Hippocampal mechanisms of cocaine-memory reconsolidation

可卡因记忆重建的海马机制

• 批准号: 10736775
• 负责人: Rita A Fuchs Lokensgard
• 金额: $ 56.22万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-03-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736775
• 关键词: Abstinence; Animal Model; Basic Science; Behavior; Cells; Cocaine; Cocaine use disorder; Data; Development; Dorsal; Drug Modelings; Drug Targeting; Electrophysiology (science); Environment; Exhibits; Exposure to; Future; Genetic Recombination; Glutamates; Goals; Hippocampal Formation; Hippocampus; Immunohistochemistry; Impairment; Individual; Interneurons; Label; Literature; Maintenance; Maps; Memory; Mental disorders; Molecular; Motivation; Neurobiology; Neuronal Plasticity; Output; Pathologic; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Population; Process; Protein Biosynthesis; Protocols documentation; Publishing; Pyramidal Cells; Recovery; Relapse; Research; Rest; Retrieval; Rhodopsin; Role; Stimulus; Stratum Lucidum; Subgroup; Substance Use Disorder; Synapses; Synaptic plasticity; System; Testing; Therapeutic; Time; Update; Work; cell type; cocaine exposure; cocaine seeking; craving; dentate gyrus; drug craving; drug relapse; drug seeking behavior; effective therapy; hippocampal pyramidal neuron; in vivo; insight; interest; long term memory; memory recall; memory retrieval; mossy fiber; neural; neural circuit; novel; optogenetics; patch clamp; preservation; prevent; relapse prevention; response; src-Family Kinases; therapeutic target; therapeutically effective; therapy development; transmission process

PROJECT SUMMARY/ABSTRACT Pathologically strong or intrusive cocaine memories elicit uncontrollable drug craving and can trigger drug relapse in cocaine-predictive environments even after protracted abstinence, yet the contributions of long-term memory maintenance mechanisms to substance use disorders have been understudied. Cocaine memories are not necessarily retained over time; they become destabilized upon retrieval (memory reactivation) and need to be reconsolidated into long-term memory stores to be maintained, updated, and potentially strengthened. Thus, interference with memory reconsolidation weakens cocaine memories in animal models of drug relapse and reduces craving in individuals suffering from substance use disorders. The long-term goal of this proposal is to advance our understanding of the neural basis of cocaine-memory reconsolidation so that cellular/molecular processes and neural circuits suitable for effective therapeutic targeting can be identified in the future. We have discovered that the CA3 region of the dorsal hippocampus (dCA3) plays a critical role in the reconsolidation of cocaine memories. Building on this finding and strong preliminary data, Specific Aim 1 will be to identify cellular and synaptic-plasticity mechanisms of cocaine-memory reconsolidation within the dCA3. We will test the hypothesis that reconsolidation requires glutamatergic pyramidal neuronal activity in the dCA3 stratum pyramidale (SP) cell layer and GABAergic interneuronal activity in the dCA3 SP and stratum lucidum (SL) cell layers. We will identify and phenotype engram cells in the SP and SL and, also, evaluate the hypothesis that the maintenance of cocaine-memory strength via reconsolidation is associated with lasting plasticity in dentate gyrus mossy fiber (MF)dCA3 engram cell synapses, but not in dCA3 non-engram cell synapses. Specific Aim 2 will be to map dCA3 efferent circuits that regulate cocaine-memory strength during reconsolidation and determine related synaptic plasticity mechanisms. Based on extant literature and strong preliminary data, we will test the hypothesis that direct dCA3dCA1 intra-hippocampal and dCA3dorsolateral septum (dlS) extra-hippocampal circuits regulate cocaine-memory strength in an opposite manner during reconsolidation. Further, we will examine the hypothesis that cocaine-memory maintenance after reconsolidation is associated with increased polysynaptic transmission (MFdCA3dCA1/dlS) and excitatory synaptic plasticity in dCA3dCA1/dlS engram cell synapses. The proposed studies will utilize an instrumental model of drug-memory reconsolidation and relapse, engram cell tagging using Targeted Recombination in Active Population protocols, cell type- and pathway-specific in vivo and ex vivo optogenetics, pharmacology, multi-label immunohistochemistry, and whole cell patch-clamp electrophysiology to increase our understanding of how hippocampal-memory reconsolidation processes regulate cocaine memory strength and drug relapse. The findings are expected to provide an essential conceptual framework for future research and insights for the development of effective treatments for substance- use disorders and other psychiatric disorders characterized by intrusive maladaptive memories.

项目总结/摘要 病理性的强烈或侵入性的可卡因记忆会引起无法控制的药物渴望，并可能引发药物依赖。 即使在长期禁欲后，可卡因预测环境中的复发， 物质使用障碍的记忆维持机制尚未得到充分研究。回忆是 不一定会随着时间的推移而保留;它们在检索时变得不稳定（记忆重新激活），需要 重新整合成长期记忆库，以保持，更新和潜在的加强。因此，在本发明中， 在药物复吸的动物模型中，对记忆再巩固的干扰削弱了可卡因记忆， 减少患有物质使用障碍的个体的渴望。该提案的长期目标是 推进我们对可卡因记忆再巩固的神经基础的理解， 将来可以确定适合于有效治疗靶向的过程和神经回路。我们有 发现背侧海马CA 3区（dCA 3）在脑缺血再巩固中起着关键作用。 可卡因的记忆基于这一发现和强有力的初步数据，具体目标1将是确定细胞 和可卡因记忆在dCA 3内再巩固的突触可塑性机制。我们将测试 假设再巩固需要dCA 3层中的多巴胺能锥体神经元活动 dCA 3 SP和透明层（SL）细胞中的GABA能中间神经元活性 层次。我们将鉴定SP和SL中的印迹细胞，并对其表型进行分析，同时评估SP和SL中的印迹细胞可能是一种免疫缺陷细胞的假说。 通过再巩固维持可卡因记忆强度与齿状回的持久可塑性有关 苔藓纤维（MF）在dCA 3的记忆颗粒细胞突触中有分布，而在dCA 3的非记忆颗粒细胞突触中无分布。具体目标2将 在再巩固过程中，绘制调节可卡因记忆强度的dCA 3传出回路，并确定 相关的突触可塑性机制。基于现有文献和强大的初步数据，我们将测试 海马内dCA 3与海马内dCA 1直接连接，海马外dCA 3与背外侧隔（dlS）直接连接假说 在再巩固期间，神经回路以相反的方式调节可卡因记忆强度。此外，我们将 检查可卡因记忆维持后再巩固的假设与增加 多突触传递（MF → dCA 3 → dCA 1/dlS）和dCA 3 → dCA 1/dlS的兴奋性突触可塑性 记忆细胞突触拟议的研究将利用药物记忆再巩固的工具模型 和复发，在活跃人群方案中使用靶向扩增的印迹细胞标记，细胞类型和 途径特异性体内和离体光遗传学、药理学、多标记免疫组织化学和全 细胞膜片钳电生理学，以增加我们的理解， 过程调节可卡因记忆强度和药物复发。预计这些发现将提供一个重要的 未来研究的概念框架和发展有效治疗物质的见解- 使用障碍和其他以侵入性适应不良记忆为特征的精神障碍。