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

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DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This project, based on the clinical observations that a large proportion of heart attack patients subsequently develop anxiety or post-traumatic stress disorder, aims to utilize animal models of anxiety and fear to investigate the post-heart attack mechanism triggering these psychiatric disorders. I expect that inflammatory signaling in the brain will play a major role in the development of anxiety and fear after heart attack, and that these pathways will be novel targets for treatment and prevention of anxiety and post-traumatic stress disorder.