Stress, emotion and cognition : role of mineralo- and glucocorticoid receptors
Brinks, V.
Citation
Brinks, V. (2009, February 19). Stress, emotion and cognition : role of mineralo- and glucocorticoid receptors. Retrieved from https://hdl.handle.net/1887/13503
Version: Corrected Publisher’s Version
License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden
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Stress, emotion and cognition
Role of mineralo- and glucocorticoid receptors
Vera Brinks
Vera Brinks
Stress, emotion and cognition: role of mineralo- and glucocorticoid receptors Thesis, Leiden University
February 19, 2009 ISBN: 978-90-9023842-5
Cover: Vera Brinks and Thomas Dijkmans
Printing: PrintPartners Ipskamp, Enschede, The Netherlands
©2009, Vera Brinks
No parts of this thesis may be reproduced or transmitted in any form or by any means without written permission of the author.
Stress, emotion and cognition
Role of mineralo- and glucocorticoid receptors
Proefschrift
ter verkrijging van
de graad van Doctor aan de Universiteit Leiden, op gezag van Rector Magnifcus prof. Mr. P.F. van der Heijden,
volgens besluit van het College voor Promoties te verdedigen op donderdag 19 februari 2009
klokke 13.45 uur
door
Vera Brinks geboren te Rotterdam
in 1980
Promotiecommissie
Promotoren Prof. Dr. M.S. Oitzl Prof. Dr. E.R. de Kloet
Overige leden Prof. Dr. M. Danhof
Prof. Dr. P. Gass (Universität Heidelberg, Mannheim) Dr. H. J. Krugers (Universiteit Amsterdam, Amsterdam)
Prof. Dr. P. Spinhoven
Prof. Dr. B. M. Spruijt (Universiteit Utrecht, Utrecht) Dr. E. Vermetten
Prof. Dr. F.G. Zitman
The studies described in this thesis have been performed at the Division of Medical Pharmacology of the Leiden/Amsterdam Center for Drug Research (LACDR) and Leiden University Medical Center (LUMC), The Netherlands. The studies presented in chapter 6 were carried out at the Swammerdam Institute for Life Sciences (SILS), Amsterdam, The Netherlands. This research was financially supported by the Dutch Organisation for Scientific Research (NWO cognition: 051.02.010).
Printing of this dissertation was sponsored by:
Leiden/Amsterdam Center for Drug Research (LACDR) J.E. Jurriaanse Stichting
DFG-NWO International Research and Training Group (IRTG) Leiden-Trier (NWO-DN 95-420)
Noldus Information Technology BV
Table of contents
Preface
Chapter 1 General introduction 1
Chapter 2 Differential MR/GR activation results in emotional 45 states beneficial or impairing for cognition
Chapter 3 Emotion and cognition in high and low stress 71 susceptible mouse strains: a combined
neuroendocrine and behavioural study in BALB/c and C57BL/6J mice
Chapter 4 Strain specific fear behaviour and glucocorticoid 105 response to aversive events: modelling
PTSD in mice
Chapter 5 Corticosterone facilitates extinction of fear 115 memory in BALB/c mice but strengthens cue
related fear in C57BL/6 mice
Chapter 6 Mineralocorticoid receptors control emotional 137 arousal and fear extinction
Chapter 7 General discussion 155
Chapter 8 Summary 177
Samenvatting (Dutch)
Chapter 9 List of abbreviations 190
Curriculum Vitae 192
Publications 193
“The more emotional an event, the better it will be remembered”. Stress hormones such as cortisol (man) and corticosterone (rodent) are crucial for this intricate link between emotion and cognition. The hormones enhance motivation, mood and emotions, and have a profound influence on cognitive processes. This action exerted by the steroids is of evolutionary advantage and promotes health, but if dysregulated the cognitive-emotional changes become detrimental eventually precipitating stress-related diseases like Post-Traumatic Stress Disorder (PTSD). Why only some individuals experience the detrimental effects of stress, while and others remain healthy under similar conditions is a key question in cognitive neurobiology
The objective of this thesis is to identify the contribution of corticosteroids and their receptors to the integration of emotional and cognitive processes.
Corticosteroids are secreted from the adrenals in response to stress, and act in the brain via mineralo- (MR) and glucocorticoid receptors (GR). Emotional and cognitive performance of mice with genetically different MR and GR or pharmacologically-induced differential activation of these receptors was assessed in a variety of behavioural paradigms specifically designed to study the integration between emotional and cognitive domains. In this thesis I describe studies performed with two strains: the stress-susceptible BALB/c mouse strain and the stress-resistant C57BL/6J. We found that:
x Emotional arousal and cognitive performance are optimally integrated in mice with predominant MR- and additional moderate GR activation.
x The stress-susceptible BALB/c mice have an emotionally biased superior memory performance as compared to the resistant C57BL/6J mice;
cognitive performance correlates with MR and GR expression in limbic brain areas.
x BALB/c mice generalize their fear responses to context and cue while C57BL/6J mice discriminate between context and cue.
x Injection of corticosterone before or after fear conditioning destabilizes the memory consolidation and facilitates extinction in BALB/c mice;
C57BL/6J respond with augmented fear memory and lack of extinction.
x Mutant MRCaMKCre mice with forebrain-specific ablation of the MR gene display increased fear responses during all phases of memory formation and retrieval.
In conclusion, corticosteroids modulate the integration of emotional arousal and cognitive performance via a combined MR- and GR-mediated central action. It is proposed that C57BL/6J mice provide an animal model for PTSD and that the MR is a novel target for treatment of anxiety-related symptomatology.
