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 创伤几乎影响了每个人的生活，并在塑造我们的心理健康方面起着关键作用 容易受到一系列令人衰弱的心理状况的个人，包括创伤后压力 疾病，药物使用障碍，焦虑和抑郁症。许多创伤研究集中在如何 形成了创伤事件的回忆，对多方面过程的重视程度较小 为这些条件做出贡献。进一步强调了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学上是可分离的。 这是创伤的潜水员病理后果可能需要个性化的治疗目标。 该提案中的实验将采用一种行为程序，该程序将允许潜水员的后果 创伤仅在小鼠中简单地研究，并结合一组复杂的技术来隔离 生物学差异，允许解散其生物学起源。在此的K99部分 提案 - 在Drs的心态下，将在西奈山的伊坎医学院完成。 丹妮丝·凯（Denise Cai）（主要导师），伊恩·迷宫（Ian Maze）（同事）和斯科特·鲁索（Scott Russo）（Co-Contor） - 我将首先测试 创伤引起杏仁核创伤合奏的持久变化的假设（即神经元活跃 对创伤的反应），导致对随后的压力源的反应增强，但没有其他类似焦虑的焦虑 表型。这将是使用体内钙成像和选择性光遗传学的组合来实现的 在随后的行为测试中抑制创伤集团的抑制。此外，我将使用RNA测序 创伤合奏以确定这些细胞特有的转录变化，以期发现 干预的新目标。 K99部分下的技术培训将包括光遗传学，荧光 活化的核分子和转录组分析。此外，我将获得重要的职业发展 培训与实验室和人员管理有关的主题，赠款写作，沟通/网络， 并在一流的学术研究机构中进入任期轨道职位。在此的R00部分 提案，我将利用一组类似的技术来检验腹侧海马创伤的假设 合奏支持创伤后的持续类似动画的行为。这项工作将提供两个关键见解 创伤如何持续影响我们实验室的第一个赠款的动画般的行为和强大的初步数据 申请。当我建立成功时，该奖项提供的培训和支持将具有重要意义 职业专注于创伤如何使个体患有神经精神疾病。