Thesis (Ph.D.) - Indiana University, Department of Psychological and Brain Sciences and the Program in Neuroscience, 2019Stress increases the risk for a number of psychological disorders, including mood and anxiety disorders. Prefrontal cortex dysfunction likely contributes to the cognitive symptoms associated with these disorders. Notably, women are at an increased risk for many stress-related disorders, although the neurobiological mechanisms underlying this enhanced vulnerability have yet to be elucidated. Evidence from rodent models suggests that male rats are susceptible to the effects of chronic stress on the structure and function of medial prefrontal cortex (mPFC), with numerous neurobiological and behavioral changes observed shortly after the cessation of stress. In contrast, female rats often do not exhibit these same deleterious effects of chronic stress. In this dissertation I investigated if chronic stress-induced changes in the structure and function of mPFC persist following the cessation of stress, and if sex differences in the initial response to chronic stress result in sex-specific changes following a novel stress challenge. In Experiment 1, I showed that dendritic remodeling of neurons in mPFC is sex-specific during the post-stress period. To assess whether these changes might give rise to functional changes, I developed a “two-hit stress” paradigm in which rats were exposed to chronic stress, given a no-stress rest period, and then exposed to a novel stress challenge (i.e., a “second hit”). Using this paradigm, I demonstrated in Experiment 2 that males, but not females, have a persistent reduction in novel stress-induced neuronal activation in mPFC. I then showed in Experiment 3 that, behaviorally, male rats have a deficit in extradimensional set-shifting immediately after chronic stress. This deficit is ameliorated following a rest period, and does not re-emerge following the second “hit.” In contrast, female rats only show a behavioral deficit following the second “hit.” Finally, in Experiment 4 I began to investigate mechanisms that may contribute to these sex differences and showed that there are sex-specific changes in the expression of genes related to glutamatergic and GABAergic neurotransmission in mPFC that occur during the post-stress period. These data suggest that chronic stress likely leads to the recruitment of sex-specific stress adaptation mechanisms that contribute to sex differences in response to subsequent stress exposure.