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.

抽象的 最近的研究表明，记忆是由小组神经元组成和表达的 合奏，在与记忆有关的大脑区域内。重复使用药物建立与毒品有关的记忆 被认为可以驱动复发。当这些记忆通过重新暴露于药物相关的线索，上下文或 毒品本身，它们变得不稳定几个小时，然后重新整合以维持或加强它们。然而， 在召回后不久，对某些柔软的药物或行为操纵也可能会破坏它们。 我们已经表明，可卡因记忆的重新整合可以通过操纵前比一部分来破坏 大鼠内侧前额叶皮层（PL PFC）。 PL PFC神经元投射到伏隔核（NAC）批判性的PL PFC神经元 控制恢复原状是人类复发的啮齿动物模型。在我们的初步研究中，这种记忆破坏可能 取决于在内存重新激活过程中更新内存，以使其变得不稳定。 更新训练有素的（习惯）记忆，例如在可卡因在老鼠中自我管理期间学到的记忆似乎 取决于创建预测错误；也就是说，通过按下杠杆和 按下杠杆以接收可卡因后，它实际收到的东西。我们的初步研究表明我们是否使用相同 加强时间表，如许多自我管理训练日，固定比率1（FR1），记忆 可能不会因中断而变得不稳定，但是不同的加固时间表，可变比率5（VR5）是 不可预测的，可能会允许内存中断。但是，我们不知道哪些神经元的合奏 在PL PFC中，这些记忆变得不稳定。在这里，我们建议在大鼠中使用一个新的 高度敏感的鲁棒活性标记（RAM）系统，以识别由PL PFC中激活的PL PFC中的神经集合 两种类型的内存重新激活会话，其中一个涉及内存更新，另一种不进行内存更新。 具体而言，我们将1）确定可卡因记忆期间PL PFC中激活了哪些神经集合 可卡因自我管理大鼠的重新激活，2）确定这些合奏的表型，3）开始定义 内存更新涉及的神经电路。我们将使用双重病毒注射，行为和免疫组织化学 方法。该提议很重要，因为它将使我们能够破译基础神经合奏 这种难以破坏可卡因的回忆使人的破坏不断变化，其长期目标是减少 复发到可卡因。