Detailed project information

Glucocorticoids (GC), the adrenal steroid hormones secreted in response to stress, are essential for function and viability of hippocampal neurons. Excess GC, occuring during chronic stress, can compromise hippocampal structure and function, resulting in cognitive deficits and impaired behavioral adaptation.

The effects of excess GC are mediated by the glucocorticoid receptor (GR), a ligand-activated transcription factor controlling expression of target genes in hippocampal neurons. Importantly, excess GC differentially affects different hippocampal subregions. Recently, I have identified GC-responsive gene patterns underlying physiological responses to acute GR-activation and in response to chronic stress in whole hippocampal homogenates. Despite partial overlap of these patterns, we did not yet provide direct evidence whether specific GC-responsive genes indeed underlie the harmful effects of chronic stress, nor how the differential effects on the different subregions are mediated. The objective is therefore to investigate the mechanism underlying the differential harmful effects of excessive GR-signalling in discrete hippocampal subregions known to differ in their response to stress. Based on our previous experiments, we test the hypothesis that the deleterious effects of chronic stress in hippocampal subregions are mediated by site-specific GR-signalling cascades activated by excessive GC concentrations.

Specific aims:

1) to identify differentially expressed gene patterns in discrete hippocampal subregions upon exposure to chronic stress with or without a GR antagonist. This allows us to define the role of GR per subregion (subproject 1)

2) to investigate the role of specific GR-responsive genes on structure and function of hippocampal neurons by manipulating their expression in hippocampal subregions using locally applied siRNA/lentiviral approaches (subproject 2)

This will result in the identification of GR-dependent gene patterns linked to the changes in neuronal structure and function observed in chronic stress and will provide insight in the neurobiological mechanism underlying the differential response to excessive GR-signalling in different hippocampal neuronal populations.

Articles

• Dr. N.A. Datson, Ing. P.J. Steenbergen, Dr. M.C. Morsink, Prof.Dr. M. Joels, Prof.Dr. E.R. de Kloet, Dr. N.G. van Gemert (2007). Rapid glucocorticoid effects on the expression of hippocampal neurotransmission-related genes. Brain Research. pp. 14-20
• Dr. N.A. Datson (2008). Scaling down SAGE: from miniSAGE to microSAGE. Current Pharmaceutical Biotechnology. pp. 351-361
• (2008). Scaling down SAGE: from miniSAGE to microSAGE. Current Pharmaceutical Biotechnology. pp. 351
• (2008). Central corticosteroid actions: search for gene targets. Eur J Pharmacol. pp. 272-289
• Dr. O.C. Meijer, Dr. M.C. Morsink, Prof.Dr. E.R. de Kloet, Dr. N.A. Datson (2008). Central corticosteroid actions: search for gene targets. Eur J Pharmacol . pp. 272-289
• Msc. Y. Aubert, Ing. P.J. Steenbergen, Prof.Dr. E.R. de Kloet, Dr. M.C. Morsink, E. Fuchs, Dr. N.A. Datson, C. Schlumbohm (2009). A molecular blueprint of gene expression in hippocampal subregions CA1, CA3, and DG is conserved in the brain of the common marmoset.. Hippocampus. pp. 
• Dr. O.C. Meijer, Dr. N.A. Datson, Dr. C.P. Fitzsimons, Dr. E. Vreugdenhil, Prof.Dr. E.R. de Kloet (2009). Glucocorticoid signalling and stress-related limbic susceptibility pathway: about receptors, transcription machinery and microRNA. Brain Research. pp. 

Proefschriften

• Dr. M.C. Morsink (2007). Glucocorticoid control of gene transcription in neural tissue. Universiteit Leiden. promotiedatum 26-6-2007
• (2007). Glucocorticoid control of gene transcription in neural tissue. . promotiedatum 26-6-2007
• (2007). Molecular mechanisms of epithelial host defense in the airways. . promotiedatum 11-1-2007

Bijdragen aan boeken

• Dr. M.C. Morsink, Dr. N.A. Datson, G. Fink (2007). Expression Profiling of Stress-Responsive Gene Patterns. in: Encyclopedia of Stress. : . pp. 
• Prof.Dr. M.S. Oitzl, Dr. N.A. Datson, Dr. Y. Revsin, Dr. D.L. Champagne, Prof.Dr. E.R. de Kloet, D. Pfaff, Y. Christen, C. Kordon, P. Chanson (2008). Brain corticosteroid receptor function in response to psychosocial stressors. in: Hormones and social behavior. : . pp.