Effect of Corticosterone on Gene Expression in the Context of Global Hippocampal Transcription.

The composition of genomic mediators of glucocorticoid actions in the brain remains elusive because of low-statistical-power experiments and the associated transcriptomic data with very low consistency. The problem is further exaggerated by the underrepresentation of chronic experiments and the interpretation of differentially expressed genes without understanding their contribution to the total transcriptomic activity. To fill existing gaps in knowledge, we have performed a large transcriptomic experiment, testing the effects of prolonged treatment with corticosterone on the hippocampal transcriptome (RNA sequencing). The experiment showed that prolonged treatment with corticosterone induced a set of transcriptomic effects that were replicable across treatment durations, including genes relevant for human PTSD (Opalin, Pllp, Ttyh2, Lpar1) and prolonged stress in animals (Cnp, Fam163a, Fcrls, Tmem125). Some of the affected genes are specific for oligodendrocytes, neurons, astrocytes, immune cells, the vascular system, and brain ventricles, indicating that glucocorticoids may affect all central nervous system components. The data also showed that the largest changes in expression of corticosterone-responsive genes are restricted to genes with a relatively low expression level and small contribution to the overall pool of mRNAs in the hippocampus. As a result, even a large change in the number of affected genes leads to a small change in the number of newly synthesized mRNA copies. This means, in turn, that the transcriptomic changes induced by corticosterone have low-cost effects on the brain. This specificity of transcriptomic responses also poses a challenge for the interpretation of data and constitutes a potential source of reporting bias in past studies. Therefore, there is a need for further research on products of gene expression, both at the transcriptomic and proteomic levels, during stress conditions.