Anxiety disorders are thought to result from abnormal emotional responses associated with memories of aversive events. Most forms of anxiety are accompanied by generalized distress in response to threatening environments that can be modeled by context-dependent fear conditioning. Humans and rodents rapidly acquire fear responses to environmental contexts by classical conditioning procedures. A single pairing of a context with a stimulus perceived as harmful leads to the formation of long-term memory of the aversive episode persisting for years. Nevertheless, several re-exposures to the conditioning context without the harmful stimulus commonly lead to a decline of the fear response, a phenomenon termed extinction. In spite of its increasingly recognized significance in anxiety disorders, the molecular basis of extinction, in particular extinction of context-dependent fear is not well understood. The proposed research is designed to identify the key molecular mechanisms leading to extinction and delineate them from mechanisms underlying acquisition of contextual fear. Rodent models have been successfully employed to establish that hippocampal signaling encompassing protein phosphorylation and gene expression is essential for context- dependent fear conditioning. We hypothesize that altered coupling of these intracellular signaling pathways to gene responses contributes to extinction. By combining immunohistochemical and immunoblot approaches we expect to identify the main hippocampal substrates of the cAMP-dependent protein kinase, protein kinase C and mitogen-activated and extracellular signal regulated kinase during extinction. The role of these pathways in the regulation of gene responses and fear extinction of will be determined by combining pharmacological approaches with genetic mouse models. We expect to demonstrate that the hippocampus significantly contributes to the neuronal circuitry regulating extinction of contextual fear. The identified signal transduction pathways may serve as potential targets for the development of new therapeutic approaches that would eliminate persistent fear of threatening environmental contexts as observed in general anxiety and post-traumatic stress disorder.
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