Conditional overexpression of corticotropin-releasing hormone – an animal model for understanding the development of corticotropin-releasing hormone-mediated brain pathology

The corticotropin-releasing hormone (CRH) plays a central role in the stress response. Besides its function in modulating a wide range of behaviors CRH is the major regulator of the hypothalamic-pituitary-adrenocortical (HPA) system. Chronically elevated CRH levels are implicated in the pathogenesis and maintenance of depression. To study the effects of central CRH hyperdrive we generated a mouse line overexpressing CRH in a spatio-temporally regulated fashion. Restricting CRH overexpression to the CNS enabled us to investigate the CNS effects of CRH without affecting the peripheral CRH system or the circadian HPA axis regulation under basal conditions. In contrast, under stress these mice showed a hyperactive HPA axis and an antidepressant-like behavior in respective screening paradigms, which is mediated via catecholamines. To investigate the molecular mechanisms underlying this phenotype we studied mRNA and protein expression levels. In situ hybridization was performed to reveal changes in transcription of genes related to the CRH system and the immediate early genes c-fos and zif-268, and protein expression of CRHR1 and CRHR2 was monitored via ligand binding autoradiography. Altogether, we found profound and brain region-specific alterations in gene expression of the analyzed targets in response to chronic CRH exposure as well as in response to stress. In conclusion our conditional CRH overexpressing mice have proven as a valuable tool for testing effects of CRH excess.