BIOGRAPHY

Born in Maarssen, I studied Chemistry and got my PhD in the Neuroendocrinology (promotor prof. dr. David de Wied & dr Johan van der Vies) at the University of Utrecht, while employed with the pharmaceutical company Organon in Oss. After a post-doc period of 2 years at the Rockefeller University in New York City with Bruce McEwen, I worked with David de Wied until 1990 in the Rudolf Magnus Institute in Utrecht as a basic neurobiologist on the action of neuropeptides in the regulation of learning and memory processes and on corticosteroid action in the brain.  From October 1, 1990 I became full professor in Medical Pharmacology at Leiden University & Leiden University Medical Center. In 2004 followed my appointment as Academy professor of the Royal Netherlands Academy of Arts and Sciences until 2014, which allowed me to continue working while becoming emeritus in 2009.

Research

Our research has led to a fundamental understanding how the stress hormone cortisol acts in the brain. During salient experiences cortisol acts as a double edged sword: first it promotes appraisal processes to assess the valence of the novel experience and to facilitate emotional expressions such as fear and aggression. Subsequently, the hormone promotes executive functions engaged in behavioural adaptation, termination of the stressful state of the organism and storage of the experience in the memory for future use.

Discovery

We discovered that these actions exerted by cortisol are mediated by two complementary receptor systems, the mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) that are co-expressed in limbic-forebrain regions engaged in processing of stressful information.

Mineralocorticoid receptor:  MR mediates, in sex-specific manner, the action of CORT in a limbic brain network involved in appraisal of salient events and in flexibility of decisions - such as is this individual a friend or a foe? - and in its subsequent emotional reactions such as fear and aggression.

Glucocorticoid receptor:  While the MR has a role in the anticipation and prediction of upcoming stressful events, either real of imagined, GR becomes progresssively activated once the stress response develops and CORT concentrations rise. GR operates as the off-button of the stress reaction. To achieve this CORT re-allocates via GR energy to fronto-cortical networks engaged in executive functions concerned with behavioural adaptation and memory storage of the experience for future use.

MR:GR balance:  If out of balance, these MR:GR-mediated actions were shown to compromise mental health during stress. MR:GR imbalance occurs by genetic variation of the receptors, their chaperones and co-regulators as well as by epigenetic changes induced particularly in early life by experience-related factors.

 

Chronic Stress:  In animal models of chronic stress, experienced cumulatively from early life through puberty into adult life, we found in response to an acute CORT and/or stressor challenge a dramatic change in the response pattern of limbic signalling pathways governed by e.g. growth factors, CREB-binding protein or mTOR. Hence, MR- and GR-susceptible pathways brought out of balance by stress, present an inroad towards novel targets to treat stress-related brain disorders.

 

 

 

 

 

 

 

 

 

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