In addition, one should keep in mind that BAY 87-2243? categorically dis tinct acute stressors elicit distinct transcriptional profiles in the PVN. Nevertheless, a few genes were found in both studies, for example ATP synthase, H trans porting mitochondrial F1 complex and ribosomal pro tein L30. In principle, all genes that we found differentially expressed or differentially regulated between the two mouse strains are candidates for the explanation of the differential response to some stressors, reflecting the previously proposed differences in corticosteroid signal ling. In addition, we checked genes with known functions that could contribute to the strain differences such as POMC1, GR, CRHR1 and CRHR2. Only GR showed differential regulation, namely a down regula tion in DBA 2J mice 4 h after stress.

Causality is diffi cult to prove in feedback systems such as the HPA axis, i. e. when considering the complex connections of com pensatory mechanisms that emerged in this evolutiona rily old threat response system. Nevertheless, this difference could be indicative of differential stress signalling, as GR is the most important mediator of cor ticosteroid action. Since DBA 2J mice also exhibit a higher sensitivity to antidepressants than C57BL 6 we also specifically investigated genes that had been associated with antide pressant response before, such as the immunophilin FKBP5, which is an efficient regulator of GR, the multidrug resistance protein ABCB1A B that deter mines brain tissue penetration of many antidepressant drugs, the serotonin receptor 5 hT2A, and the transporter proteins SLC6A4 and SLC6A15.

Among those, SLC6A15 was down regulated 4 h after stress in DBA 2J mice, but not in C57BL 6 mice. Since stress and GR action is intertwined with the action of antidepressants, also any of the stress induced genes could contribute to the action of antidepressants. Like with other screening studies, it is certainly premature to delineate direct candidates for novel antidepressant tar gets or for diagnostic markers from this study. However, the synopsis of our results together with results from different screening efforts in genetics, proteomics, metabolomics etc. will yield convergence and thus allow selection of the most promising candidates. Our study provides strong evidence for a time phased response of the PVN transcriptome to the stressor.

We have previously described a phased stress response for the Dacomitinib CA3 hippocampal region as well. This suggests that this might be not an area specific phenomenon, but rather a more general mechanism. Interestingly, a num ber of genes are regulated by stress in the hippocampal CA3 as well as in the PVN, e. g. DPYSL2, SNAP25, GNAO1. Like for the stress regulated genes in CA3, we used also for the regulated genes in the PVN a pathway building program to propose novel signal trans duction pathways elicited after stress.