Investigation of neurofunctional reorganization in cocaine addiction using mGluR5 PET and fMRI

项目摘要/摘要 可卡因使用障碍(Cud)仍然是一个重要的公共卫生问题，对当前的 治疗并与影响多种认知功能的神经生物学改变相关。挑战 治疗CUD包括神经功能系统的失衡，神经功能系统重新连接大脑，从而产生食欲 习惯性的过程指导着不适应的决策和行为。这项拟议的研究旨在 通过研究与以下相关的神经功能系统，深入了解CUD中的这种重新组织的回路 谷氨酸和脑功能网络。 代谢型谷氨酸5受体(MGluR5)是一种突触后受体，参与神经再生 机制，并与调节CUD成瘾行为的获得和持续有关。 对CUD中mGluR5的研究表明，在早期禁欲期间，可获得性普遍下降； 然而，关于mGluR5在当前用户中的可用性以及与重组大脑的关系，人们知之甚少 认知功能背后的回路。静息状态和基于任务的(例如，反应抑制)表现 参与已知功能脑网络的协调活动和CUD连接模式的改变 对成瘾行为的核心回路(例如额顶系统)的重组提供洞察力。这 应用建议通过高选择性的PET成像研究mGluR5的分布 放射性配基[18F]FPEB(目标1)和静息状态下与反应抑制相关的功能网络活性 在当前使用的CUD患者和匹配的健康个体的fMRI期间使用Go/NoGo任务(Aim 2) 比较参与者。将使用其他复杂的分析方法(例如，独立分量分析) 集成这些多模式数据(目标3)，为这些数据之间的关系提供新的见解 CUD的神经功能系统。 这一研究和培训计划将整合最先进的生物医学成像设施 耶鲁大学医学院。导师团队由国际知名的成瘾专家组成。 精神病学、计算统计学和分子神经科学。该计划将为应聘者提供 成为成瘾领域的独立调查员所需的技能和经验 神经科学。为了实现这一目标，候选人提议在三个小学生方面进行进一步培训 领域：(1)进行人体PET研究方案和图像分析方法；(2)尖端技术 多模式神经成像数据整合的统计；和(Iii)分子神经科学 上瘾精神病学。该奖项提供的机会将使候选人能够开始一项 全面、有组织的5年培训和研究计划，旨在培养 创新的神经生物学研究方法，以成为一名独立的成瘾调查员。

PROJECT SUMMARY/ABSTRACT Cocaine use disorder (CUD) remains a significant public health concern that is resistant to current treatments and associated with neurobiological alterations impacting multiple cognitive functions. Challenges to treating CUD include an imbalance in neurofunctional systems that ‘re-wire’ the brain such that appetitive and habitual processes direct maladaptive decision-making and behavior. The proposed research aims to provide insight into this reorganized circuitry in CUD by investigating neurofunctional systems related to glutamate and functional brain networks. The metabotropic glutamate 5 receptor (mGluR5) is a postsynaptic receptor involved in neuroplastic mechanisms, and associated with modulating the acquisition and persistence of addictive behavior in CUD. Studies of mGluR5 in CUD demonstrate a widespread reduction in availability during early abstinence; however, less is known regarding mGluR5 availability in current users, and relationships to reorganized brain circuitry underlying cognitive functioning. Resting-state and task-based (e.g., response inhibition) performance involve coordinated activity in known functional brain networks and alterations in connectivity patterns in CUD lend insight in a reorganization of circuitry (e.g., fronto-parietal systems) central to addictive behaviors. This application proposes to investigate the distribution of mGluR5 through PET imaging using the highly-selective radioligand [18F]FPEB (Aim 1), and functional network activity at resting-state and related to response inhibition using a Go/NoGo task during fMRI (Aim 2) in currently-using individuals with CUD and matched healthy comparison participants. Additional sophisticated analytics (e.g., independent component analysis) will be used to integrate these multi-modal data (Aim 3), providing novel insight into the relationship between these neurofunctional systems in CUD. This program of research and training will integrate state-of-the-art biomedical imaging facilities at the Yale School of Medicine. The mentorship team consists of internationally renowned experts in addiction psychiatry, computational statistics and molecular neuroscience. The program will provide the candidate with the requisite skills and experience to become an independent investigator in the field of addictions neuroscience. In pursuit of this goal, the candidate proposes to undertake further training in three primary areas: (i) the conduct of human PET research protocols and image analysis methods; (ii) sophisticated statistics toward the integration of multi-modal neuroimaging data; and (iii) the molecular neuroscience of addictions psychiatry. The opportunities afforded by this award would enable the candidate to embark on a comprehensive, structured 5-year program of training and research designed to develop an expertise in innovative neurobiological research methods toward a career as an independent addictions investigator.