Aversive stress impairs plasticity and neuronal architecture in both the prefrontal cortex and hippocampus. Moreover, stress and elevated glucocorticoids negatively impact behaviors associated with these brain regions, by impairing cognitive function and enhancing anxiety. Recent studies have shown that positive or rewarding stress protects the prefrontal cortex and hippocampus from the damaging effects of elevated glucocorticoids by promoting neuronal growth, enhancing cognitive function and relieving anxiety. Although the prefrontal cortex and hippocampus are interconnected, very little is known about how these brain regions influence one another under conditions of positive or negative stress. The neuropeptide oxytocin may play a protective role under rewarding social situations, but its influence over hippocampal-prefrontal cortex circuitry remains unexplored. This proposal is designed to explore interactions between the hippocampus and prefrontal cortex under environmental conditions that are detrimental compared to those that are beneficial. The role of oxytocin in protecting these brain regions from a potentially damaging hormonal milieu will also be explored. To investigate these issues, we will employ positive and negative social stress paradigms, temporary inactivation of specific brain regions, manipulations of oxytocin receptors, cognitive and anxiety behavioral assays and measures of structural plasticity. The results of these studies will inform us of the interplay between the hippocampus and prefrontal cortex in mediating positive and negative outcomes in response to stress. Mood disorders are associated with cognitive dysfunction and volumetric decreases in the hippocampus and prefrontal cortex. Stress predisposes individuals to develop psychopathology, including depression and anxiety. Understanding the interplay between the hippocampus and prefrontal cortex as these areas respond to experience may enable the development of effective therapies that emphasize growth-promoting mechanisms conducive to improved cognitive function and reduced anxiety. PUBLIC HEALTH RELEVANCE: This research is relevant to public health because it is focused on identifying mechanisms that protect the hippocampus and prefrontal cortex from the damaging effects of stress. Since the hippocampus and prefrontal cortex are dysfunctional in depression and anxiety disorders, this work may suggest targets for therapeutic interventions in mood disorders.