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.

项目摘要/摘要 病理上强或侵入性可卡因的记忆引起无法控制的药物渴望，可以触发药物 即使持久节制后，可卡因预测的环境中的复发，但长期的贡献 已经了解了对物质使用障碍的记忆维持机制。可卡因的记忆是 不一定会随着时间的流逝而保留；它们在检索（记忆重新激活）时变得不稳定，需要 重新整合到长期的存储店中，以维护，更新并可能加强。那， 干扰记忆重新溶解会削弱可卡因的记忆，以释放药物的动物模型和 减少患有药物使用障碍的人的渴望。该提议的长期目标是 促进我们对可卡因内存重新溶解的神经基础的理解，以便细胞/分子 将来可以确定适合有效治疗靶向的过程和神经回路。我们有 发现背侧海马（DCA3）的CA3区域在重新整合中起着至关重要的作用 可卡因的回忆。在这一发现和强大的初步数据的基础上，具体目标1将是识别蜂窝 DCA3内可卡因记忆重新固化的突触塑性机制。我们将测试 重新溶解需要谷氨酸能锥体神经元活性的假设 DCA3 SP和Lucidum（SL）细胞中的金字塔（SP）细胞层和GABA能中神经元活性 层。我们将在SP和SL中识别和表型器官细胞，并评估以下假设。 通过重新溶解来维持可卡因 - 内存强度与齿状回的持久可塑性有关 苔藓纤维（MF）DCA3Engram细胞突触，但在DCA3非ENGRAGR细胞突触中不进行。具体目标2将 绘制DCA3有效的电路，该电路在重新溶解过程中调节可卡因记忆强度并确定 相关的合成可塑性机制。根据额外的文献和强大的初步数据，我们将测试 直接DCA3 DCA1在海马内和DCA3内外侧隔膜（DLS）超海马的假设 在重新溶解过程中，电路以相反的方式调节可卡因记忆强度。此外，我们会的 检查以下假设，即可卡因在重新整合后的可卡因记忆维持与增加有关 多突触传输（MFDCA3DCA1/DLS）和DCA3中的兴奋性合成可塑性 Engram单元格突触。拟议的研究将利用药物记忆重新整合的仪器模型 并继电器，在主动种群方案，细胞类型和细胞类型中使用靶向重组的器官细胞进行标记 途径特异性体内和离体光遗传学，药理学，多标签免疫组织化学和整个 细胞斑块钳电生理学，以增加我们对海马记忆重新溶解的理解 过程调节可卡因记忆力强度和药物继电器。期望这些发现将提供必不可少的 未来研究的概念框架和开发有效治疗底物的概念框架 - 使用疾病和其他以侵入性适应记忆为特征的精神疾病。