Cannabinoid control of fear extinction neural circuits in post-traumatic stress d

该K 01指导研究科学家奖将提供必要的指导和支持，以建立候选人作为翻译精神神经科学的独立研究人员，重点是通过综合方法桥接神经精神药理学，脑成像和焦虑症治疗研究。该应用程序的培训部分建立在候选人在基础科学研究方面的专业知识，研究涉及调节恐惧记忆消退的神经回路，以及她在健康对照中的基本神经成像方法/分析和药物功能磁共振成像研究的实施方面的技能。她的高级培训将集中在三个关键目标：1）增强神经精神药理学的知识; 2）神经影像学（fMRI）研究方法的高级培训，在创伤后应激障碍（PTSD）患者中分析和实施药物fMRI;和3）对PTSD的临床方面（病因，评估和治疗）的深入了解。职业发展活动将由Israel Liberzon博士（初级导师）、Sheila Rauch博士（共同导师）、Scott Peltier博士（共同导师）、K. Luan Phan（联合导师）和Mohammed Milad博士（顾问）;一个研究团队，共同拥有非重叠，但高度相关的专业知识和指导初级教师的特殊记录。拟议的K 01项目将在密歇根大学精神病学系内进行。密歇根大学以其跨学科的研究举措而闻名， 精神病学系是特殊的，它的子专业诊所和实验室致力于转化研究。这是一个智力刺激但支持的环境 该中心为促进合作的学术互动提供了大量机会，并在指导初级调查人员方面有着良好的记录。 研究部分将调查大麻素系统作为改善恐惧消退保留的潜在药理学靶点及其对PTSD患者潜在神经回路的影响治疗PTSD的一种常见的，经临床验证的方法是延长暴露疗法（PE），其中一个组成部分涉及重复暴露于与恐惧相关的线索以产生恐惧的“灭绝”。PE通常是有效的，但大量患者的反应不完全或无法随着时间的推移而持续改善。提高疗效和可持续性的新策略可以显着提高缓解率，减少这种常见疾病的公共卫生负担。有限的疗效和缺乏可持续性可能是由于这样一个事实，即灭绝学习，这是基于确定性的治疗的活性成分，容易受到影响。 恐惧的回归先前的研究表明，消退学习的保持取决于边缘额叶脑网络（海马[HPC]，腹内侧前额叶皮层[vmPFC]）。PTSD患者在这些区域表现出缺陷，实际上表现出差的消退保持。解决vmPFC-HPC功能障碍和纠正消退保留缺陷的辅助干预措施在增强暴露的有效性和可持续性方面可能特别有效 治疗创伤后应激障碍 候选人工作中令人信服的新证据表明，急性口服剂量的9-四氢大麻酚（THC），一种1型大麻素受体（CB 1）激动剂，在健康志愿者的灭绝学习之前给予，通过增加vmPFC和HPC的激活和功能连接，促进维持和成功检索灭绝记忆的能力。鉴于在PTSD患者中观察到了消退保留缺陷和vmPFC-HPC功能障碍，并且增强大麻素传递有助于消退回忆，大麻素系统是改善治疗中进行的学习的有希望的靶点，并且可能增加PE治疗PTSD的疗效和持久性（例如，缩短治疗，同时加强和延长增益）。然而，大麻素对消退回忆和相关神经回路的影响的直接测试尚未在PTSD患者中进行。拟议项目的目的是测试的假设，管理THC将增强回忆的恐惧消退PTSD患者，这些影响将介导通过增加激活和功能连接的vmPFC和HPC。候选人将在功能磁共振成像和皮肤电导反应（SCR）记录中结合标准巴甫洛夫恐惧消退范式，以比较在消退学习之前给予80名创伤暴露个体（n=40）和没有创伤后应激障碍（n = 40）和40名健康成年志愿者的THC（与安慰剂[PBO]）的效果，在消退学习后24小时测试消退回忆。这项随机、双盲、安慰剂对照研究将提供THC在PTSD中作用的最直接的转化和关键测试，促进我们对消退学习的神经生物学的理解，并可能加速大麻素系统的新型药理学调节剂的开发，以最大限度地提高暴露疗法对焦虑症的疗效。 在此职业发展期间获得的知识，技能和数据将被合成到R 01奖项应用程序中，以测试大麻素激动剂是否可以用作“灭绝回忆增强剂”，当与传统的，经过验证的暴露疗法相结合时，以提高疗效，改善灭绝保留，和/或加快创伤后应激障碍和其他焦虑症的治疗反应速度。

DESCRIPTION (provided by applicant): This K01 Mentored Research Scientist Award will provide the mentorship and support necessary to establish the Candidate as an independent researcher in translational psychiatric neuroscience, with a focus on bridging neuropsychopharmacology, brain imaging, and treatment studies in anxiety disorders through an integrative approach. The training component of this application builds on the Candidate's expertise in basic science research investigating the neural circuits involved in regulating extinction of fear memories, as well as her skills in basic neuroimaging methods/analysis and implementation of pharmaco-fMRI studies in healthy controls. Her advanced training will be focused on three key objectives: 1) enhanced knowledge of neuropsychopharmacology; 2) advanced training in neuroimaging (fMRI) research methodology, analyses and implementation of pharmaco-fMRI in post-traumatic stress disorder (PTSD) patients; and 3) advanced understanding of the clinical aspects (etiology, assessment, and treatment) of PTSD. The career development activities will be mentored by Dr. Israel Liberzon (Primary Mentor), Dr. Sheila Rauch (Co-Mentor), Dr. Scott Peltier (Co-Mentor), Dr. K. Luan Phan (Co-Mentor), and Dr. Mohammed Milad (Consultant); a team of researchers that collectively possess non-overlapping, but highly related expertise and exceptional records of mentoring junior faculty. The proposed K01 project will take place within the Department of Psychiatry at the University of Michigan. The University of Michigan is noted for its interdisciplinary research initiatives and the Department of Psychiatry is exceptional with its subspecialty Clinics and laboratories dedicated to translational research. It is an intellectually stimulating yet supportive environment that promotes numerous opportunities for scholarly interactions, which foster collaborations, and has an established track record for mentoring junior investigators. The research component will investigate the cannabinoid system as a potential pharmacological target for improving the retention of fear extinction and its effect on the underlying neural circuits in patients with PTSD A common, empirically-validated approach to treat PTSD is Prolonged Exposure Therapy (PE), one component of which involves repeated exposure to fear-linked cues to produce "extinction" of fear. PE is generally effective, but a significant number of patients have incomplete responses or fail to sustain improvements over time. New strategies to improve efficacy and sustainability could significantly enhance remission rates and reduce the public health burden of this common disorder. Limited efficacy and lack of sustainability could be due to the fact that extinction learning, which is the active ingredient of exposure-based therapy, is vulnerable to the return of fear. Prior studies have shown that retention of extinction learning depends upon limbic-frontal brain networks (hippocampus [HPC], ventromedial prefrontal cortex [vmPFC]). PTSD patients show deficits in these regions, and in fact exhibit poor extinction retention. Adjunct interventions that address vmPFC-HPC dysfunction and redress extinction retention deficits could be particularly potent in enhancing both the efficacy and sustainability of exposure therapy for PTSD. Compelling new evidence from work by the Candidate has shown that an acute oral dose of ¿9- tetrahydrocannibinol (THC), a type 1 cannabinoid receptor (CB1) agonist, given prior to extinction learning in healthy volunteers, facilitates the ability to maintain and successfully retrieve extinction memory via increased activation and functional connectivity of the vmPFC and HPC. Given that extinction retention deficits and vmPFC-HPC dysfunction have been observed in patients with PTSD, and that enhancing cannabinoid transmission helps extinction recall, the cannabinoid system is a promising target for improving the learning that goes on in therapy and perhaps increasing efficacy and durability of PE in treating PTSD (e.g., shortening treatment while strengthening and prolonging gains). However, direct tests of cannabinoid effects on extinction recall and associated neural circuits have not yet been conducted in PTSD patients. The objective of the proposed project is to test the hypotheses that administration of THC will enhance recall of fear extinction in patients with PTSD and that these effects will be mediated via increased activation and functional connectivity of the vmPFC and HPC. The Candidate will couple a standard Pavlovian fear extinction paradigm in fMRI and skin conductance response (SCR) recordings to compare the effects of THC (vs. placebo [PBO]) administered prior to extinction learning in 80 trauma-exposed individuals with (n=40) and without (n =40) PTSD and 40 healthy adult volunteers, testing extinction recall 24 hours after extinction learning. This randomized, double- blind, placebo-controlled study will provide the most direct translational and critical test of THC effects in PTSD, advancing our understanding of the neurobiology of extinction learning and potentially hastening the development of novel pharmacological modulators of the cannabinoid system to maximize the efficacy of exposure therapy for anxiety disorders. The knowledge, skills, and data obtained during this career development period will be synthesized into a R01 award application to test whether cannabinoid agonists can be used as an 'extinction recall enhancer' when coupled with conventional, validated exposure therapies to enhance the efficacy, improve extinction retention, and/or expedite the pace of treatment response in PTSD and other anxiety disorders.