Molecular Determinants of Individual Differences in Fear Reactivity and Recovery

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DESCRIPTION (provided by applicant): Anxiety disorders often develop following exposure to stress or trauma. These frequently have a significant fear component and are sometimes called "fear/anxiety" disorders. Examples include post- traumatic stress disorder (PTSD) and simple phobias. Because only a minority of persons with comparable levels of exposure to stress or trauma develops these disorders, the affected individuals must possess some innate genetic or epigenetic vulnerability. The identification of such vulnerabilities is a major goal of biological psychiatry, and is the main focus of our studies. Most existing knowledge about the brain mechanisms of fear, and hence about the basic biological mechanisms that may be altered in fear/anxiety disorders has been obtained in animal studies of fear conditioning. These studies have pinpointed particular circuits in the amygdala in the acquisition, storage, expression, and regulation of fear responses. Most of these studies have focused on the mechanisms of fear in random populations of animals. However, because most humans with fear/anxiety disorders are believed to represent extremes in the degree of underlying vulnerability, studies in random populations of animals may not be ideal for determining these vulnerabilities. A more promising alternative is to use animals expressing extremes of fear phenotypes. One popular view is that, in particular individuals, vulnerability to the development of fear/anxiety disorders after trauma exposure may, at least in part, involve exaggerated fear learning/memory in response to trauma and/or failure to recover following trauma cessation. To capture these biological phenotypes, we propose to identify animals with (1) extreme fear reactivity behavior (i.e., exhibiting the highest and the lowest levels of conditioned fear responses) and (2) extreme fear extinction behavior (i.e., exhibiting the slowest and the fastestrate of fear memory extinction)as well as animals that exhibit the intermediate levels of fear reactivity and fear extinction, and thus represent average ("normal") individuals. Using fear conditioning paradigms developed in our laboratory, animals exhibiting extreme fear reactivity, extreme fear extinction, and intermediate phenotypes will be separated from within a population of outbred rats. Next, using state-of-the art technology [whole transcriptome sequencing (RNA-Seq)]and weighted gene co-expression network analysis, we will study gene expression differences in particular nuclei of the amygdala among the highest, the intermediate, and the lowest fear reactivity phenotypes as well as among the slowest, the intermediate, and the fastest fear extinction phenotypes. The identified differences will help to pinpoint genes and pathways that characterize individuals with high or low liability t fear/anxiety disorders as well as individuals who are resistant to these disorders. These comprehensive studies will determine specific molecular targets for future focused research of fear-related behaviors and illnesses. PUBLIC HEALTH RELEVANCE: Over the past two decades, key aspects of the neural basis of fear have been elucidated through studies of Pavlovian fear conditioning, which have been mostly performed in random populations of animals. However, because most humans with fear/anxiety disorders (e.g., post dramatic stress disorder) are believed to represent extremes in the degree of underlying vulnerability, studies in random populations of animals may not be ideal for determining these vulnerabilities. To pinpoint molecular networks that characterize individuals with high or low liability to fear/anxiety disorders, in the present proposal we will focus on behaviorally identified phenotypes that represent extremes of fear-related behaviors in rats.