Central glucocorticoid system dysfunction in a mouse model of extreme anxiety: clinical implications

Abstract

Animal models of psychiatric disorders are useful tools for elucidating associations between behavioral symptoms and biological abnormalities and for suggesting possible treatment strategies for psychiatric diseases. Here we describe phenotypic, neuroendocrine and molecular traits of a mouse model of extreme inborn high anxiety-related behavior (HAB) from the perspective of clinical application to study central mechanisms of psychiatric abnormalities. HABs consistently show higher anxiety and depression-like behavior, increased contextual fear and inhibitory avoidance learning compared to normal anxiety-related behaviour (NAB) mice. While basal blood corticosterone (CORT) was found to be an unimportant endocrine parameter in our mouse model, HABs responded with significantly reduced CORT to stressful stimuli. The DEX-CRH test revealed much stronger suppression of the hypothalamic pituitary adrenal (HPA) axis after Dex infusion and a blunted response to CRH stimulation in HABs. Analysis of glucocorticoid receptors showed significantly higher amounts in almost all brain areas of HABs, whereas levels of free CORT in these brain regions were reduced. An increased expression of enzymes involved in CORT metabolism is likely to be critically involved in HAB mice. All together, these data suggest that the mouse model of high anxiety resembles behavioral and endocrine symptomatologies of psychiatric disorders with the focus on a dysregulation of the central glucocorticoid system. This study was supported by Max-Planck-Gesellschaft.