Mineralocorticoid receptor in human brain : a key player in resilience Klok, M.D.

Mineralocorticoid receptor in human brain : a key player in resilience

Klok, M.D.

Citation

Klok, M. D. (2011, December 15). Mineralocorticoid receptor in human brain : a key player in resilience. Retrieved from https://hdl.handle.net/1887/18250

Version: Corrected Publisher’s Version

License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden Downloaded from: https://hdl.handle.net/1887/18250

Note: To cite this publication please use the final published version (if applicable).

L ia n e K lo k

Liane Klok

Mineralocorticoid  receptor  in  human  brain  

A  key  player  in  resilience  

Melanie Diane Klok

Liane Klok

Mineralocorticoid receptor in human brain: a key player in resilience

Thesis, Leiden University December 15, 2011 ISBN: 978-90-8891-353-2

Cover: design by Daniel Brouwer & Liane Klok Print: Boxpress BV, proefschriftmaken.nl

© 2011 Liane Klok

No part of this thesis may be reproduced or transmitted in any form or by any

means without written permission of the author.

Mineralocorticoid  receptor  in  human  brain  

A  key  player  in  resilience  

Proefschrift

ter verkrijging van de graad van Doctor aan de Universiteit Leiden,

op gezag van Rector Magnificus Prof. Mr. P.F. van der Heijden, volgens besluit van het College voor Promoties

te verdedigen op donderdag 15 december 2011 klokke 11:15 uur

door

Melanie Diane Klok

geboren te Winschoten in 1979

Promotiecommissie  

Promotores: Prof. Dr. E.R. de Kloet Prof. Dr. F.G. Zitman Co-promotor: Dr. R.H. de Rijk

Overige leden: Prof. Dr. B.W.J.H. Penninx (VUmc, Amsterdam) Prof. Dr. P.E. Slagboom

Dr. J.W. Koper (Erasmus Universiteit, Rotterdam) Prof. Dr. A.J.W. van der Does

Dr. E.J. Giltay Prof. Dr. M. Danhof

The research described in this thesis was performed at the division of Medical Pharmacology of the Leiden/Amsterdam Center for Drug Research and Leiden University Medical Center, Leiden University, Leiden, The Netherlands. This research was financially supported by the Royal Netherlands Academy of Arts and Sciences (KNAW), the Netherlands Brain Foundation (Hersenstichting Nederland, 10F02(2).37), psychiatric hospital Rivierduinen and the International Research Training Group (IRTG) funded by the DFG (GRH 1389/1) and NWO (DN95-420).

Printing of this dissertation was kindly supported by:

• International Research Training Group (IRTG) funded by the DFG (GRH 1389/1) and NWO (DN95-420)

• Leiden/Amsterdam Center for Drug Research (LACDR)

• J.E. Jurriaanse Stichting

5

Table  of  contents

Abbreviations 6

Preface 7

Chapter 1 General introduction 9

Part 1 Molecular studies 29

Chapter 2 Decreased expression of mineralocorticoid receptor mRNA and its 31

splice variants in postmortem brain regions of patients with major depressive disorder Chapter 3 Functional haplotypes in the human mineralocorticoid receptor 45

gene promoter region Part 2 Genetic association studies among individuals selected from 59

the general population Chapter 4 A functional mineralocorticoid receptor gene haplotype associates 61

with higher dispositional optimism in elderly women not men Chapter 5 A functional mineralocorticoid receptor gene haplotype associates 77

with decreased cognitive reactivity to sad mood in young women not men Part 3 Genetic association studies among depressed patients 97

Chapter 6 Common functional mineralocorticoid receptor polymorphisms 99

modulate the cortisol awakening response, interaction with SSRIs Chapter 7 A common and functional mineralocorticoid receptor gene 115

haplotype associates with a lower risk for major depressive disorder in females Chapter 8 General discussion 127

Summary 147

Samenvatting 150

References 155

Curriculum Vitae 172

Dankwoord 175

6

Abbreviations

-RT without reverse transcriptase 11β-HSD 11β-hydroxysteroid dehydrogenase

Acb nucleus accumbens

ACTH adrenocorticotrophic hormone

Amg amygdala

ANOVA analysis of variance

AUCg area under the curve with respect to the ground AUCi area under the curve with respect to the increase

Bp basepairs

CAR cortisol awakening response

cDNA complementary deoxyribonucleic acid

CgG cingulate gyrus

CRH corticotrophin-releasing hormone CSF cerebrospinal fluid

DNA deoxyribonucleic acid

dNTP deoxyribonucleotide triphosphate GR glucocorticoid receptor

Hi hippocampus

HPA hypothalamic-pituitary-adrenal HWE Hardy-Weinberg equilibrium IFG inferior frontal gyrus

Kb kilobases

LD linkage disequilibrium MDD major depressive disorder MgCl 2 magnesium chloride MR mineralocorticoid receptor mRNA messenger ribonucleic acid PCR polymerase chain reaction PFC prefrontal cortex

PVN paraventricular nucleus of the hypothalamus qPCR quantitative polymerase chain reaction

RIN RNA integrity number

RLU relative light unit

SD standard deviation

SNP single nucleotide polymorphism SSRI selective serotonin reuptake inhibitor TF transcription factor

UTR untranslated region

7

Preface  

It sounds a bit contradictory: stress is essential for health. But…a stressor exists in many flavors, including a physical assault to the body or a psychological challenge, for example when an individual prepares for an exam. In either case, the stressor elicits a stress response, which is the spectrum of physiological and behavioral adaptations aimed to defend the integrity of body and brain and to restore homeostasis, but also to modulate emotional arousal, learning and memory processes. These adaptations are coordinated by the sympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis. Blood levels of adrenaline rise, glucose is made available to tissues, while blood pressure and heart rate go up. Then, stress-induced cortisol promotes the mobilization of energy resources, facilitates the processing of relevant information and helps to select a behavioral reaction appropriate for coping with the stressor.

However, stress can also be harmful. If coping and adaptation fails, the sympathetic nervous system and HPA axis may keep on running in high gear, eventually leading to depletion of energy resources. An individual may experience exhaustion, become fearful or develop disturbances in cognition and mood. Still, after a long-lasting stressful period, many people can wrap themselves together and move on doing their daily activities. Unfortunately, there are also the unlucky ones, who get physically sick, anxious or depressed. The question then arises, what makes these individuals different from each other? Why are some people able to cope with stress while others are not?

This thesis describes the identification of genetic variants of the mineralocorticoid receptor

(MR) that protection against depression. MR transcript expression was found to be lower in

postmortem limbic brain regions of depressed patients compared to non-depressed

subjects. In addition, a specific and common MR gene variant was identified that results in

higher MR expression in vitro. This gene variant was found to associate with personality

traits and cognitive reactivity to sad mood in such a manner that it decreases the risk of

depression later in life. Interestingly, in a large cohort study this same MR gene variant

associated with a lower risk of depression. All associations were found only in women and

not in men. In conclusion, the data described in this thesis designate the MR as an

important determinant of resilience; increased MR expression seems to be protective

against depression.