Post-traumatic stress disorder (PTSD) is a widely prevalent neuropsychiatric disorder linked to dysregulation of the hypothalamic-pituitary adrenal (HPA) axis and characterized by an inability to extinguish fearful memories when no longer appropriate. The HPA axis is the neuroendocrine component of the body's physiological response to stress. Following activation, glucocorticoids are secreted at the culmination of the stress response. Glucocorticoids then act at glucocorticoid receptors (GR) in various regions of the brain to provide feedback inhibition of the HPA axis, direct the transcription of numerous genes, and modulate behavioral functions (e.g., memory and anxiety). GR is highly expressed in the medial prefrontal cortex (mPFC), which is a brain region believed to be critical for the regulation of behavioral flexibility and is known to contribute to stress-related pathologies such as PTSD. Notably, both glucocorticoid secretion and behavioral flexibility are disrupted in this disorder, suggesting a link between prefrontal cortical GR signaling and stress-related disease. [Thus, the objective of the current proposal is to test the overarching hypothesis that dysfunction in GR signaling in the infralimbic prefrontal cortex (ilPFC) exacerbates PTSD-like behavioral symptomology. Our hypothesis is that down regulation of the GR in the ilPFC in conjunction with chronic stress will interfere with normal neural processing of stressful information, resulting in disproportionate and inappropriate behavioral responses to emotional stimuli (e.g., inappropriate responses to fearful stimuli and impaired extinction recall). Specific Aim I tests the role of GR signaling and chronic stress in fear-related behavior, with the working hypothesis that shRNA-mediated knockdown of GR in the ilPFC only and in the context of chronic stress will impair extinction recall. Specific Aim II tests the effect of disrupted GR signaling in the ilPFC on behavioral flexibility in the delayed spatial win-shift paradigm (in an 8-arm radial maze) with the working hypothesis that knockdown of GR in the ilPFC only and in the context of chronic stress will impair non- fear related mnemonic functions mediated by the ilPFC.] These studies explore the role of an important signaling pathway in the genesis of stress pathology. Given the medical consequences of PTSD, there is a clear need for understanding the underlying mechanisms of stress dysfunction that contribute to these disease states. PUBLIC HEALTH RELEVANCE: Post-traumatic stress disorder (PTSD) is a widely prevalent neuropsychiatric disorder affecting combat and non-combat civilians around the world. While the etiology of this disorder is unknown, it appears that dysfunction of the prefrontal cortex and stress may underlie the development and severity of this condition. [Therefore, studies that test the impact of stress on mnemonic functions mediated by the prefrontal cortex (such as conditioned fear and behavioral flexibility) are essential for developing effective therapies for PTSD.]