Nguyen-Duong H, Univ. Ulm, 89079 Ulm, Deutschland

Stress resilience is understood as the very variably developed human ability to withstand psycholo-gically stressful life events without major detrimental consequences. The causes of this variability can be derived from an analysis of the complex modulation mechanisms that underlie the stress-associated neural networks. As well known, increased stress vulnerability can be traced back to an overactivated hypothalamus-pituitary-adrenal cortex (HPA) axis. Although some recent studies have shown that the HPA axis is characterized by a pulsating release of glucocorticoids from the adrenal cortex resulting from overlapping circadian and ultradian rhythms, little is still known about the downstream implications of such short-term fluctuations on target cerebral tissues. The rhythmic transcription of two genes, namely the FKBP5 and FKBP4 genes, which code for two evolutionarily related co-chaperones belonging to the immunophile family, seems to play a decisive role in modulating via epigenetic demethylation the affinity of glucocorticoidreceptors (GR) for cortisol. On the one hand, disinhibition of the FKBP5-gene leads to an increased expression of FKBP5, which in turn lowers the affinity of GR for cortisol. The resulting ultra-short cellular negative feedback loop is responsible for the resistance to cortisol, which by increasing the activity of the HPA axis, leads to more circulating cortisol. On the other hand, the twin co-chaperone FKBP4 increases the affinity of GR for cortisol, which results in a reduced secretion of cortisol from the adrenal glands. Obviously a more in-depth analysis of the fine-regulated mechanisms inherent to the HPA-axis would be very helpful in identifying internal biomarkers allowing thereby in combination with an adequate magnesium substitution therapy an improved resilience for certain professional groups.