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

基本信息

批准号：
10656479
负责人：
Hilary Marusak
金额：
$ 14.52万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10656479
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 Dedications Development Endocannabinoids Environment Enzymes Exhibits Exposure to Extinction Failure Female Fright Functional Magnetic Resonance Imaging Funding Galvanic Skin Response Genes Genetic Polymorphism Goals Hippocampus 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 Productivity Psychophysiology Reporting Research 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 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

项目摘要

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抑制或消除恐惧。成功的灭绝学习及其后来的召回取决于海马（HPC） - 韦特罗尼尔前额叶皮层（VMPFC）电路，患有创伤后应激障碍（PTSD）的成年人显示激活和连通性降低这些地区和灭绝不佳的回忆。不断增长的研究确定了内源性大麻素的关键作用（欧洲央行）系统调节恐惧灭绝和基础HPC-VMPFC电路的系统，使欧洲央行系统成为焦虑症的新机械和治疗靶点。来自动物模型的新兴数据表明欧洲央行信号传导在青春期早期急剧下降，然后在青春期稳定为个人接近成年年轻，这与焦虑症的出现相对应。然而，有限的证据表明欧洲央行信号在青春期中如何变化以及潜在的联系欧洲央行信号传导和灭绝召回和基础HPC-VMPFC电路之间。这项训练的目标 Pi Marusak的项目要发展概念和方法论专业知识，并且是独立的科学知识研究计划，以评估青少年的新颖假设：（1）害怕灭绝召回能力（2）与年龄相关的灭绝召回率的增加与增加 HPC-VMPFC电路的激活，（3）欧洲央行（AEA）的血液水平较高在青少年中，HPC-VMPFC电路内的更好的消灭召回和/或更高的激活。参与这个受保护的培训时间将使PI能够制定以研究为重点的创新，翻译计划关于青春期焦虑，通过弥合她的背景和神经发育的培训来填补独特的利基市场，儿童逆境和神经影像学在4个新领域具有新兴专业知识：（1）翻译研究恐惧和与恐惧有关的病理学，（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和（4）职业发展。研究和培训计划利用广度以及指导团队在恐惧调节和灭绝，焦虑症和新颖欧洲央行方面的专业知识成人治疗（Rabinak导师），创伤，焦虑症以及恐惧调节和灭绝，儿童，青少年和成年人（联合主管Jovanovic），人类药理，影响和吸毒疾病（Greenwald）以及基于恐惧的学习的分子神经生物学和动物模型（共同）李的导师）。戈什（Ghosh）是一位生物统计学家，在临床试验设计和统计分析方面具有专业知识。与韦恩州立大学的丰富环境一起，该奖项将提供专注的培训和致力于促进我们对理解的生产独立职业所需的试验数据神经发育机制导致焦虑症，并利用这些知识发展更多有效的干预措施来规避高危青年焦虑的发展（例如，收入较低，暴露于逆境）。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Editorial: Growing up in a High-Stigma Context: An Unseen Driver of Neurodevelopment, Health, and Pathology.

DOI：
10.1016/j.jaac.2021.10.008
发表时间：
2022-06
期刊：
JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY
影响因子：
13.3
作者：
Marusak, Hilary A.
通讯作者：
Marusak, Hilary A.

Pediatric cancer, posttraumatic stress and fear-related neural circuitry.

DOI：
10.2217/ijh-2019-0002
发表时间：
2019-07-11
期刊：
International journal of hematologic oncology
影响因子：
0
作者：
Marusak, Hilary A;Harper, Felicity W;Rabinak, Christine A
通讯作者：
Rabinak, Christine A

Martial arts-based curriculum reduces stress, emotional, and behavioral problems in elementary schoolchildren during the COVID-19 pandemic: A pilot study.

DOI：
10.1111/mbe.12307
发表时间：
2022-03
期刊：
MIND BRAIN AND EDUCATION
影响因子：
1.8
作者：
Marusak, Hilary A.;Borg, Breanna;Morales, Austin;Smith, Jamila Carrington;Blankenship, Kelly;Allen, Junior Lloyd;Goldberg, Elimelech;Bluth, Martin H.
通讯作者：
Bluth, Martin H.

Bridging the gap: preparing the next generation of brain scientists to communicate with the general public and lawmakers.