Neural and Molecular Mechanisms of Emotional Dysfunction after Sepsis

脓毒症后情绪功能障碍的神经和分子机制

基本信息

批准号：
10175045
负责人：
Joanna Louise Spencer-Segal
金额：
$ 19.66万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10175045
关键词：
Acute Adrenal Cortex Hormones Adult Respiratory Distress Syndrome Affective Symptoms American Animal Experimentation Animal Model Animals Anxiety Area Attention Behavior Behavioral Brain Brain region Candidate Disease Gene Cardiac Surgery procedures Chronic Clinical Communication Research Corticosterone Critical Illness Data Data Analyses Development Development Plans Disease Doctor of Medicine Doctor of Philosophy Emotional Emotions Endocrinology Environment Feedback Female Functional disorder Future Gene Expression Glucocorticoid Receptor Glucocorticoids Goals Hippocampus (Brain)Hydrocortisone Immediate-Early Genes In Situ Hybridization Institution Intensive Care Internal Medicine Intervention Investigation Investigative Techniques Knowledge Lead Learning Life Long-Term Depression Measures Mediating Mediator of activation protein Medical Mental Depression Mental disorders Mentors Mentorship Messenger RNA Microscope Mineralocorticoid Receptor Modeling Molecular Mood Disorders Mus Output Pathological anxiety Patients Physiological Post-Traumatic Stress Disorders Prevention strategy Psychiatric therapeutic procedure Public Health Publications Pyramidal Cells Recording of previous events Recovery Reporting Research Research Personnel Resources Rodent Role Scientist Sepsis Signal Transduction Stress Survivors Swimming Symptoms Techniques Testing Training Translating Translations Trauma Update acute stress anxiety-like behavior apprenticeship awake behavioral outcome behavioral phenotyping biological adaptation to stress career career development cecal ligation puncture comorbidity computerized data processing design emotional behavior experience experimental study hypothalamic-pituitary-adrenal axis in vivo calcium imaging male medical specialties meetings member mouse model negative affect neural circuit neurobiological mechanism neuroendocrine phenotype novel optogenetics post-traumatic symptoms prevent psychologic relating to nervous system skills stressor symposium transcriptome sequencing

项目摘要

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.

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。超过三分之一的危重病幸存者长期患有抑郁、焦虑或创伤后症状应激障碍。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是必要的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策略危重疾病幸存者的疾病。使用鼠败血症模型、盲肠结扎和穿刺（CLP）的初步研究表明， CLP 幸存者小鼠的焦虑样行为，原位杂交研究表明，腹侧海马体。在第一个特定目标中，考生将研究腹侧的作用通过检查 CLP 后腹侧 CA1 锥体细胞的活性来观察 CLP 后海马的焦虑样行为 CLP 使用体内钙成像，并确定腹侧光遗传学激活的效果海马体对焦虑样行为的影响。对经历过包括危重病在内的创伤经历的患者的研究表明，创伤期间循环的糖皮质激素可以预防幸存者的创伤后应激症状。在第二个具体目标，考生将调查患病期间是否接受糖皮质激素治疗期可以预防 CLP 幸存者的负面情绪行为，并使用 RNA-seq 来识别介导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。申请人拥有医学博士和博士学位。学位并完成了内科临床专业培训医学和内分泌学。她之前有使用小鼠进行行为内分泌学研究的经验模型。该应用程序包括一个职业发展计划，旨在更新她的科学技能研究清醒、自由行为动物的行为神经回路的技术，以及设计以及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、实践学徒以及通过出版物和研究成果的交流在全国会议上的演讲。导师团队包括多个部门/部门的成员和多个机构，以支持这个本质上跨学科的项目。导师们能够提供具有充足资源的研究环境来完成拟议项目。