Stress can disrupt cognitive and emotional behavior and can precipitate or exacerbate many psychological disorders. Sex is an important variable influencing many stress-related disorders. Thus, understanding the basis of this sex difference is an important goal in developing appropriate interventions for stress-related disorders. Stress has profound effects on the morphology of corticolimbic structures including the hippocampus, amygdala, and prefrontal cortex. A growing body of work has documented sex differences in many behavioral, neurochemical, and morphological responses to stress. We have recently shown that chronic stress decreases the number and length of apical dendritic branches of pyramidal neurons in medial prefrontal cortex of male rats, but has the opposite effect in females, increasing apical dendritic length. We have further demonstrated that estradiol mediates this stress-induced dendritic hypertrophy in females: Both sham-operated and ovariectomized females with estradiol implants show stress-induced increases in apical dendritic material, whereas ovariectomy without estradiol replacement prevents the stress-induced increase. Interestingly, while ovariectomy without estradiol replacement prevented the stress-induced hypertrophy, it did not produce the male pattern of stress effects. This suggests that gonadal hormones may be permissive of stress-induced structural plasticity, but produce different effects in males and females, through either different hormones or different hormonal mechanisms. To more fully characterize potential sex differences in stress effects in mPFC, we will assess unit activity in the infralimbic cortex during performance on an emotion regulation task and dendritic morphology of pyramidal cells in the infralimbic cortex in stressed and unstressed male versus female rats. To determine whether gonadal hormones are permissive of the effects of chronic stress on structure and function of neurons in infralimbic cortex of males, we will assess unit activity in prefrontal cortex during performance on an emotion regulation task and dendritic morphology of pyramidal cells in infralimbic cortex in stressed and unstressed rats that have undergone castration and implantation of either no hormone, testosterone, dihydrotestosterone, or estradiol. To determine whether androgen administration can produce a male pattern of chronic stress effects on morphology and physiology of neurons in infralimbic cortex of females, we will assess unit activity in prefrontal cortex during performance on an emotion regulation task and dendritic morphology of pyramidal cells in infralimbic cortex in female stressed and unstressed rats that have undergone ovariectomy and implantation of either no hormone, testosterone, dihydrotestosterone, or estradiol. Results of the proposed studies will contribute to our understanding of the mechanisms underlying the sex difference seen in prefrontal stress effects. PUBLIC HEALTH RELEVANCE: This research will contribute to our understanding of the neurobiological mechanisms underlying sex differences in the influence of stress on emotional processing and negatively motivated behaviors. It will also aid in our understanding of how stress differentially influences mental illnesses such as posttraumatic stress disorder, depression, or schizophrenia in men and women.