Long-term kindling as an animal model to study the neural mechanisms of fear-mediated behaviour

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The general purpose of our research is to study the behavioral and neural changes concomitant with fear sensitization. All animals respond fearfully in novel or threatening situations. Most of these responses are adaptive in that they serve to protect animals from harm. However, fear can be sensitized so that it eventually results in behavioral responses that are maladaptive. Accordingly, the level of fear experienced by an animal can range from what we would consider "normal" to what we would consider "pathological". Using amygdala-kindled rats, we have developed an animal model that permits us to systematically study the sensitization of fearful behavior. Kindling is a process by which daily administration of electrical brain stimulations results in the gradual development and intensification of motor seizures. In addition to its epileptogenic effects, kindling also sensitizes brain circuits responsible for behavioral manifestations of fear. Kindled rats display fearful behavior that increases in magnitude as the rats receive a greater number of stimulations. Kindling thus provides an excellent opportunity to study the sensitization of fearful behavior, and to correlate changes in fearful behavior with neural changes in the brain.       The specific objective of the research proposed in this application is to investigate the role of a brain region called the hippocampus in the sensitization of fear. We have evidence to suggest that kindling-induced fear might result from hippocampal dysfunction. To test this idea, we will assess the effect of kindling on behavioral tasks that are mediated by the hippocampus. We will also investigate whether kindling alters the morphological and electrophysiological characteristics of cells in the hippocampus. Finally, we will determine whether kindling-induced fear can be reduced by environmental enrichment, and whether these beneficial effects occur via neural changes within the hippocampus. The results of our experiments will provide fundamental information about the neural basis of fear-mediated behavior and should rapidly accelerate our progression toward new therapies for treating disorders characterized by extreme fear.