Previous studies have shown that the function of hypothalamic-pituitary-adrenal (HPA) axis is involved in the characterization of personality traits. FK506-binding protein 51 (FKBP51 or FKBP5) is a co-chaperone of heat-shock protein 90, and plays an important role in the negative feedback regulation of HPA axis function. It has been reported that a C/T single nucleotide polymorphism in the intron 2 of FKBP5 gene (rs1360780) affects FKBP5 protein levels and cortisol response to dexamethasone and psychological stress tests. Therefore, it is hypothesized that the FKBP5 polymorphism affects personality traits. In the present study, we studied the association between this polymorphism and personality traits in 826 Japanese healthy subjects. Personality traits were assessed by the Temperament and Character Inventory (TCI), and the FKBP5 genotype was detected by a real-time PCR and cycling probe technology for SNP typing. In total subjects, the group with the T allele predictive of impaired negative feedback regulation of the HPA axis had higher scores of harm avoidance (HA) (p = 0.043) and lower scores of cooperativeness (CO) (p = 0.019) compared to that without the T allele. The T allele was associated with higher scores of HA in females (p = 0.020) and lower scores of CO in males (p = 0.015). The present study thus suggests that the FKBP5 polymorphism affects HA and CO in healthy subjects, with gender specificity.

Hypersecretion of central corticotropin-releasing hormone (CRH) has been implicated in the pathophysiology of affective disorders. Both, basic and clinical studies suggested that disrupting CRH signaling through CRH type 1 receptors (CRH-R1) can ameliorate stress-related clinical conditions. To study the effects of CRH-R1 blockade upon CRH-elicited behavioral and neurochemical changes we created different mouse lines overexpressing CRH in distinct spatially restricted patterns. CRH overexpression in the entire central nervous system, but not when overexpressed in specific forebrain regions, resulted in stress-induced hypersecretion of stress hormones and increased active stress-coping behavior reflected by reduced immobility in the forced swim test and tail suspension test. These changes were related to acute effects of overexpressed CRH as they were normalized by CRH-R1 antagonist treatment and recapitulated the effect of stress-induced activation of the endogenous CRH system. Moreover, we identified enhanced noradrenergic activity as potential molecular mechanism underlying increased active stress-coping behavior observed in these animals. Thus, these transgenic mouse lines may serve as animal models for stress-elicited pathologies and treatments that target the central CRH system.

Conditional mouse mutants overexpressing corticototropin-releasing hormone (CRH) restricted to the central nervous system exhibit enhanced active stress-coping behavior. A highly flexible gain-of-function mouse model was created by combining the properties of the ubiquitously expressed ROSA26 locus with those of the Cre/loxP system. The knock-in of a Crh-LacZ expression unit, which is sensitive to activation by Cre recombinase, allows the spatio-temporally controlled overexpression of CRH at different dosages. In control mice (left), only endogenous CRH expression was detectable in the brain, whereas heterozygous (middle) and homozygous (right) CRH-COE-Nes mice expressed increasing levels of exogenous CRH throughout the brain. The pattern of CRH induction paralleled the activation of the simultaneously introduced LacZ reporter gene (left brain half). CRH-COE-Nes mice exhibited a marked gene-dosage-dependent increase in active stress-coping behavior as reflected by reduced immobility in the forced swim test (bottom), which depends on catecholaminergic transmission and enhanced activation of the locus coeruleus. For more information on this topic, please refer to article by Deussing et al. on pages 1028–1042.

The establishment of site-specific recombinases such as Cre, Flp and fC31 has revolutionized mouse genetics by providing means to delete, insert, invert, or exchange chromosomal DNA with high fidelity (for review see: Nagy, 2000). The available genetic toolbox favours the mouse as the ideal model organism to functionally approach gene function and to model human disease. To specifically target CRH expressing neurons we are currently generating transgenic mice, which will express conventional and inducible Cre-recombinase under the control of the CRH promotor. To achieve this goal we applied Red/ET-cloning techniques and BAC/Fosmid transgenesis in order to guarantee a Cre-recombinase expression matching the endogenous pattern of CRH expression. Random integration of the CRH-Cre constructs has been performed by pronucleus injection and transfection of embryonic stem cells. First transgenic founders have been obtained and transgenic offspring will be characterized. Established Cre lines will be bred with conditional CRH overexpressing mice in order to model central CRH hyperdrive as observed in patients with major depression. Moreover, these Cre mice could prove as extremely useful for analyzing CRH signaling pathways in vivo.