In vivo imaging of dynamic structural plasticity driving morphine conditioned place preference

驱动吗啡条件位置偏好的动态结构可塑性的体内成像

• 批准号: 9282579
• 负责人: Edward Bing Han
• 金额: $ 19.06万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9282579
• 关键词: Abstinence; Actins; Animals; Automobile Driving; Behavior; Behavioral; Biological Neural Networks; Brain; Cells; Conditioned Reflex; Conflict (Psychology); Dendrites; Dendritic Spines; Dorsal; Event; Extinction (Psychology); Functional Imaging; Goals; Grant; Guanosine Triphosphate Phosphohydrolases; Head; Hippocampus (Brain); Image; Image Analysis; Individual; Label; Learning; Mediating; Memory; Methods; Morphine; Morphology; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Opiate Addiction; Opiates; Pharmaceutical Preparations; Play; Population; Protocols documentation; Pyramidal Cells; Relapse; Reporting; Research; Resolution; Retrieval; Rewards; Role; Signal Transduction; Slice; Structure; Substance Use Disorder; Time; Training; Vertebral column; Virus; Visuospatial; addiction; awake; classical conditioning; conditioning; density; drug induced behavior; drug of abuse; ex vivo imaging; experimental study; functional plasticity; high resolution imaging; hippocampal pyramidal neuron; imaging approach; imaging modality; in vivo; in vivo imaging; novel; preference; prevent; receptor; restoration; rho; surveillance network; temporal measurement; tool; two-photon; virtual; virtual reality; way finding

Although significant advances in the treatment of opiate addiction have been made, relapse to opiate use after abstinence continues to impede successful treatment, highlighting the need for efforts to dissect the mechanism of opiate-dependent changes in brain plasticity. Recent studies have attempted to determine the role of structural plasticity in drug-induced behavior with conflicting findings which may result from the complexity of the intracellular signaling mechanisms underlying structural plasticity of dendritic spines caused by drugs of abuse. In this application we propose to develop novel in vivo approaches that will allow us to image the dynamic structural and functional plasticity that is triggered following opiate exposure and that may play a role in the mechanisms underlying reinstatement of drug seeking. To determine the relationship between dendrite structure and the formation and retrieval of drug associated memories, we propose to investigate how morphine exposure in a novel context modifies hippocampal dendritic spine morphology. In vivo imaging is a powerful tool to track rewiring in the hippocampal neural network, at the level of individual spines, throughout the learning, acquisition, expression, extinction and subsequent reinstatement of morphine conditioned place preference (CPP). Ideally one would be able to observe neural networks, in real time, as morphine CPP and reinstatement take place. The advent of virtual reality training paradigms during two-photon imaging makes this combination of behavior and network surveillance possible. In vivo imaging will enable us to follow the dynamics of spine remodeling and allow us to determine whether spine changes are cause or consequence of CPP. In addition, we will be able to visualize whether alterations in dendritic spines persist even following extinction which would indicate that spine remodeling may help store the latent memory driving drug-context associations. Therefore, the goals proposed in this application are: 1) to use in vivo 2-photon imaging in the dorsal hippocampus to follow structural changes in dendritic spines in CA1 neurons during the acquisition and expression of morphine CPP, and following its reinstatement; 2) to implement novel virtual reality spatial navigation protocols that enable us to conduct structural and functional imaging analyses of hippocampal cells in vivo during the formation of morphine-context associations. Overall, in this proposal we will conduct in vivo imaging analyses in awake mice to elucidate the temporal dynamics of hippocampal dendritic spine remodeling and its relationship to the formation of drug-context associations that may play a role in the mechanisms underlying reinstatement of drug seeking. In addition we will implement novel virtual navigation approaches to examine hippocampal circuit dynamics during the formation of morphine-context associations. The imaging methods and behavioral training protocols pioneered in this grant will be widely disseminated to the addiction field to advance the boundaries of current research.

虽然在阿片类药物成瘾的治疗方面已经取得了重大进展，但在阿片类药物成瘾后复吸的情况仍然存在。 禁欲继续阻碍成功的治疗，突出表明需要努力剖析 阿片依赖性改变脑可塑性的机制。最近的研究试图确定 结构可塑性在药物诱导行为中的作用， 树突棘结构可塑性的细胞内信号机制的复杂性， 滥用药物。在本申请中，我们提出开发新的体内方法，使我们能够 成像阿片类药物暴露后触发的动态结构和功能可塑性， 在重新吸毒的潜在机制中发挥作用。以确定关系 树突结构与药物相关记忆的形成和恢复之间的关系，我们建议 研究吗啡暴露在新环境下如何改变海马树突棘形态。在 活体成像是在个体水平上追踪海马神经网络中重新布线的有力工具。 在吗啡的学习、获得、表达、消退和随后的恢复过程中， 条件位置偏好（CPP）理想情况下，人们将能够观察神经网络，在真实的时间，因为 吗啡CPP和恢复发生。双光子期间虚拟现实训练范例的出现 成像使得这种行为和网络监视的结合成为可能。活体成像将使我们能够 以跟踪脊柱重塑的动力学，并使我们能够确定脊柱变化是否是导致或 CPP的后果此外，我们将能够可视化树突棘的改变是否持续存在， 即使在灭绝之后，这表明脊柱重塑可能有助于储存潜在的记忆驱动， 毒品关联因此，本申请提出的目标是：1）在体内使用2-光子 在背侧海马成像，以跟踪在CA 1神经元中树突棘的结构变化， 吗啡CPP的获得和表达，以及随后的恢复; 2）实施新的虚拟 现实空间导航协议，使我们能够进行结构和功能成像分析， 海马细胞在体内形成吗啡上下文协会。总的来说，在本提案中， 将在清醒小鼠中进行体内成像分析，以阐明海马神经元的时间动力学。 树突棘重塑及其与药物背景相关性形成的关系， 在复吸机制中的作用。此外，我们将实施新的虚拟 吗啡背景形成过程中海马回路动力学的导航方法 协会.这项资助开创的成像方法和行为训练方案将广泛应用于 传播到成瘾领域，以推进当前研究的边界。