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

项目摘要 精神病学系致力于候选人的职业发展。因此，他是 被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， 在普通精神病学司，计划在不久的将来过渡到终身教职轨道。他会被提供给 有超过75%的保护研究时间。职业发展计划旨在确保过渡到 独立。职业发展委员会将指导这一过渡，萨钦·帕特尔博士是主要的 门托。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·卡什博士将担任 北卡罗来纳大学教堂山分校作为外部成员。应聘者计划接受技术培训 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 方法体内单细胞钙成像和扩大他的知识在光遗传学，微量输注，和 小鼠行为模型。这将在利用Vanderbilt和 它的大学环境。 据估计，多达一半寻求治疗药物使用障碍的患者患有创伤后应激障碍，而这些 在这两种情况下，个人的治疗结果都更差。阿片类药物使用障碍是一种常见的后遗症。 在创伤后，并与创伤后应激障碍高度共存。这项名为“阿片类药物-BNST相互作用”的项目 创伤相关障碍和阿片类药物常见底物对创伤诱发焦虑状态的调节 使用障碍共病。“将重点阐明创伤后并发症的神经生物学机制 应激障碍和阿片类药物使用障碍，这是一个极具破坏性的组合。这项提议旨在检验这部小说 假设在创伤性事件发生后，内源性阿片系统在床上变得失调 终纹核(BNST)反过来导致调节失调的焦虑，并可以解释易感性 阿片类药物的使用。目的1阐明杏仁基底内侧核(BMA)至BNST的抗焦虑环路 下丘脑外侧核(Lh)。目标2将评估BMA-BNST-LH环是如何被MU阿片受体调制的 以减少恐惧和焦虑行为，以及创伤应激后这一系统是如何被破坏的。目标3将 重点研究BNST-1H神经元在自由行为小鼠恐惧和抑郁状态下的体内神经活动 焦虑分析，在创伤性事件后，这个信号如何被扰乱，以及被扰乱的电路如何 与外源性阿片类药物一起恢复正常。 这个项目利用了独立的科学思考、技术和专业的机会。 来自Patel博士和指导委员会的培训，以及Vanderbilt的资源 允许他从导师那里区分出来，朝着一个重要的新颖科学方向前进。收到K08将会 通过增加重要的受保护时间和资源来最大限度地提高候选人的培训效率，以确保及时 发展成功的内科医生-科学家职业生涯。

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.