Endocannabinoids and the development of extinction recall neural circuitry in adolescents

项目总结/摘要 焦虑症的特征是不能适当地抑制或消除恐惧。成功灭绝 学习，以及后来的回忆依赖于海马（HPC）-腹内侧前额叶皮层（vmPFC）电路， 而患有创伤后应激障碍（PTSD）的成年人表现出减少的激活和连接， 这些地区和贫穷的灭绝回忆。越来越多的研究确定了内源性大麻素的关键作用 (eCB)系统在调节恐惧消退和潜在的HPC-vmPFC电路，使eCB系统 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，然后福尔斯急剧下降，然后在青春期后期稳定下来， 个体接近青年期，这与焦虑症的出现相对应。然而，在这方面， 关于eCB信号在人类青春期如何变化的证据有限， eCB信号传导和消退回忆以及潜在的HPC-vmPFC电路之间的联系。这次培训的目的是 项目是PI Marusak发展概念和方法的专业知识，以及一个独立的科学 研究计划，以评估在青少年的新的假设，即：（1）恐惧消退回忆能力 （2）与年龄相关的灭绝回忆增加与年龄相关的灭绝回忆增加相对应。 HPC-vmPFC回路的激活，以及（3）较高的eCB anandamide（AEA）血液水平对应于 在青少年中，HPC-vmPFC回路的消退回忆更好和/或激活更高。从事 这一受保护的培训时间将使主要研究者能够制定一个创新的、转化的研究计划， 青少年焦虑，填补了一个独特的利基桥梁，她的背景和训练，在神经发育， 儿童逆境和神经影像学与新兴的专业知识在4个新领域：（1）转化研究 恐惧和恐惧相关病理学，（2）大麻素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 以及导师团队在恐惧条件反射和消退、焦虑症和新型eCB方面的专业知识 成人治疗（Mentor Rabinak），创伤，焦虑症，恐惧条件反射和消退， 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 疾病（Co-Mentor Greenwald），以及基于恐惧学习的分子神经生物学和动物模型（Co-Mentor Greenwald）。 Mentor Lee）。Co-Mentor Ghosh是一名生物统计学家，具有临床试验设计和统计分析方面的专业知识。 加上韦恩州立大学丰富的环境，这个奖项将提供重点培训， 一个富有成效的独立职业所需的试点数据，致力于推进我们对以下问题的理解： 神经发育机制导致焦虑症，并利用这些知识来发展更多 有效的干预措施，以避免在风险青年焦虑的发展（例如，收入较低， 逆境）。

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).