Assessing Behavioural Effects of Chronic HPA Axis Activation Using Conditional CRH-Overexpressing Mice

The corticotropin-releasing hormone (CRH) and its cognate receptors have been implicated in the pathophysiology of stress-related disorders. Hypersecretion of central CRH and elevated glucocorticoid levels, as a consequence of impaired feedback control, have been shown to accompany mood and anxiety disorders. However, a clear discrimination of direct effects of centrally hypersecreted CRH from those resulting from HPA axis activation has been difficult. Applying a conditional strategy, we have generated two conditional CRH-overexpressing mouse lines: CRH-COE Del mice overexpress CRH throughout the body, while CRH-COE APit mice selectively overexpress CRH in the anterior and intermediate lobe of the pituitary. Both mouse lines show increased basal plasma corticosterone levels and consequently develop signs of Cushing’s syndrome. However, while mice ubiquitously overexpressing CRH exhibited increased anxiety-related behaviour, overexpression of CRH in the pituitary did not produce alterations in emotional behaviour. These results suggest that chronic hypercorticosteroidism alone is not sufficient to alter anxiety-related behaviour but rather that central CRH hyperdrive on its own or in combination with elevated glucocorticoids is responsible for the increase in anxiety-related behaviour. In conclusion, the generated mouse lines represent valuable animal models to study the consequences of chronic CRH overproduction and HPA axis activation.