Identifying Prefrontal Cortex Neural Ensembles in Cocaine-associated Memories

识别可卡因相关记忆中的前额皮质神经元

• 批准号: 9766804
• 负责人: Barbara A Sorg
• 金额: $ 26.29万
• 依托单位: LEGACY EMANUEL HOSPITAL AND HEALTH CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766804
• 关键词: Abbreviations; Amygdaloid structure; Area; Behavior; Behavior Control; Behavioral; Brain; Cells; Chondroitin ABC Lyase; Cocaine; Complex; Cues; Dependovirus; Drug usage; Exposure to; Extracellular Matrix; FOS gene; Future; Glutamates; Goals; Habits; Hour; Human; Injections; Measures; Medial; Memory; Mus; Neural Pathways; Neurons; Nucleus Accumbens; Output; Pharmaceutical Preparations; Phenotype; Prefrontal Cortex; Protocols documentation; Rattus; Reinforcement Schedule; Relapse; Rodent Model; Self Administration; Stress; System; Testing; Time; Tracer; Training; Update; Viral; frontal lobe; memory recall; neural circuit; optogenetics; preference; promoter; relating to nervous system; response; retrograde transport; translational study

ABSTRACT Recent studies have demonstrated that memories are formed and expressed from small groups of neurons, neural ensembles, within brain areas pertinent to the memory. Repeated drug use establishes drug-related memories thought to drive relapse. When these memories are recalled by re-exposure to drug-associated cues, context, or the drug itself, they become labile for several hours and are then reconsolidated to maintain or strengthen them. However, they can also be disrupted with certain amnestic agents or behavioral manipulations given shortly after recall. We have shown that reconsolidation of cocaine memories can be disrupted by manipulating the prelimbic portion of the rat medial prefrontal cortex (PL PFC). PL PFC neurons projecting to the nucleus accumbens (NAc) critically control reinstatement, the rodent model for relapse in humans. In our Preliminary Studies, this memory disruption may depend on updating the memory during a memory reactivation session so that it becomes labile for disruption. Updating a well-trained (habit) memory, such as that learned during cocaine self-administration in rats, appears to depend on creating prediction error; that is, a difference in what the rat expects to receive by pressing a lever and what it actually receives after pressing the lever to receive cocaine. Our Preliminary Studies show if we use the same reinforcement schedule as given during the many self-administration training days, a fixed ratio 1 (FR1), the memory may not become labile for disruption, but that a different reinforcement schedule, a variable ratio 5 (VR5) that is unpredictable, may allow for the memory to be disrupted. However, we do not know which ensembles of neurons in the PL PFC allow these memories to become labile for disruption. Here we propose to use in rats a new, highly sensitive robust activity marking (RAM) system to identify neural ensembles in the PL PFC activated by two types of memory reactivation sessions, one that involves memory updating and the other that does not. Specifically, we will 1) identify which neural ensembles are activated within the PL PFC during cocaine memory reactivation in cocaine self-administering rats, 2) identify the phenotype of these ensembles, and 3) begin to define the neural circuitry involved in memory updating. We will use dual viral injections, behavioral, and immunohistochemical approaches. This proposal is significant because it will allow us to decipher the underlying neural ensembles that render difficult-to-disrupt cocaine memories labile for disruption, with the long-term goal of reducing relapse to cocaine.

摘要 最近的研究表明，记忆是由一小群神经元形成和表达的， 在与记忆相关的大脑区域内。重复使用药物建立与药物有关的记忆 被认为会导致复发当这些记忆通过再次暴露于与药物相关的线索、背景或环境而被唤起时， 药物本身，他们变得不稳定几个小时，然后重新巩固，以维持或加强他们。然而，在这方面， 也可以用某些遗忘剂或在回忆后不久给予的行为操纵来破坏它们。 我们已经证明，可卡因记忆的重新巩固可以通过操纵大脑前边缘系统部分来破坏。 大鼠内侧前额叶皮质（PL PFC）。PL PFC神经元投射到延髓核（NAc）的临界点 对照复发，人类复发的啮齿动物模型。在我们的初步研究中，这种记忆中断可能 依赖于在存储器重新激活会话期间更新存储器，使得其变得不稳定以用于中断。 更新训练有素的（习惯）记忆，如大鼠在可卡因自我给药期间学习的记忆，似乎 依赖于产生预测误差;也就是说，大鼠通过按压杠杆预期接收的差异， 在按下控制杆接收可卡因后它实际接收到的是什么。我们的初步研究表明，如果我们使用相同的 在许多自我管理训练日期间给出的强化时间表，固定比率1（FR 1），记忆 可能不会因为中断而变得不稳定，但是不同的强化时间表，即可变比率5（VR 5）， 不可预测的，可能会导致记忆中断。然而，我们不知道哪些神经元 在PL PFC中，这些记忆变得不稳定，容易被破坏。在这里，我们建议在大鼠中使用一种新的， 高度敏感的鲁棒活动标记（RAM）系统，以识别PL PFC中的神经集合， 两种类型的内存重新激活会话，一种涉及内存更新，另一种不涉及。 具体来说，我们将1）确定在可卡因记忆过程中PL PFC内哪些神经系综被激活 重新激活可卡因自我管理大鼠，2）确定这些合奏的表型，和3）开始，以确定 参与记忆更新的神经回路我们将使用双重病毒注射，行为，和免疫组织化学 接近。这项提议意义重大，因为它将使我们能够破译潜在的神经系统 这使得难以破坏的可卡因记忆不稳定，长期目标是减少 可卡因复发