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: 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
• 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

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).

项目概要/摘要 焦虑症的特点是无法适当抑制或消除恐惧。成功灭绝 学习及其后来的回忆取决于海马（HPC）-腹内侧前额叶皮层（vmPFC）电路， 患有创伤后应激障碍（PTSD）的成年人之间的激活和连接性降低 这些地区的灭绝记忆很差。越来越多的研究证实了内源性大麻素的关键作用 (eCB) 系统调节恐惧消退和底层 HPC-vmPFC 电路，使 eCB 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，然后在青春期后期稳定下来，如下所示： 个体接近成年早期，这与焦虑症的出现相对应。然而， 关于 eCB 信号在人类青春期如何变化以及潜在联系的证据有限 ECB 信号传导和灭绝召回以及底层 HPC-vmPFC 电路之间的关系。本次培训的目的 该项目旨在让 PI Marusak 开发概念和方法方面的专业知识，并建立一个独立的科学团队 研究计划，以评估青少年的新假设：（1）恐惧消退回忆能力 整个青春期的增加，（2）与年龄相关的消退记忆的增加与增加相对应 HPC-vmPFC 电路的激活，以及 (3) eCB anandamide (AEA) 的较高血液水平与 青少年 HPC-vmPFC 回路中更好的消退记忆和/或更高的激活。从事 这段受保护的培训时间将使 PI 能够开发一个创新的、以研究为重点的转化计划 关于青少年焦虑症，通过弥合她的背景和神经发育训练，填补了一个独特的空白， 童年逆境，以及神经影像学在 4 个新领域的新兴专业知识：(1) 转化研究 恐惧和恐惧相关的病理学，(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，以及（4）职业发展。研究和培训计划利用了广度 以及导师团队在恐惧调节和消除、焦虑症和新型 eCB 方面的专业知识 成人治疗（导师 Rabinak）、创伤、焦虑症以及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 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（共同导师 李老师）。联合导师 Ghosh 是一位生物统计学家，拥有临床试验设计和统计分析方面的专业知识。 结合韦恩州立大学丰富的环境，该奖项将提供有针对性的培训和 富有成效的独立职业所需的试点数据致力于增进我们对 导致焦虑症的神经发育机制，并利用这些知识来发展更多 采取有效的干预措施，以避免高危青少年（例如，收入较低、接触过 逆境）。

项目成果

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
• 作者: Marusak, Hilary A;Harper, Felicity W;Rabinak, Christine A
• 通讯作者: Rabinak, Christine A

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

• DOI: 10.1038/s41386-021-01084-5
• 发表时间: 2021-12
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
• 作者: Singh SD;Marusak HA
• 通讯作者: Marusak HA

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.

Martial Arts-Based Therapy Reduces Pain and Distress Among Children with Chronic Health Conditions and Their Siblings.

• DOI: 10.2147/jpr.s283364
• 发表时间: 2020
• 期刊: Journal of pain research
• 影响因子: 2.7
• 作者: Marusak HA;Iadipaolo AS;Cohen C;Goldberg E;Taub JW;Harper FWK;Bluth MH;Rabinak CA
• 通讯作者: Rabinak CA

The role of cannabinoids in shaping lifespan neurodevelopment.

• DOI: 10.1002/jnr.25012
• 发表时间: 2022-03
• 期刊: JOURNAL OF NEUROSCIENCE RESEARCH
• 影响因子: 4.2
• 作者: Marusak, Hilary A.