Cytokine Signaling as a Mediator of Fear and Anxiety After Myocardial Infarction

项目总结 我的长期目标是开发一个独立的研究计划，调查如何改变 正常的记忆和情绪处理有助于精神障碍的发展，而 导致从正常到病态转换的机制。到目前为止，我主要是用我的行为 和分子神经科学培训，以研究恐惧记忆和 外部环境应激源在调节这些过程中的作用。内部事件，包括严重的 疾病和心脏病发作也经常导致焦虑、抑郁和创伤后应激障碍的增加，然而 在这些内部事件发生后，调节失调的机制仍不清楚。 为了有效地研究焦虑和恐惧的内在诱因，我将需要额外的培训和 支持。因此，我组建了一个顾问小组，由我的导师耶琳娜·拉杜洛维奇博士和 分子和行为神经科学和神经免疫学专家，以及免疫学和 分别是斯蒂芬·米勒博士和道格拉斯·洛索多博士。有了这些 咨询师，我会得到免疫学技术和概念的培训，学到手术方法 在拉杜洛维奇医生的指导下，我将接受关于 与焦虑和恐惧的动物模型有关的问题，以及关于 神经免疫学和其他分子技术。 该项目旨在研究特定脑区细胞因子信号对脑功能的影响。 焦虑和过度恐惧的出现。为了做到这一点，我将开发一个新的模型，集成一个手术模型 引发全身细胞因子反应的心脏病发作(心肌梗死，MI)的行为模型 焦虑和恐惧。我将使用免疫学和分子神经科学技术来确定信号 雄性和雌性小鼠的这些行为改变的相关性和原因。在目标1中，我将确定 心肌梗塞后出现焦虑和夸张的恐惧。目标2将确定心肌梗死后细胞因子的失调 大脑中与焦虑和恐惧相关的区域。最后，目标3将检查细胞内依赖的细胞因子 调节焦虑和恐惧增加的分子信号机制。在所有的实验中，我会 同时研究雄性和雌性小鼠。我猜想结果是焦虑和恐惧加剧。 在心肌梗死后的几周和几个月内出现并持续。在这些行为变化的同时，我 预计大脑中调节焦虑和恐惧的区域中的促炎细胞因子会增加。最后，我假设 这种细胞因子依赖的JAK/STAT信号介导了MI后的情绪和记忆力失调。 这些发现将与心脏病发作后创伤后应激障碍的具体病因以及更多因素高度相关 一般的问题是，在慢性外部应激后，是否同样的机制调节了创伤后应激障碍。 在该项目的指导阶段，我将执行目标1和目标2，这将为 实验数据，以及我将在其中独立阶段获得的技能和知识 确定细胞因子介导的JAK/STAT信号通路在心肌梗死后焦虑发生中的激活和作用 精神障碍和创伤后应激障碍。该项目将提供一个框架，以支持我正在进行的、 独立研究生涯。我预计研究的两个主要方向是根据这个产生的数据 项目将是(1)对行为或信号中出现的性别差异进行详细的机械研究 心肌梗死后的改变，以及(2)细胞因子信号在从应激的急性适应性效应到 慢性适应不良综合症。 我在这个项目的指导阶段的培训将在耶莱纳博士的实验室进行 西北大学精神病学和行为科学系的拉杜洛维奇说。在这里，我有 访问许多资源，包括协作讨论、进行 为培训的广度和深度以及专业发展提供实验、研讨会和课程 机会，包括研讨会和研究报告。此外，我还可以访问这些资源 和我的顾问和顾问小组成员米勒和洛索多博士的专业知识，用于细胞因子分析和 心肌梗死和组织学检查。 通过这个项目获得的培训，我将学习免疫学、外科和其他 行为和分子神经科学技能，开发多学科模型用于后续研究 项目，并生成数据，作为未来研究方向的基础。因此，在被指导的 在这个阶段，我将拥有设计、执行和分析实验的技能和知识，这些实验将阐明 内部和外部事件调节记忆和情绪处理的分子机制， 从而导致精神障碍。

PROJECT SUMMARY My long-term goal is to develop an independent program of research investigating how alterations of normal memory and emotional processing contributes to the development of psychiatric disorders, and the mechanisms that cause the switch from normal to pathological. To date, I have primarily used my behavioral and molecular neuroscience training to investigate the molecular mechanisms underlying fear memory and the role of external environmental stressors in the modulation of these processes. Internal events, including severe illness and heart attack, also frequently cause increased anxiety, depression and PTSD, however the mechanisms that mediate dysregulation after these internal events remain unknown. In order to effectively study internal triggers of anxiety and fear, I will require additional training and support. As such, I have assembled an advisory panel consisting of my mentor, Dr. Jelena Radulovic, an expert in molecular and behavioral neuroscience and neuroimmunology, as well as experts in immunology and models of cardiovascular disease, Dr. Stephen Miller and Dr. Douglas Losordo respectively. With these consultants, I will obtain training on immunological techniques and concepts, be taught the surgical methods for induction of myocardial infarction, and, under the mentorship of Dr. Radulovic, I will receive guidance on issues related to animal models of anxiety and fear, as well as specific tutelage on concepts in neuroimmunology and additional molecular techniques. This project aims to investigate the contribution of cytokine signaling in specific brain regions to the emergence of anxiety and excessive fear. To do this I will develop a new model, integrating a surgical model of heart attack (myocardial infarction, MI) that triggers a systemic cytokine response, with behavioral models of anxiety and fear. I will use immunological and molecular neuroscience techniques to determine the signaling correlates and causes of these behavioral alterations in male and female mice. In Aim 1, I will determine the emergence of anxiety and exaggerated fear after MI. Aim 2 will determine post-MI dysregulation of cytokines in brain regions related to anxiety and fear. Finally, Aim 3 will examine the cytokine-dependent intracellular molecular signaling mechanisms that mediates increased anxiety and fear. In all experiments I will concurrently study male and female mice. I hypothesize that anxiety and enhanced fear will be a consequence of MI, emerging and persisting in the weeks and months after MI. In parallel to these behavioral changes, I expect increased pro-inflammatory cytokines in brain regions mediating anxiety and fear. Finally, I hypothesize that cytokine-dependent JAK/STAT signaling mediates emotional and mnemonic dysregulation after MI. These findings will be highly relevant both for the specific etiology of post-heart attack PTSD, and for the more general question of whether the same mechanisms mediate PTSD after chronic external stressors. During the mentored phase of this project, I will execute Aims 1 and 2, which will provide a solid basis in both experimental data, and acquired skills and knowledge, for the independent phase in which I will determine the activation and role of cytokine-mediated JAK/STAT signaling the post-MI emergence of anxiety disorders and PTSD. This project will provide a framework to sustain ongoing research in my ongoing, independent research career. I expect that two main directions for research following data generated by this project will be (1) detailed mechanistic studies of sex differences emerging in behavioral or signaling alterations after MI, and (2) the role of cytokine-signaling in the switch from acute, adaptive effects of stress, to chronic, maladaptive syndromes. My training during the mentored phase of this project will be conducted in the laboratory of Dr. Jelena Radulovic in the department of Psychiatry and Behavioral Sciences at Northwestern University. Here, I have access to many resources including collaborative discussions, the equipment required to conduct the experiment, seminars and classes for the breadth and depth of training, and professional development opportunities, including workshops and research presentations. In addition, I will have access to the resources and expertise of my consultants and advisory panelists, Drs. Miller and Losordo, for cytokine analysis and myocardial infarction and histology, respectively. Through the training gained through this project I will learn immunological, surgical, and additional behavioral and molecular neuroscience skills, develop a multidisciplinary model to use in subsequent research projects, and generate data on which to base future research directions. As such, by the end of the mentored phase, I will have the skills and knowledge to design, execute, and analyze experiments that will elucidate the molecular mechanisms by which internal and external events modulate memory and emotional processing, and thereby contribute to psychiatric disorders.