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.

与药物相关的条件刺激（CS）或提示，有助于进展和持久性 成瘾。我们和其他人一样，假设可卡因会议记忆的重新整合可以 防止提示引起的缓解。重新溶解是一个过程，使内存重新激活使其不稳定 并且容易受到干扰。我们发布的数据以及其他数据证实，边缘 - 纹状体多巴胺（DA） - 可卡因会议重新固定涉及依赖性和几种可塑性调节的信号传导机制 过程。在这个新的建议中，我们假设违反可卡因 - 库ue的预期会导致记忆 通过触发记忆不稳定来使可卡因提示的记忆更加敏感，从而使记忆不稳定 随后遭到羊膜剂的破坏。诱导可卡因会议记忆不稳定的能力 可能是能够使用靶向药物疗法阻止可卡因证明记忆的关键因素 重新溶解和治疗适应不良的记忆。我们建议直接研究预期在 通过改变可卡因会议记忆的重新整合及其对随后的浮雕行为的影响 在重新激活过程中的预期和经历之间的差异以及中脑的照片刺激 含DA的VTA神经元，以中和或诱导预测误差（PE）样信号。 在AIM 1中，我们将通过违反A）美国的期望来重新激活可卡因的记忆（即可卡因） 大小和b）CS-US临时连续性。这些操作应当时产生类似PE的信号 记忆检索。根据我们的假设和初步数据，阳性和负PE样 信号应引起不稳定并使提示记忆容易受到阻滞（即重新固化） 由弱化的药物减少随后对寻求毒品行为的缓解。复发般的行为将会 包括提示诱导的和药物定位的恢复和其他措施， 长期以来可卡因自我管理的数周。选择潜在和选择性更改内存的代理 重新溶解过程 - 蛋白质合成抑制剂雄霉素（ANI）和组蛋白乙酰基转移酶 （HAT）抑制剂藤黄酚 - 将用于使不稳定的记忆受到柔韧性封锁。 在AIM 2中，我们将基于光遗传学的中脑VTA DA神经元（TH-CRE+大鼠）的光刺激 在可卡因 - 提示记忆重新激活期间 人为地充当负面或正面的信号，以破坏提示记忆并渲染它 容易受到赦免的影响，最终减少了可卡因救济行为的措施。 这些研究将共同​​定义新的行为条件，破坏稳定机制可以 被用来使记忆更容易受到柔滑剂的影响，以阻止可卡因库的重新溶解 回忆，减少继电器般的行为，并激发创新的治疗策略的发展 适应不良的记忆。