Neural and Molecular Mechanisms of Emotional Dysfunction after Sepsis

项目摘要/摘要 这份提案描述了一项为期四年的职业发展计划，旨在引导PI成为一名 独立的临床科学家，研究严重疾病后情绪易感性的机制。 超过三分之一的危重病幸存者长期遭受抑郁、焦虑或创伤后的痛苦 应激障碍。关于这一主题的动物研究很少，但为了更好地理解 评估脆弱性的机制，并确定干预目标。这项研究的长期目标是 确定严重医疗后情绪易感性背后的分子机制和神经回路 并将这一知识转化为预防和治疗精神病的有效战略 危重病幸存者的精神障碍。 使用小鼠脓毒症模型盲肠结扎和穿刺术(CLP)的初步研究表明， CLP幸存者小鼠的焦虑样行为，以及原位杂交研究表明， 腹侧海马体。在第一个具体目标中，候选人将研究腹侧 CLP后腹侧CA1区锥体细胞活性检测对焦虑样行为的影响 用活体钙显像法测定CLP对腹侧光发生激活的影响 海马体对类焦虑行为的影响。 对包括危重疾病在内的创伤经历后患者的研究表明， 创伤期间循环中的糖皮质激素可能会保护幸存者免受创伤后应激症状的影响。在……里面 第二个具体目标是，候选人将调查疾病期间是否接受糖皮质激素治疗 经期对CLP存活者的负性情绪行为有保护作用，并使用RNA-SEQ识别 CLP和糖皮质激素对海马腹侧功能影响的候选基因 和情绪化行为。 申请人拥有医学博士学位，并已完成内科临床专业培训 医学和内分泌学。她以前有使用小鼠进行行为内分泌学研究的经验 模特们。这份申请包括一份职业发展计划，旨在更新她在 在清醒、自由行为的动物中研究行为的神经回路的技术，以及在设计中 以及大规模基因表达数据的分析。培训将包括授课培训、会议和 实验室会议、实践学徒以及通过出版物和 在国家会议上的发言。指导团队包括来自多个部门/部门的成员 以及多个机构，以支持这一本质上跨学科的项目。导师们能够 为完成拟议的项目提供充足资源的研究环境。

Project Summary/Abstract This proposal describes a four-year career development plan designed to lead the PI to a career as an independent clinician scientist studying the mechanisms of emotional vulnerability after severe medical illness. More than one third of critical illness survivors suffer long term from depression, anxiety, or post-traumatic stress disorder. Animal research on this topic is scarce, but is necessary in order to better understand the mechanisms of vulnerability and to identify targets for intervention. The long-term goal of this research is to identify the molecular mechanisms and neural circuitry behind emotional vulnerability after severe medical illness, and to translate this knowledge into effective strategies for the prevention and treatment of psychiatric disorders in critical illness survivors. Preliminary studies using a murine sepsis model, cecal ligation and puncture (CLP), showed increased anxiety-like behavior in CLP survivor mice, and in situ hybridization studies suggested a possible role for the ventral hippocampus. In the first Specific Aim, the candidate will investigate the role of the ventral hippocampus in anxiety-like behavior after CLP by examining the activity of ventral CA1 pyramidal cells after CLP using in vivo calcium imaging, and determining the effect of optogenetic activation of the ventral hippocampus on anxiety-like behavior. Studies of patients after traumatic experiences including critical illness have suggested that elevated circulating glucocorticoids during trauma may protect against post-traumatic stress symptoms in survivors. In the second Specific Aim, the candidate will investigate whether glucocorticoid treatment during the illness period can protect against negative emotional behavior in CLP survivors, and use RNA-seq to identify candidate genes that could mediate the effects of CLP and glucocorticoids on ventral hippocampal function and emotional behavior. The applicant holds M.D. and Ph.D. degrees and has completed clinical specialty training in Internal Medicine and Endocrinology. She has previous experience in behavioral endocrinology research using mouse models. This application includes a career development plan designed to update her scientific skills in techniques for investigating the neural circuits of behavior in awake, freely behaving animals, and in the design and analysis of large-scale gene expression data. The training will include didactic training, conferences and lab meetings, hands-on apprenticeship, and the communication of research findings through publications and presentation at national meetings. The mentorship team includes members of multiple departments/divisions and multiple institutions, in order to support this inherently interdisciplinary project. The mentors are able to provide a research environment with adequate resources to complete the proposed project.