Neural and Molecular Mechanisms of Emotional Dysfunction after Sepsis

项目概要/摘要 该提案描述了一个为期四年的职业发展计划，旨在引导PI成为一名 独立临床科学家，研究严重疾病后情绪脆弱的机制。 超过三分之一的重症幸存者长期患有抑郁症，焦虑症或创伤后 应激障碍关于这一主题的动物研究很少，但为了更好地理解这一主题， 研究脆弱性机制，并确定干预目标。这项研究的长期目标是 确定严重医疗事故后情绪脆弱性背后的分子机制和神经回路 疾病，并将这些知识转化为预防和治疗精神疾病的有效战略， 危重病幸存者的疾病。 使用小鼠脓毒症模型，盲肠结扎穿孔（CLP）的初步研究显示， 原位杂交研究表明， 腹侧海马在第一个特定目标中，候选人将研究腹侧的作用。 海马在CLP后焦虑样行为中的作用，通过检查CLP后腹侧CA 1锥体细胞的活性， CLP使用体内钙成像，并确定腹侧核的光遗传学激活的作用。 海马体对焦虑样行为的影响 对创伤经历（包括危重病）后患者的研究表明， 在创伤期间循环的糖皮质激素可以防止幸存者的创伤后应激症状。在 第二个具体目标，候选人将调查是否糖皮质激素治疗期间的疾病 周期可以防止CLP幸存者的负面情绪行为，并使用RNA-seq来识别 可能介导CLP和糖皮质激素对腹侧海马功能影响的候选基因 和情绪行为。 申请人持有医学博士学位。和博士学位，并已完成内部临床专业培训 医学和内分泌学。她有使用小鼠进行行为内分泌学研究的经验 模型此应用程序包括职业发展计划，旨在更新她的科学技能， 研究清醒、自由行为的动物的行为神经回路的技术， 和大规模基因表达数据的分析。培训将包括教学培训、会议和 实验室会议，实践学徒，并通过出版物和 在国家会议上发言。指导团队包括多个部门/部门的成员 和多个机构，以支持这一固有的跨学科项目。导师们能够 提供一个有足够资源的研究环境，以完成拟议的项目。

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.