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

项目摘要 我的长期目标是开发一个独立的研究项目，调查基因的改变是如何发生的。 正常的记忆和情绪处理有助于精神障碍的发展， 导致从正常到病态转变的机制。到目前为止，我主要使用我的行为 和分子神经科学训练，以研究恐惧记忆的分子机制， 外部环境压力在这些过程的调制中的作用。内部事件，包括严重 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增加，然而， 在这些内部事件之后介导失调的机制仍然未知。 为了有效地研究焦虑和恐惧的内部触发因素，我需要额外的训练， 支持.因此，我组建了一个顾问小组，由我的导师Jelena Radulovic博士， 分子和行为神经科学和神经免疫学专家，以及免疫学专家， 心血管疾病模型，斯蒂芬米勒博士和道格拉斯Losordo博士分别。与这些 我将接受免疫技术和概念的培训，学习手术方法， 在Radulovic博士的指导下，我将接受以下指导： 与焦虑和恐惧的动物模型有关的问题，以及对概念的具体指导， 神经免疫学和其他分子技术。 本项目旨在研究特定脑区细胞因子信号对脑缺血再灌注损伤的作用。 焦虑和过度恐惧的出现。为此，我将开发一种新的模型， 心脏病发作（心肌梗死，MI）引发全身细胞因子反应， 焦虑和恐惧我将使用免疫学和分子神经科学技术来确定 这些行为改变的相关性和原因在雄性和雌性小鼠。在目标1中，我将确定 MI后出现焦虑和过度恐惧。目的2将确定心肌梗死后细胞因子的失调 与焦虑和恐惧有关的大脑区域。最后，目标3将检查依赖于精氨酸的细胞内 介导焦虑和恐惧增加的分子信号机制。在所有的实验中， 同时研究雄性和雌性小鼠。我假设焦虑和恐惧的加剧 心肌梗死后数周和数月内出现和持续。在这些行为变化的同时，我 预期大脑区域中调节焦虑和恐惧的促炎细胞因子会增加。最后，我假设 脑梗死后，依赖于多巴胺的JAK/STAT信号通路介导情绪和记忆功能失调。 这些发现将与心脏病发作后PTSD的具体病因以及更多的 是否相同的机制介导慢性外部应激后的PTSD的一般问题。 在这个项目的指导阶段，我将执行目标1和2，这将提供一个坚实的基础， 实验数据，以及获得的技能和知识，为独立阶段，我将 确定马槟榔碱介导的JAK/STAT信号传导在MI后焦虑出现中的激活和作用 和创伤后应激障碍这个项目将提供一个框架，以维持正在进行的研究， 独立的研究生涯。我预计，根据这一研究产生的数据， 项目将是（1）详细的机制研究性别差异出现在行为或信号 心肌梗死后的变化，以及（2）在从急性，适应性应激反应， 慢性适应不良综合征 我在这个项目的指导阶段的培训将在耶莱娜博士的实验室进行 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 获得许多资源，包括协作讨论，进行 实验，研讨会和培训班的广度和深度，和专业发展 机会，包括研讨会和研究报告。另外，我还能得到 我的顾问和咨询小组成员米勒博士和洛索多博士的专业知识，用于细胞因子分析， 心肌梗死和组织学。 通过这个项目获得的培训，我将学习免疫学，外科手术和其他 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，以作为未来研究方向的基础。这样，在指导结束时， 阶段，我将有技能和知识来设计，执行和分析实验，将阐明 内部和外部事件调节记忆和情绪处理的分子机制， 从而导致精神疾病

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.