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.

项目总结/摘要 创伤影响着几乎每个人的生活，并在塑造我们的心理健康方面发挥着关键作用， 易受一系列使人衰弱的心理状况，包括创伤后应激障碍影响的个人 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 对创伤性事件的记忆形成，对多方面过程的重视程度大大降低 有助于这些条件。进一步强调检查多发性创伤终点的重要性， 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。的 在这个提议中的实验将利用一种行为程序，这种程序将允许不同的后果， 同时在小鼠中研究创伤，结合一套复杂的分离技术， 生物变异，允许解开它们的生物起源。在K99部分， 建议-将在西奈山伊坎医学院完成的指导下博士。 Denise Cai（主要导师）、Ian迷宫（共同导师）和Scott Russo（共同导师）-我将首先测试 假设创伤诱导杏仁核创伤集合的持久变化（即，神经元活跃于 对创伤的反应），导致对后续压力源的反应增强，但不是其他焦虑样反应。 表型这将使用体内钙成像和选择性光遗传学方法的组合来实现。 在随后的行为测试中抑制创伤组合。此外，我将使用RNA测序， 创伤合奏，以确定转录的变化，具体到这些细胞，希望发现 新的干预目标。K99部分的技术培训将包括光遗传学、荧光 激活核分选和转录组分析。此外，我将获得重要的职业发展 与实验室和人员管理、赠款撰写、通信/网络有关的主题培训， 并进入顶级学术研究机构的终身职位。在R 00部分下， 建议，我将利用一套类似的技术来测试假设，腹海马创伤 合奏支持创伤后持续的焦虑样行为。这项工作将提供关键的见解， 创伤如何持续影响焦虑样行为以及我实验室第一次资助的可靠初步数据 应用.该奖项提供的培训和支持将有助于我建立一个成功的 职业生涯专注于创伤如何使个体易患神经精神疾病。