Endocannabinoids and the development of extinction recall neural circuitry in adolescents

内源性大麻素与青少年消退回忆神经回路的发展

• 批准号: 10425325
• 负责人: Hilary Marusak
• 金额: $ 17.42万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425325
• 关键词: Adolescence; Adolescent; Adolescent Development; Adult; Affect; Age; Amygdaloid structure; Animal Model; Anxiety; Anxiety Disorders; Area; Award; Behavior; Binding; Blood; Blood specimen; Brain; Cannabinoids; Catabolism; Child; Clinical Trials Design; Coupled; Data; Development; Endocannabinoids; Environment; Enzymes; Exhibits; Exposure to; Extinction (Psychology); Failure; Female; Fright; Functional Magnetic Resonance Imaging; Funding; Galvanic Skin Response; Genes; Genetic Polymorphism; Goals; Hippocampus (Brain); Human; Individual; Intervention; Knowledge; Learning; Link; Low income; Measures; Mentors; Mentorship; Methodology; Molecular Neurobiology; National Institute of Mental Health; Neurobiology; Neurosciences Research; Pathology; Patients; Peripheral; Pharmacology; Positron-Emission Tomography; Post-Traumatic Stress Disorders; Prefrontal Cortex; Psychophysiology; Reporting; Research; Research Training; Risk; Rodent; Role; Sampling; Series; Serum; Sex Differences; Statistical Data Interpretation; Substance Use Disorder; Testing; Time; Tracer; Training; Translational Research; Trauma; Universities; Validation; Variant; Work; Youth; age related; anandamide; animal data; base; career; career development; childhood adversity; clinical trial implementation; conditioned fear; design; early adolescence; effective intervention; endocannabinoid signaling; endogenous cannabinoid system; falls; fatty acid amide hydrolase; high risk; innovation; insight; learning extinction; mouse model; neural circuit; neurodevelopment; neuroimaging; neuromechanism; novel; preadolescence; programs; recruit; response; skills; therapeutic target; training project; translational neuroscience; translational research program; trauma exposure; urban setting; virtual reality; young adult

PROJECT SUMMARY/ABSTRACT Anxiety disorders are characterized by a failure to appropriately inhibit or extinguish fear. Successful extinction learning, and its later recall depend on hippocampal (HPC)-ventromedial prefrontal cortex (vmPFC) circuitry, and adults with posttraumatic stress disorder (PTSD) show decreased activation and connectivity between these regions and poor extinction recall. Growing research establishes the key role of the endocannabinoid (eCB) system in modulating fear extinction and underlying HPC-vmPFC circuitry, making the eCB system a novel mechanistic and therapeutic target for anxiety disorders. Emerging data from animal models suggest that eCB signaling peaks and falls sharply during early adolescence and then stabilizes in late adolescence as individuals approach young adulthood, which corresponds with the emergence of anxiety disorders. However, there is limited evidence of how eCB signaling changes in humans across adolescence, and potential links between eCB signaling and extinction recall and underlying HPC-vmPFC circuitry. The goal of this training project is for PI Marusak to develop conceptual and methodological expertise, and an independent scientific research program, to evaluate in adolescents the novel hypotheses that: (1) fear extinction recall ability increases across adolescence, (2) age-related increases in extinction recall correspond with increased activation of HPC-vmPFC circuitry, and (3) higher blood levels of the eCB anandamide (AEA) correspond with better extinction recall and/or higher activation within HPC-vmPFC circuitry among adolescents. Engaging in this protected training time will allow the PI to develop an innovative, translational program of research focused on adolescent anxiety that fills a unique niche by bridging her background and training in neural development, childhood adversity, and neuroimaging with emerging expertise in 4 new areas: (1) translational research on fear and fear-related pathology, (2) cannabinoid neurobiology and pharmacology, (3) clinical trials design and statistical analysis, and (4) career development. The research and training plan take advantage of the breadth and expertise of the mentorship team in fear conditioning and extinction, anxiety disorders, and novel eCB treatments in adults (Mentor Rabinak), trauma, anxiety disorders, and fear conditioning and extinction, in children, adolescents, and adults (Co-Mentor Jovanovic), human pharmacology, affect, and substance use disorders (Co-Mentor Greenwald), and molecular neurobiology and animal models of fear-based learning (Co- Mentor Lee). Co-Mentor Ghosh is a biostatistician with expertise in clinical trials design and statistical analysis. Together with the rich environment of Wayne State University, this Award will provide the focused training and pilot data needed for a productive independent career dedicated to advancing our understanding of neurodevelopmental mechanisms leading to anxiety disorders, and to using that knowledge to develop more effective interventions to circumvent the development of anxiety in at-risk youth (e.g., lower income, exposed to adversity).

项目摘要/摘要 焦虑症的特征是未能适当地抑制或消除恐惧。成功灭绝 学习和后来的记忆依赖于海马体(HPC)-腹内侧额叶皮质(VmPFC)电路， 患有创伤后应激障碍(PTSD)的成年人表现出激活和连接性降低 这些地区和贫穷的灭绝回忆起来。越来越多的研究确定了内源性大麻素的关键作用 (欧洲央行)调节恐惧消退和底层HPC-vmPFC电路的系统，使欧洲央行系统成为 焦虑症的新机制和治疗靶点。来自动物模型的新数据表明， ECB信号在青春期早期达到峰值并急剧下降，然后在青春期晚期稳定下来，因为 个体接近青壮年，这与焦虑症的出现相对应。然而， 关于ECB信号如何在青春期期间在人类中发生变化的证据有限，以及潜在的联系 ECB信号和消光召回以及底层HPC-vmPFC电路之间的关系。这次培训的目标是 该项目是为了让Pi Marusak发展概念和方法方面的专门知识，以及一项独立的科学 研究计划，在青少年中评估新的假设：(1)恐惧消退回忆能力 青春期的增加，(2)与年龄相关的灭绝回忆增加与增加相对应 HPC-vmPFC通路的激活，以及(3)较高的ECB-ANDA(AEA)水平与 青少年在HPC-vmPFC回路中有更好的消光回忆和/或更高的激活。从事 这一受保护的培训时间将使PI能够制定一项创新的、以研究为重点的翻译计划 通过将她的背景和神经发展方面的培训联系起来，她的青春期焦虑填补了一个独特的利基市场， 童年逆境和神经成像在4个新领域的新兴专业知识：(1)关于 恐惧和恐惧相关的病理学，(2)大麻类神经生物学和药理学，(3)临床试验设计和 统计分析；(4)职业发展。研究和培训计划利用了广度 指导团队在恐惧条件作用和消退、焦虑症和新颖的ECB方面的专业知识 成人治疗(拉比纳克导师)，创伤，焦虑症，恐惧条件反射和消退，在 儿童、青少年和成人(共同导师Jovanovic)、人类药理学、情感和物质使用 精神障碍(共同导师格林沃尔德)，以及基于恐惧的学习的分子神经生物学和动物模型(联合 李导师)。共同导师戈什是一名生物统计学家，在临床试验设计和统计分析方面拥有专业知识。 该奖项将与韦恩州立大学丰富的环境一起，提供有针对性的培训和 致力于促进我们对以下方面的理解的高效独立职业生涯所需的试验数据 导致焦虑症的神经发育机制，并利用这些知识发展出更多 有效的干预措施，以避免高危青少年的焦虑发展(例如，低收入、暴露于 逆境)。