Differential activation of CRF receptor subtypes removes stress-induced memory deficit and anxiety

The objective of this study was to investigate the role of corticotropin-releasing factor receptors 1 (CRF₁) and 2 (CRF ₂) in anxiety-like behavior and learning of C57BL/6J mice after exposure to a stressful stimulus. When C57BL/6J mice were exposed to immobilization (1 h) serving as stressful stimulus, context- and tone-dependent fear conditioning were impaired if the training followed immediately after immobilization. The stress-induced impairment of context-dependent fear conditioning was prevented by specific blockade of CRF₂ of the lateral septum (LS) with anti-sauvagine-30. Immobilization did not only affect conditioned fear, but also enhanced, through CRF₂ of the LS, anxiety-like behavior determined with the elevated plus maze. Recovery from stress-induced anxiety and impairment of context-dependent fear conditioning was observed after 1 h delay of training and required hippocampal CRF₁, as indicated by the finding that this recovery was prevented by blockade of intrahippocampal CRF₁. It was concluded that exposure to a stressor initially affected both anxiety-like behavior and contextual conditioned fear through septal CRF₂, while the later activation of hippocampal CRF₁ resulted in the return to baseline levels of both processes. Intraventricular injection of mouse urocortin 2, a CRF₂-selective agonist, removed the stress-induced anxiety and learning impairment, but did not reduce the activation of the hypothalamic pituitary adrenal axis indicative of the hormonal stress response. We propose that the enhanced anxiety is the component of the stress response responsible for the memory deficit.