Brain corticotropin-releasing factor (CRF) systems play an essential role in coordinating stress-induced endocrine, autonomic, behavioral, and immune responses. In the amygdala, CRF peptide and receptors are located in nuclei implicated in fear and anxiety. Importantly, pathophysiology of CRF systems and the amygdala is associated with mental illness including anxiety disorders, depression, and drug abuse. Thus, the long-term goal of this research program is to understand how CRF systems contribute to psychopathology. The overall aim of this proposal is to provide an in-depth analysis on the functional significance of stress-induced central amygdala CRF secretion and its putative actions on basolateral CRF1 receptors to activate fearful memories and promote anxiety. We hypothesize that stress-induced CRF secretion from the central amygdala acts on the high affinity CRF1 receptor located in the basolateral amygdala to facilitate the acquisition and retrieval of conditioned fear. We further hypothesize that stress-induced central amygdala CRF secretion plays a key role in promoting anxiety behavior by acting on basolateral CRF1 receptors. To test these hypotheses, behavioral studies in rodents will be performed that combine site-specific CRF receptor antagonist microinfusions, ex vivo receptor binding, in vivo microdialysis, and gene disruption techniques. Establishing the role of CRF peptide and receptor subtypes located in specific amygdala nuclei will provide the foundation for future studies aimed at determining the downstream cellular and molecular mechanisms underlying the effects of stress on fear conditioning and anxiety. Knowledge of amygdala CRF biology may yield valuable insights into the neural basis of emotional predispositions and the pathogenesis of psychiatric disorders.