Disentangling the Consequences of Trauma

理清创伤的后果

• 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
• 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

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.

项目摘要/摘要 创伤几乎影响到每个人的生活，并在塑造我们的心理健康方面发挥着关键作用， 易受一系列令人衰弱的心理疾病影响的个人，包括创伤后应激障碍 精神障碍、物质使用障碍、焦虑和抑郁。许多创伤研究都集中在如何 创伤事件的记忆是形成的，对多方面的过程的重视程度要低得多 造成这些情况的原因。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，创伤的后果在行为和生物上是不可分离的。 因此，创伤的不同病理后果可能需要个性化的治疗目标。这个 该提案中的实验将利用一种行为程序，该程序将允许以下各种后果 创伤将在小鼠身上同时进行研究，并结合一套复杂的分离技术 生物变异，使它们的生物起源解开了纠缠。在本文件的K99部分下 提案-将在西奈山的伊坎医学院完成，由Dr。 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 假设创伤导致杏仁核创伤整体的持久变化(即，神经元活跃在 对创伤的反应)，这导致对后续应激源的反应增强，但不是其他类似焦虑的反应 表型。这将通过体内钙成像和选择性光遗传相结合来实现。 在随后的行为测试中抑制创伤集合。此外，我将使用RNA测序 创伤组来确定这些细胞特有的转录变化，希望发现 新的干预目标。K99部分下的技术培训将包括光遗传学、荧光 启动了核分类和转录分析。此外，我将获得至关重要的职业发展 关于实验室和人事管理、补助金撰写、通信/联网、 并进入一家顶级学术研究机构的终身教职轨道。在此的R00部分下 提案中，我将使用一组类似的技术来检验腹侧海马区损伤的假设 合奏支持创伤后持续的类似焦虑的行为。这项工作将为以下两方面提供关键见解 创伤如何持续影响焦虑样行为和我的实验室第一笔拨款的可靠初步数据 申请。这个奖项提供的培训和支持将对我建立一个成功的 职业生涯专注于创伤如何使个人容易患上神经精神疾病。