The Leiden University Medical Centre is represented by the
Devision of Medical Pharmacology of the Leiden /Amsterdam Centre of Drug Research (LACDR)

The LACDR is a graduate school which participates in the ULLA, a consortium of pharmacological/pharmaceutical institutes in Uppsala / London / Leiden / Amsterdam, also including Copenhagen and Paris since last year, providing advanced training in drug research. The mission is of the Medical Pharmacology is to identify novel glucocorticoid and stress-induced signalling pathways in brain which are linked to specific psychic domains of emotion, cognition and behavioural adaptation. Members of the Division test the hypothesis that disruption of these stressor-driven signalling pathways is fundamental for the pathogenesis of stress-related brain disorders. For this purpose they focus on the action of glucocorticoid hormones secreted by the adrenal gland, which readily enter the brain and target discrete neuronal circuits including those underlying emotion and cognition. This action exerted by the glucocorticoids is a key topic in the EUROSTERONE consortium. The current research involves approaches from molecular genetics and cell biology to physiology and behaviour using rats and (transgenic) mice. Using SAGE and microarrays, we have recently identified patterns of stress-responsive genes that predict specific differences in structural plasticity of brains of genetically selected mouse lines characterised by extreme differences in coping with stress (Feldker et al. 2003). This work and the current expertise in genomics enable the Division to deliver the development of the marmoset cDNA microarray (EUMAMA).

In 1985 de Kloet et al. (see for review de Kloet et al. 1998; 1999) discovered that cortisol action is mediated by two nuclear receptor types (mineralocorticoid receptors [MR] and glucocorticoid receptors [GR]). These receptorsoperate in a co-ordinate manner to control gene expression. Our large-scale genomic screening revealed 700 corticosteroid-responsive genes, some of them a characteristic feature of the stress response gene patterns identified in the mouse lines (Datson et al. 2001). Present research suggests that under conditions of MR/GR imbalance, corticosteroid control of a complex genetic programme in the brain is altered. As a consequence, some corticosteroid-responsive genes become dysregulated and function as "candidate vulnerability genes". These genes may enhance vulnerability to brain damage, cognitive decline and negative mood. In this respect, the Leiden group is ideally suited to investigate the long-term impact of prenatal glucocorticoid on health in marmoset monkeys, inasmuch as increased long-term exposure to endogenous glucocorticoids has been linked to the premature onset of diseases associated with ageing. Sharing existing experience in structural and molecular neurobiology as well as in forefront microarray technology with the other members of the network will make a significant contribution to the quality and success of the programme.

References:
Feldker DEM, Datson NA, Veenema AH, Meulmeester E, De Kloet ER, Vreugdenhil E (2003) Serial analysis of gene expression predicts structural differences in hippocampus of long attack latency and short attack latency mice. Eur J Neuroscience 17: 379-387.
Datson NA, Van der Perk J, De Kloet ER, Vreugdenhil E (2001) Identification of corticosteroid-responsive genes in rat hippocampus using serial analysis of gene expression. Eur J Neuroscience 14: 1-17.
De Kloet ER, Oitzl MS, Joëls M  (1999) Stress and cognition: Are corticosteroids good or bad guys? Trends Neurosci 22: 422-426.
De Kloet ER, Vreugdenhil E, Oitzl MS, Joëls M (1998) Brain corticosteroid receptor balance in health and disease. Endocrine Reviews 19: 269-301.

 Contribution to the project:

• measurement of corticosteroid responsive gene markers in the brain (hippocampus, paraventricular neurons, the antero-ventral hypothalamus and the catecholaminergic cell body regions). In situ hybridisation for quantification of mRNA's of interest in neuroanatomically defined brain regions and individual neurons will be used.
• partial cloning from marmoset cDNA ,
• development of marmoset-specific cDNA microarrays.

Prof. E. Ronald de Kloet, Ph.D.
Division of Medical Pharmacology (LACDR-LUMC)
Gorlaeus Laboratories, University of Leiden
Einsteinweg 55
P.O. Box 9502
2300 RA Leiden
the Netherlands
Phone: +31-71-527 6210,  Fax: +31-71-527 4715
e-mail: E.Kloet@lacdr.leidenuniv.nl

Nicole Datson, Ph.D.
Division of Medical Pharmacology (LACDR-LUMC)
Gorlaeus Laboratories, Leiden University
P.O. Box 9502
2300 RA Leiden
the Netherlands
Phone: +31-71-527 6222, Fax +31-71-527 4715
e-mail: datson_n@lacdr.leidenuniv.nl

http://www.medicalpharmacology.leidenuniv.nl