Disentangling the Consequences of Trauma

理清创伤的后果

基本信息

批准号：
10571405
负责人：
Zachary Thomas Pennington
金额：
$ 12.61万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10571405
关键词：
Acute Affect Amygdaloid structure Animals Anxiety Applications Grants Auditory Award Behavior Behavioral Behavioral Assay Biological Brain Calcium Cells Communication Darkness Data Data Set Dedications Development Disease Event Fluorescence Fright Future Gene Expression Genes Genetic Transcription Goals Grant Health Hippocampus Image Individual Institution Intervention Laboratories Learning Life Light Measures Memory Mental Depression Mental Health Mental disorders Mentors Mentorship Modeling Molecular Molecular Profiling Monitor Mood Disorders Multiple Trauma Mus Neurons Nuclear Pathologic Personnel Management Phenotype Play Positioning Attribute Post-Traumatic Stress Disorders Procedures Process Protein Synthesis Induction Psyche structure Research Research Personnel Role Shapes Sorting Stimulus Stress Substance Use Disorder Synaptic Transmission Techniques Testing Time Training Trauma Trauma Research Vulnerable Populations Work Writing anxiety-like behavior behavior test biobehavior biological adaptation to stress career career development defined contribution differential expression experience experimental study gene network in vivo calcium imaging individualized medicine insight medical schools neural neuropsychiatry novel optogenetics post-trauma programs psychologic response stressor tenure track tool transcriptome sequencing transcriptomics traumatic event

项目摘要

PROJECT SUMMARY/ABSTRACT Trauma impacts the life of nearly every individual and plays a pivotal role in shaping our mental health, leaving individuals vulnerable to an array of debilitating psychological conditions, including post-traumatic stress disorder, substance use disorders, anxiety, and depression. Much trauma research has focused on how memories for traumatic events are formed, with considerably less emphasis on the multifaceted processes contributing to these conditions. Further highlighting the importance of examining multiple trauma endpoints, growing evidence indicates that the consequences of trauma are behaviorally and biologically dissociable. Thus, the diverse pathological consequences of trauma may require individualized treatment targets. The experiments in this proposal will utilize a behavioral procedure that will allow the diverse consequences of trauma to be simultaneously studied in mice, combined with a sophisticated set of techniques for isolating biological variance, allowing for the disentanglement of their biological origins. Under the K99 portion of this proposal – to be completed at the Icahn School of Medicine at Mount Sinai under the mentorship of Drs. Denise Cai (primary mentor), Ian Maze (co-mentor), and Scott Russo (co-mentor) – I will first test the hypothesis that trauma induces lasting changes in amygdala trauma ensembles (i.e., neurons active in response to trauma) that results in enhanced responses to subsequent stressors, but not other anxiety-like phenotypes. This will be achieved using a combination of in vivo calcium imaging and selective optogenetic inhibition of trauma ensembles during subsequent behavioral tests. Further, I will use RNA sequencing of trauma ensembles to determine the transcriptional changes specific to these cells, in hopes of discovering novel targets for intervention. Technical training under the K99 portion will include optogenetics, fluorescence activated nuclear sorting, and transcriptomic analyses. Additionally, I will receive vital career development training on topics related to laboratory and personnel management, grant writing, communication/networking, and entering a tenure track position at a top-tier academic research institution. Under the R00 portion of this proposal, I will utilize a similar set of techniques to test the hypothesis that ventral hippocampal trauma ensembles support persistent anxiety-like behaviors after trauma. This work will provide both key insights into how trauma persistently influences anxiety-like behavior and robust preliminary data for my lab’s first grant applications. The training and support provided by this award will be instrumental as I establish a successful career focused on how trauma predisposes individuals to neuropsychiatric illness.

项目概要/摘要创伤几乎影响每个人的生活，并在塑造我们的心理健康方面发挥着关键作用，容易遭受一系列使人衰弱的心理状况的人，包括创伤后应激障碍许多创伤研究都集中在如何导致精神障碍、药物滥用障碍、焦虑和抑郁。对创伤事件的记忆已经形成，但对多方面过程的重视程度却大大降低进一步强调检查多个创伤终点的重要性，越来越多的证据表明，创伤的后果在行为上和生物学上都是不可分离的。因此，创伤的不同病理后果可能需要个体化的治疗目标。该提案中的实验将利用一种行为程序，该程序将允许产生不同的后果创伤将同时在小鼠身上进行研究，并采用一套复杂的隔离技术生物学差异，允许在其 K99 部分下解开它们的生物学起源。提案 - 将在西奈山伊坎医学院在博士的指导下完成。 Denise Cai（主要导师）、Ian Maze（共同导师）和 Scott Russo（共同导师）——我将首先测试假设创伤会引起杏仁核创伤整体的持久变化（即活跃的神经元）对创伤的反应）会导致对后续压力源的反应增强，但不会增强对其他类似焦虑的反应这将通过结合体内钙成像和选择性光遗传学来实现。此外，我将使用 RNA 测序来抑制后续行为测试中的创伤整体。创伤整体来确定这些细胞特有的转录变化，希望能发现 K99 部分的新干预目标将包括光遗传学、荧光学。此外，我还将获得重要的职业发展。与实验室和人事管理、资助写作、沟通/网络相关的主题培训，并在顶级学术研究机构的 R00 部分获得终身教职。建议，我将利用一套类似的技术来检验腹侧海马创伤的假设这项工作将为创伤后持续的类似焦虑的行为提供支持。创伤如何持续影响类似焦虑的行为以及我实验室第一笔资助的可靠初步数据该奖项提供的培训和支持将有助于我成功建立一个成功的项目。职业重点是创伤如何使个人容易患上神经精神疾病。