The overall hypothesis being explored is that the amygdala plays a significant role in normal and pathological fear, and that interactions between the amygdala, hippocampus and mPFC play key roles in the normal regulation of fear and the modulation of fear by stress. In particular, we propose that stress alters the function and/or structure of fear circuits (involving areas within and connections between the amygdala, hippocampus, and medial prefrontal cortex) and thereby gives rise to exacerbated fear reactions that are unconstrained by the context in which they are learned. The studies proposed examine humans and experimental animals. Study 1, performed together with Liz Phelps, will use fMRI to examine the normal patterns of functional activation occurring during fear conditioning. These studies will involve collaborations with Silbersweig, Stern, and Gorman and will serve to establish techniques and basal conditions under which to evaluate functional changes seen in patients with fear disorders, as explored in Project 2 by Silbersweig, Stem and Gorman. The facilities and expertise of the Functional Neuroimaging Core are used throughout Study 1. The remaining studies turn to experimental animals (rats) and explore various issues related to fear and stress. Study 2 maps the pathways through which fear stimuli processed by the amygdala control HPA function. Study 3 uses amygdala and hippocampal-dependent aspects of fear conditioning to test the hypothesis that the amygdala and hippocampus are affected in opposite ways by stress. Study 4 examines the effects of drugs with clinical efficacy in treating anxiety disorders (especially the SSRI class of drugs) on fear conditioning and on the effects of stress on fear conditioning. The studies draw upon the expertise of the LeDoux lab in physiological and behavioral approaches to the fear system, and involve collaborations with McEwen's lab (Project 4) on various studies involving stress, and with Morrison (Project 3) in studies of morphological changes in glutamate receptors induced by fear conditioning and stress. The morphological studies also rely on the Quantitative Morphology Core. Project 1 thus involves collaborations with all aspects of the Center and serves as the conceptual launch pad for several of the other investigations.
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