Mechanisms of glucocorticoid signaling

Three recent publications illustrate our significant contributions to understanding the mechanisms of glucocorticoid signaling in the brain: Lachize et al published in PNAS (2009) that the coregulator protein SRC-1 is involved in specific stress-related effects of glucocorticoids in the brain. Vreugdenhil et al demonstrated in a paper in Endocrinology (2009) that members of the newly discovered class of miRNA molecules are potent regulators of the amount of glucocorticoid receptors that are present in brain cells. Finally, Fitzsimons et al demonstrated in Molecular Endocrinology (2008) a novel cell-specific level of control of glucocorticoid signaling, the ligand-activated glucocorticoid receptor translocation from cytoplasm to nucleus. These novel pathways involved in vulnerability and resilience provide almost immediate input for analysis in the cohorts that are available for genetic associations in human populations.

Mechanistic studies have long suffered from their dependence on in vitro techniques. The development of effective lentiviral delivery of shRNA into specific brain areas, and the possibility to evaluate regulation of relevant direct MR and GR genes in vivo by qPCR and ChIP techniques, allow more direct in vivo approaches. We are currently busy with a number of projects that induce local knockdown of stress-related factors in hippocampus and amygdala, to bridge the gap between the molecular steroid pharmacology and the neuronal circuits underlying resilience of the organism.