Brain Mineralocorticoid receptors As Resilience factor Under Adverse life conditions

176 Pages·2016·4.7 MB·English

Brain
Mineralocorticoid
receptors

As
Resilience factor
Under
Adverse life
conditions
Sofia Kanatsou
Author: Sofia Kanatsou
Cover design: Thorolf Horn Tonjum
Printing: Gildeprint
Print support: UMC Utrecht Brain Center Rudolf Magnus Institute
ISBN: 978-90-393-6502-1

© S. Kanatsou, 2016
All rights reserved. No part of this publication may be reproduced or transmitted
in any form by any means, without permission of the author.
Brain
Mineralocorticoid
receptors
As
Resilience factor
Under
Adverse life conditions

Mineralocorticoid receptoren in de
hersenen als beschermende factor
voor negatieve gebeurtenissen?
(met een samenvatting in het Nederlands)
Proefschrift
ter verkrijging van de graad van doctor
aan de Universiteit Utrecht op gezag van de
rector magnificus, prof. dr. G.J. van der Zwaan,
ingevolge het besluit van het college voor
promoties in het openbaar te verdedigen
op woensdag 20 april 2016 des ochtends te 10:30 uur
door
SOFIA KANATSOU
geboren op 17 mei 1982
te Ioannina, Griekenland
Promotor: Prof. dr. M. Joëls
Copromotor: Dr. H. Krugers
The research in this thesis was financially supported by NWO (The
Netherlands Organization for Scientific Research) grant 821-02-007.
Τούτ᾽ εστί το ζην, μη σεαυτώ ζην μόνον.
Μένανδρος, 4ος αιών π.Χ., Αρχαίος
Έλληνας ποιητής
This is life , not just live for yourself
Menander , 4th Century BC , Ancient
Greek poet
Contents
Chapter 1...............................................................................................9
General Introduction

Chapter 2.............................................................................................55
Transgenic overexpression of mineralocorticoid receptors
prevents chronic stress-induced hippocampal-dependent
memory deficits
Chapter 3.............................................................................................77
Effects of mineralocorticoid receptor overexpression on
behavior in female mice
Chapter 4.............................................................................................93
Mineralocorticoid receptor overexpression as a genetic
resilience factor in adulthood after exposure to early-life
stress in male mice
Chapter 5...........................................................................................113
Effects of mineralocorticoid receptor overexpression on
behavior in adulthood after exposure to early-life stress in
female mice
Chapter 6...........................................................................................131
General Discussion
Nederlandse samenvatting...................................................................167
About the author.................................................................................169
Publications.........................................................................................171
Acknowledgements..............................................................................173

Chapter 1: General Introduction
I.1 The stress system in health............................................................................10
I.1.1 Main stress pathways
I.1.2 Stress response: general features and the involvement of
corticosteroid receptors
I.1.3 Corticosteroid receptors: properties and signalling pathways
I.1.4 MR/GR balance hypothesis
I.1.5 Stress hormones and learning and memory
I.2 Disrupted HPA-axis function as risk-factor for brain disease.........................17
I.2.1 Psychopathology involving a disturbed HPA axis
I.2.2 Effects of chronic stress on structural plasticity and behavior
I.2.3 Effects of early-life stress on structural plasticity and behavior
I.3 Adult neurogenesis as a substrate...................................................................21

I.4 Resilience to effects of stress due to MR genetic background.........................24
I.4.1 Effects of MR blockade on cognition
I.4.2 The effects of MR overexpression on HPA-axis function and
behaviour in experimental animals
I.5 Methods used in this thesis...........................................................................29

I.5.1 BrdU, Ki-67 and DCX as markers for neurogenesis
I.5.2 Golgi-cox staining
I.5.3 Electrophysiology
I.5.4 Object in context task
I.5.5 Open field paradigm
I.5.6 Elevated plus maze
I.5.7 Contextual fear conditioning and extinction
I.6 Outline of this thesis.....................................................................................34

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I.1 The stress system in health
In our everyday life we all experience “stress”. Stress is here defined as an organism’s sub-
jective perception of a threat (real or anticipated), which elicits physiological and behav-
ioural responses (Selye 1973; McEwen et al., 2000). When animals (including humans)
experience stress in either a psychological or physiological form, the body will exert a
stress response. This refers to a cascade of internal reactions in order to overcome these
threatening challenges by activating a wide range of responses through neural, autonomic,
immune and metabolic systems. As part of the overall stress response, the brain processes
not only external environmental stimuli but also internal inputs from the body. This ena-
bles the brain to control and coordinate behavior and physiological adjustments. Under
normal conditions this stress response will lead to an appropriate behavioural response to
the specific kind of experienced stress and promotes (behavioural) adaptation and survival
(de Kloet et al., 2005). Stress responses to extreme or chronic challenges may fall short to
achieve adaptation and as such can be a critical risk factor for the development of brain
diseases and psychopathologies such as depression and post-traumatic stress-disorder.
I.1.1 Main stress pathways

In response to a stressful situation two physiological systems are activated (Figure 1); the auto-
nomic nervous system and the hypothalamic-pituitary adrenal (HPA) axis (de Kloet et al., 2005):
1) The autonomic nervous system triggers a fast activation of the sympatho-adre-
nomedullar nervous system in anticipation of a “fight or flight” reaction, which leads
to the release of the neurotransmitter noradrenaline (NA) from synapses and (nor)
adrenaline from the adrenal medulla, while it suppresses the activation of the para-
sympathetic nervous system (thereby reducing e.g. digestion and sexual arousal). Dur-
ing this stage, basal metabolic rates are elevated and blood-flow to vital organs, i.e.
brain, heart and (other) muscles, and attention are increased via the actions of NA.
2) The hypothalamic-pituitary-adrenal (HPA) axis is activated by the release of vasopressin
and corticotrophin releasing hormone (CRH) from the paraventricular nucleus of the hy-
pothalamus (PVN). This in turn stimulates the secretion of adrenocorticotrophic hormone
(ACTH) from the pituitary gland, which travels via the blood stream to the adrenal cortices
and promotes the release of corticosteroid hormones (in humans cortisol, in rodents corticos-
terone) into the blood. Cortisol in humans or corticosterone in rodents act via two kinds of
receptors, the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) (figure 1).
Via a negative feedback loop, corticosteroids exert a suppressing signal on the
hypothalamus and the pituitary to restrain the release of CRH and ACTH (Swaab et al.,
2005). This negative feedback loop is crucial to reduce plasma corticosterone / cortisol
levels, after exposure to a stressor.

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