male and female rats subjected to weeks of long-access cocaine self-administration. Select agents that potently and selectively alter memory reconsolidation processes – the protein-synthesis inhibitor anisomycin (ANI) and the histone acetyltransferase (HAT) inhibitor garcinol – will be used to render the destabilized memory subject to amnestic blockade. In Aim 2 we will optogenetic-based photostimulation of midbrain VTA DA neurons (TH-Cre+ rats) during cocaine-cue memory reactivation a) to artificially produce a dip or b) a spike in DA signaling, to artificially act as a negative or positive PE-like signal, respectively, to destabilize the cue memory and render it susceptible to amnestic blockade, ultimately reducing measures of cocaine relapse-like behaviors. Together these studies will define novel behavioral conditions whereby destabilization mechanisms can be used to make memories more susceptible to amnestic agents, to block reconsolidation of cocaine-cue memories, to reduce relapse-like behaviors, and to inspire the development of innovative therapeutic strategies for maladaptive memories.

药物相关的条件刺激（CS），或线索，有助于进展和持久性 上瘾的人和其他人一样，我们假设，阻断可卡因线索记忆的重新巩固可以 防止线索诱发的复发重新整合是一个记忆重新激活使其变得不稳定的过程 容易受到干扰我们发表的数据，以及其他人的数据，证实了边缘-纹状体多巴胺（DA）- 依赖性和几种可塑性调节的信号传导机制参与可卡因-线索再巩固 流程.在这个新的提议中，我们假设可卡因线索预期的违反会使记忆 通过触发记忆不稳定，从而使可卡因线索记忆对 随后被遗忘剂破坏。可卡因线索记忆的不稳定性 可能是使用靶向药物治疗阻断可卡因线索记忆的关键因素 重新巩固并治疗适应不良的记忆。我们建议直接研究预期在 可卡因线索记忆的重新巩固及其对随后复发样行为的影响， 在再激活期间和通过中脑的光刺激预期和经历之间的差异 含DA的VTA神经元中和或诱导预测误差（PE）样信号。 在目标1中，我们将通过违反a）US（即，可卡因） 幅度和B）CS-US时间连续性。这些操作应该会产生类似PE的信号， 记忆提取的过程根据我们的假设和初步数据，阳性和阴性PE样 信号应该引起不稳定并使提示记忆易于被阻断（即，重新合并） 通过遗忘剂来减少随后的吸毒行为复发。类似复发的行为 包括线索诱导和药物引发恢复以及其他措施， 几周的可卡因自我注射选择代理人，有效地和选择性地改变记忆 再巩固过程-蛋白质合成抑制剂茴香霉素（ANI）和组蛋白乙酰转移酶 (HAT)抑制剂garcinol -将用于使不稳定的记忆受到遗忘阻断。 在目的2中，我们将基于光遗传学的光刺激中脑VTA DA神经元（TH-Cre+大鼠） 在可卡因-线索记忆再激活过程中，a）人为地产生DA信号的下降或B）DA信号的尖峰， 分别人为地充当负或正PE样信号，以使线索记忆不稳定，并使其 易受遗忘阻滞，最终减少可卡因复发样行为的措施。 这些研究将共同定义新的行为条件，从而不稳定机制可以 用于使记忆更容易受到遗忘剂的影响，阻止可卡因线索的重新巩固 记忆，以减少复发样行为，并激发创新治疗策略的发展 适应不良记忆的治疗方法