Considerable progress has been made in elucidating the neural pathways underlying conditioned fear in experimental animals. This work has implicated circuits centered around the amygdala, and interactions between the amygdala, hippocampus and medial frontal cortex (mPFC), in the acquisition and/or expression of different aspects of conditioned fear. New research in humans has confirmed essential aspects of the work in animals. These facts strongly suggest that studies of fear in animals can reveal important insights into the mechanisms of fear in humans, possibly including humans with pathological fear, such as occurs in anxiety disorders and paranoid psychosis. Further, given that threatening stimuli, which are prominent in the lives of patients with fear disorders, trigger stress reactions, that stress is believed to exacerbate symptoms in psychiatric patients, including those with pathological fear, and that the same brain regions implicated in normal fear are also strongly implicated in the regulation of stress hormones, we propose that stress-induced alterations in fear circuits may contribute to the development or maintenance of pathologic fear. The goals of this proposal, therefore, are to explore the relation between fear and stress in experimental animals and to examine whether the effects of stress on fear circuits mimics changes that occur in fear-related disorders in humans. To do this, we will use the same behavioral paradigm, fear conditioning, to study rats, normal humans, and patients with fear disorders. The overall aim of the animal work is to examine the effects of stress on the behavioral functions, physiology, and morphology of fear circuits. The overall aim of the studies of normal humans is to use fMRI to both extend our understanding of fear mechanisms in the human brain and to develop new probes for testing patients with fear disorders. And the overall aim of the studies to determine whether the normal patterns of functional brain activation during fear are altered, and whether these alterations are consistent with the effects of stress on fear circuits, as determined in the animal work.
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