Cannabinoid Control of Fear Extinction Neural Circuits in Post Traumatic Stress d

描述(由申请者提供)：K01指导研究科学家奖将提供必要的指导和支持，以确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将神经精神药理学、脑成像和焦虑症治疗研究联系起来。该应用程序的培训部分基于应聘者在基础科学研究方面的专业知识，调查涉及调节恐惧记忆消退的神经回路，以及她在基本神经成像方法/分析和实施健康对照的药物-功能磁共振研究方面的技能。她的高级培训将集中在三个关键目标上：1)增强神经精神药理学的知识；2)神经成像(FMRI)研究方法的高级培训，创伤后应激障碍(PTSD)患者的药物-fMRI的分析和实施；以及3)对PTSD的临床方面(病因、评估和治疗)的深入了解。职业发展活动将由以色列·利伯松博士(主要导师)、希拉·劳赫博士(联合导师)、斯科特·佩尔蒂埃博士(联合导师)、K.Luan Phan博士(联合导师)和Mohammed Milad博士(顾问)指导；他们是一个研究团队，他们共同拥有不重叠但高度相关的专业知识和指导初级教师的杰出记录。拟议的K01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计划和 精神病学系的特殊之处在于其专科诊所和实验室致力于转化性研究。这是一个既能激发智力又能提供支持的环境 这促进了大量的学术互动机会，促进了合作，并在指导初级调查人员方面有着既定的记录。研究部分将调查大麻系统作为改善恐惧消退保持能力的潜在药理靶点，以及它对创伤后应激障碍患者潜在神经回路的影响。治疗创伤后应激障碍的一种常见的、经经验验证的方法是延长暴露疗法(PE)，其中一个组成部分是反复暴露于与恐惧有关的线索中，以产生恐惧的“消退”。PE通常是有效的，但相当数量的患者反应不完全或未能随着时间的推移而持续改善。提高疗效和可持续性的新战略可以显著提高缓解率，减轻这一常见疾病的公共卫生负担。疗效有限和缺乏可持续性可能是因为基于暴露的治疗的有效成分--灭绝学习--很容易受到 恐惧的回归。先前的研究表明，消退学习的保持依赖于边缘-额叶大脑网络(海马体[HPC]，腹内侧额前皮质[vmPFC])。创伤后应激障碍患者在这些区域表现出缺陷，事实上表现出较差的消退保持能力。解决vmPFC-HPC功能障碍和纠正灭绝保留缺陷的辅助干预措施在提高暴露的有效性和可持续性方面可能特别有效 创伤后应激障碍的治疗。候选人工作中令人信服的新证据表明，在健康志愿者进行灭绝学习之前，急性口服�9-四氢大麻酚(THc)，一种1型大麻受体(CB1)激动剂，通过增加vmPFC和HPC的激活和功能连接，促进维持和成功恢复灭绝记忆的能力。鉴于在创伤后应激障碍患者中观察到了消退保持缺陷和vmPFC-HPC功能障碍，而且加强大麻素传递有助于灭绝回忆，大麻素系统是一个很有希望的目标，可以改善在治疗中进行的学习，并可能增加PE在治疗创伤后应激障碍中的有效性和持久性(例如，缩短治疗同时加强和延长收益)。然而，在创伤后应激障碍患者中，大麻素对消亡记忆和相关神经回路的影响的直接测试尚未进行。该项目的目的是验证这样的假设，即服用THC将增强创伤后应激障碍患者的恐惧消退回忆，这些影响将通过增加vmPFC和HPC的激活和功能连接来调节。候选人将结合fMRI和皮肤电导反应(SCR)记录中的标准巴甫洛夫恐惧消退范式，比较80名有创伤后应激障碍(n=40)和没有创伤后应激障碍(n=40)的创伤暴露者和40名健康成年志愿者在消退学习前给予THC(与安慰剂[PBO])的效果，并在消退学习24小时后测试消退记忆。这项随机、双盲、安慰剂对照研究将为创伤后应激障碍的影响提供最直接的翻译和关键测试，促进我们对灭绝学习的神经生物学的理解，并有可能加速开发新的大麻素系统药物调节剂，以最大限度地发挥暴露疗法治疗焦虑症的疗效。在这一职业发展期间获得的知识、技能和数据将被综合到R01奖项申请中，以测试当与传统的、经过验证的暴露疗法相结合时，大麻类激动剂是否可以用作“消退回忆增强剂”，以提高疗效、改善消退保持和/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.