Stressful experiences significantly facilitate the formation of aversive memories. Consequently, the recall of these memories triggers exaggerated and persistent fear responses. The effects of stress on aversive learning, observed in humans as well as experimental animals, have been implicated in the pathogenesis of posttraumatic stress disorder (PTSD). Here we put forward the hypothesis that key mechanisms triggered during acute stress, but activated with a delayed time course after cessation of the stressor, are the main mediators of enhanced aversive conditioning. If our hypothesis proves correct, the effects of acute traumatic events leading to psychopathology, such as PTSD, could be significantly prevented by poststress interventions. Because the occurrence of stressful situations is commonly unpredictable, the possibility of retrograde interference with brain neurotransmitter systems would be of particular significance for the prevention of stress-enhanced fear conditioning. Studies with rodents have shown that pharmacological blockade of glutamate receptors prior to stress exposure significantly attenuates the behavioral effects of stress. It is less clear whether similar manipulations can be effective after the stressor has terminated. The objective of this proposal is to characterize in detail the delayed effects of stress on fear conditioning and attempt to block these effects by poststress inactivation of glutamate receptors. We plan to employ the contextual fear conditioning as a model of robust aversive conditioning. Mechanistic questions addressed in this proposal will identify the glutamate receptor type (Aim 1), learning process (Aim 2) and downstream glutamatergic mechanisms (Aim 3) mediating the delayed and persistent stress effects on fear conditioning. The therapeutic implications of the findings will encompass novel options to retroactively and selectively alleviate stress-enhanced aversive conditioning by blocking specific glutamatergic mechanisms. Our long-term goal is to identify the mechanisms mediating the effects of stress on subsequent acquisition and persistence of endophenotypes relevant for PTSD. In susceptible individuals, a single stressful event is sometimes sufficient to trigger posttraumatic stress disorder (PTSD) and lasting fear. We propose that the development of such fear symptoms can be prevented by inhibition of glutamate receptors in the aftermath of stress. If this hypothesis is experimentally confirmed, the results will open new therapeutic options for the risk reduction and secondary prevention of fear symptoms associated with PTSD. ? ? ?
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