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

项目摘要 精神病学系深深致力于候选人的职业发展。因此，他是 被招聘为精神病学和行为科学助理教授，在临床医生教育者轨道上， 在一般精神病学部门，计划在不久的将来过渡到终身教职。他会得到 超过75%的研究时间受到保护。职业发展计划旨在确保过渡到 独立一个职业发展委员会将指导这一过渡，萨钦·帕特尔博士将是主要负责人。 导师丹尼·温德博士和詹妮弗·布莱克福德博士将担任内部成员，托马斯卡什博士将从 北卡罗来纳州查佩尔山大学外部成员。候选人计划接受技术培训 在最先进的切片电生理学，交叉病毒方法和复杂的数据分析中， 体内单细胞钙成像的方法，并扩大他在光遗传学，微输注， 小鼠行为模型。这将在充分利用范德比尔特的许多可用资源的同时完成， 它的学院环境。 据估计，多达一半的寻求物质使用障碍治疗的患者患有创伤后应激障碍， 个体对于这两种情况具有更差的治疗结果。阿片类药物使用障碍（OUD）是一种常见的后遗症 并且与创伤后应激障碍高度共病该项目名为“阿片类药物与BNST在 创伤诱导焦虑状态的调节--创伤相关障碍和阿片类药物的共同底物 使用障碍合并症。”将重点阐述创伤后和创伤后并发症的神经生物学。 应激障碍和阿片类药物使用障碍，这是一种极具破坏性的组合。这一提议旨在检验小说 假设创伤事件后，内源性阿片系统在床上变得失调 终纹核（BNST），这反过来又导致焦虑失调，并可以解释脆弱性 阿片类药物的使用目的1将阐明一个pupelineanxiolyticcircuit，基底内侧杏仁核（BMA），BNST， 外侧下丘脑（LH）。目的2将评估μ阿片受体如何调节BMA-BNST-LH回路 以减少恐惧和焦虑行为以及这个系统是如何在创伤压力后被破坏的。目标3将 专注于表征在自由行为的小鼠在恐惧期间BNST-LH神经元的体内神经活动， 焦虑分析，这种信号是如何在创伤事件后被破坏的，以及被破坏的电路是如何被破坏的。 用外源性阿片类药物恢复正常 该项目利用了独立的科学思维，技术和专业的机会。 帕特尔博士和指导委员会的培训，以及范德比尔特的资源，同时 允许他从导师中分化出一个重要的新的科学方向。收到K 08将 通过增加重要的受保护时间和资源，最大限度地提高候选人的培训，以确保及时 一个成功的医生科学家的职业生涯的发展。

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.