Effects of corticotrophin releasing factor (CRF) overexpression and Crf1 and CRF2 receptors knockout within limbic structures on defensive behavior in mice: influence of acute and chronic stress

Abstract

Corticotrophin releasing factor (CRF) is an important coordinator of neuroendocrine, autonomic, behavioral and immunological responses to stressful stimuli. CRF is able to modulate several behaviors, such as defensive reactions, and its malfunction in humans is associated with psychiatry disorders related to stress, including anxiety and affective disorders. Most of the CRF behavioral effects are attributed to its action on extrahypothalamic neural circuits, in brain areas involved with fear and anxiety processing such as neocortex, as well as limbic and brainstem structures. CRF receptors are classified in two main types: CRF1 and CRF2. Pharmacological and global knockout studies suggest that CRF1 receptors are involved in the modulation of defensive reactions, while the role of CRF2 remains poorly understood, in view of the contradictory results obtained so far. Regarding to transgenic animals, it is not always possible to overexpress or impair the CRF system within discrete brain areas, due to the lack of site specific promoters - an alternative consists of viral vectors injection within single brain regions. Thus, the present project aims to investigate the molecular and genetic manipulation of CRF and its receptors within discrete limbic structures such as the prefrontal cortex (PFC), periaqueductal gray matter (PAG) and amygdala on anxiety-like behavior in mice. In order to fulfill these goals, there will be investigated (i) CRF overexpression and CRF1 and CRF2 knockout within PFC, PAG and amygdala of mice subjected to animal models of anxiety. Since different stress levels influence responses to CRF receptors manipulations, we will also investigate (ii) CRF1 and CRF2 knockout within the same limbic structures on the anxiety in mice previously subjected to acute or chronic social defeat as well as to(iii) chronic variable stress. (AU)