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：
10507142
负责人：
Joanna Louise Spencer-Segal
金额：
$ 5.94万
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：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10507142
关键词：
Animal Experimentation Animals Anxiety Area Behavior Behavioral Brain Candidate Disease Gene Clinical Communication Research Critical Illness Data Development Plans Doctor of Medicine Doctor of Philosophy Emotional Endocrinology Environment Functional disorder Gene Expression Glucocorticoids Goals Hippocampus (Brain)In Situ Hybridization Institution Internal Medicine Intervention Investigative Techniques Knowledge Lead Long-Term Depression Mediating Medical Mental disorders Mentors Mentorship Modeling Molecular Mus Patients Post-Traumatic Stress Disorders Prevention strategy Psychiatric therapeutic procedure Publications Pyramidal Cells Research Resources Role Scientist Sepsis Survivors Training Translating Trauma Update anxiety-like behavior apprenticeship awake career career development cecal ligation puncture design emotional behavior experience in vivo calcium imaging medical specialties meetings member mouse model neural circuit optogenetics post-traumatic symptoms relating to nervous system skills 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.

项目摘要/摘要该建议描述了一项四年的职业发展计划，旨在使PI成为职业独立的临床医生研究严重医学疾病后情绪脆弱性的机制。超过三分之一的重症疾病幸存者长期遭受抑郁，焦虑或创伤后的痛苦应力障碍。关于该主题的动物研究很少，但是为了更好地了解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病的有效策略关键疾病幸存者的疾病。使用鼠败血症模型，盲肠和穿刺（CLP）的初步研究显示 CLP幸存者小鼠中的焦虑样行为和原位杂交研究表明，腹海马。在第一个特定目标中，候选人将研究腹侧的作用 CLP后，海马在焦虑状态下，通过检查腹侧CA1锥体细胞的活性 CLP使用体内钙成像，并确定腹侧光遗传激活的影响海马在类似焦虑的行为上。对包括危害疾病在内的创伤经历后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。在第二个特定目的是，候选人将研究糖皮质激素在疾病中是否治疗时期可以防止CLP幸存者中的负面情绪行为，并使用RNA-Seq识别可以介导CLP和糖皮质激素对腹侧海马功能的影响的候选基因和情感行为。申请人拥有医学博士学位和博士学位学位，并完成了内部临床专业培训医学和内分泌学。她以前使用鼠标具有行为内分泌研究的经验型号。该申请包括一项职业发展计划，旨在更新她的科学技能调查醒着，自由行为动物的行为神经回路的技术，并在设计中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，动手学徒制以及通过出版物和在国家会议上演讲。指导团队包括多个部门/部门的成员和多个机构，以支持这个固有的跨学科项目。导师能够为研究环境提供足够的资源来完成拟议的项目。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rapid response of Nelson's syndrome to pasireotide in radiotherapy-naive patient.

DOI：
10.1186/s40842-020-00110-7
发表时间：
2020-11-07
期刊：
Clinical diabetes and endocrinology
影响因子：
0
作者：
He X;Spencer-Segal JL
通讯作者：
Spencer-Segal JL

Glucocorticoids and resilience.

糖皮质激素和恢复力。

DOI：
10.1016/j.yhbeh.2018.11.005
发表时间：
2019
期刊：
Hormones and behavior
影响因子：
3.5
作者：
Spencer-Segal,JoannaL;Akil,Huda
通讯作者：
Akil,Huda

Glucocorticoids and the Brain after Critical Illness.

DOI：
10.1210/endocr/bqaa242
发表时间：
2021-03-01
期刊：
Endocrinology
影响因子：
4.8
作者：
Hill AR;Spencer-Segal JL
通讯作者：
Spencer-Segal JL

Mental health outcomes after hospitalization with or without COVID-19.

DOI：
10.1016/j.genhosppsych.2021.07.004
发表时间：
2021-09
期刊：
General hospital psychiatry
影响因子：
7
作者：
Spencer-Segal JL;Smith CA;Slavin A;Sampang L;DiGiovine D;Spencer AE;Zhang Q;Horowitz J;Vaughn VM
通讯作者：
Vaughn VM

Future Directions for Corticosteroids in Treatment of Sepsis.

皮质类固醇治疗脓毒症的未来方向。