Opioid-BNST interactions in the regulation of trauma-induced anxiety states

阿片类药物-BNST 相互作用在调节创伤引起的焦虑状态中的作用

• 批准号: 10615979
• 负责人: Luis Eduardo Rosas-vidal
• 金额: $ 14.46万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615979
• 关键词: Adult; Amygdaloid structure; Anatomy; Anti-Anxiety Agents; Anxiety; Behavior; Behavioral Model; Behavioral Sciences; Biological; Biological Assay; Calcium; Cells; Chronic; Data; Data Analyses; Development; Development Plans; Disease; Electrophysiology (science); Ensure; Environment; Etiology; Exposure to; Freezing; Fright; Future; Hypothalamic structure; Image; Individual; Knowledge; Laboratory Finding; Lateral; Lead; Light; Link; Mediating; Mental disorders; Mentors; Methods; Morphine; Mus; Negative Reinforcements; Neurobiology; Neurons; North Carolina; Odors; Opioid; Output; Patients; Physicians; Post-Traumatic Stress Disorders; Psychiatry; Receptor Activation; Receptor Signaling; Regulation; Research; Resources; Risk; Role; Scientist; Self Medication; Signal Transduction; Slice; Stress; Structure of terminal stria nuclei of preoptic region; Substance Use Disorder; Symptoms; Synapses; System; Testing; Thinking; Time; Training; Trauma; Treatment outcome; Universities; Viral; anxiety states; avoidance behavior; base; career; career development; comorbidity; coping; design; emotional distress; endogenous opioids; experience; experimental study; gamma-Aminobutyric Acid; in vivo; insight; member; mu opioid receptors; mu receptors; neural circuit; novel; opioid misuse; opioid use; opioid use disorder; optogenetics; professor; recruit; relating to nervous system; response; stress reactivity; stress related disorder; substance use treatment; tenure track; transmission process; traumatic event; traumatic stress

Project Summary The Department of Psychiatry is deeply committed to the career development of the candidate. As such, he is being recruited as Assistant Professor of Psychiatry and Behavioral Sciences, on the Clinician Educator track, in the Division of General Psychiatry with plans to transition to tenure track in the near future. He will be provided with over 75% protected research time. The career development plan is designed to ensure a transition towards independence. A career development committee will guide this transition with Dr. Sachin Patel being the primary mentor. Dr. Danny Winder and Dr. Jennifer Blackford will serve as internal members and Dr. Thomas Kash from University of North Carolina at Chapel Hill as external member. The candidate plans to obtain technical training in state-of-the-art slice electrophysiology, intersectional viral approaches, and sophisticated data analysis methods for in vivo single cell calcium imaging and expand his knowledge in optogenetics, microinfusions, and mouse behavioral models. This will be done while leveraging on the many available resources at Vanderbilt and its collegial environment. It is estimated that up to half of patients seeking treatment for substance use disorders have PTSD, and these individuals have worse treatment outcomes for both conditions. Opioid use disorder (OUD) is a common sequela following trauma and is highly comorbid with PTSD. This project entitled “Opioid-BNST interactions in the regulation of trauma-induced anxiety states- Towards common substrates in trauma-related disorders and opioid use disorder comorbidity.” will focus on elucidating the neurobiology of co-morbidity between post-traumatic stress disorder and opioid use disorder, a highly devastating combination. This proposal aims to test the novel hypothesis that following a traumatic event, the endogenous opioid system becomes dysregulated in the bed nucleus of the stria terminalis (BNST) which in turn lead to dysregulated anxiety and could explain vulnerability to opioid use. Aim 1 will elucidate a putatively anxiolytic circuit, the basomedial amygdala (BMA) to BNST to lateral hypothalamus (LH). Aim 2 will assess how the BMA-BNST-LH circuit is modulated by mu opioid receptors to reduce fear and anxiety behaviors and how this system is disrupted following a traumatic stress. Aim 3 will focus on characterizing in vivo neural activity of BNST-LH neurons in freely behaving mice during fear and anxiety assays, how this signaling becomes disrupted following a traumatic event, and how the disrupted circuit normalizes with exogenous opioids. This project takes advantage of opportunities for independent scientific thinking, technical and professional training from Dr. Patel and the mentoring committee, and the resources at Vanderbilt while simultaneously allowing differentiation from his mentors towards an important novel scientific direction. Receiving the K08 will maximize candidate’s training by increasing important protected time and resources to ensure a timely development of a successful physician-scientist career.

项目摘要 精神病学系深深地致力于候选人的职业发展。因此，他是 在临床医生教育家轨道上被招募为精神病学和行为科学助理教授， 在普通精神病学的划分中，计划在不久的将来过渡到任期。他将被提供 超过75％的研究时间。职业发展计划旨在确保过渡 独立。职业发展委员会将指导这一过渡，萨钦·帕特尔（Sachin Patel）是主要的 导师。 Danny Winder博士和Jennifer Blackford博士将担任内部成员，以及来自的Thomas Kash博士 北卡罗来纳大学教堂山的外部成员。候选人计划获得技术培训 在最先进的切片电生理学中，交叉病毒方法和复杂的数据分析 体内单细胞钙成像的方法，并扩展他在光遗传学，微吸收和 鼠标行为模型。这将在利用Vanderbilt的许多可用资源和 它的合作环境。 据估计，寻求药物使用障碍治疗的患者中有多达一半的患者患有PTSD，这些 个人在两种情况下都有较差的治疗结果。阿片类药物使用障碍（OUD）是常见的后遗症 在创伤之后，与PTSD高度合并。该项目标题为“阿片类药物的互动 对创伤引起的动画状态的调节 - 与创伤相关疾病中的常见底物和OOID 使用障碍合并症。 应激障碍和阿片类药物使用障碍，这是一种高度破坏性的组合。该建议旨在测试小说 假设在创伤事件之后，内源性阿片类药物系统在床上失调 质子末端（BNST）的核，进而导致动画失调，可以解释脆弱性 使用绿o。 AIM 1将阐明推定的抗焦虑电路，碱性杏仁核（BMA）至BNST 下丘脑（LH）。 AIM 2将评估BMA-BNST-LH电路如何通过MU阿片类接收器调节 减少恐惧和焦虑行为以及在造成创伤压力后如何破坏该系统。目标3意志 专注于表征在恐惧和 焦虑测定，发生创伤事件后这种信号如何破坏，以及电路如何破坏 用外源阿片类药物归一化。 该项目充分利用了独立科学思维，技术和专业的机会 帕特尔博士和心理委员会的培训以及范德比尔特的资源 允许与他的导师迈向重要的新颖科学方向。接收K08将 通过增加重要的受保护时间和资源来确保及时，使候选人的培训最大化 发展成功的身体科学家职业。