Leiden University Scholarly Publications

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Klok, M.D. (2011)

Mineralocorticoid receptor in human brain : a key player in resilience

Doctoral Thesis
Depression involves multiple mental problems, including low mood, inability to experience pleasure and emotional, cognitive and behavioral problems. It has a lifetime prevalence of ~15% in the Dutch population, striking women twice as often as men. The disorder often comprises persisting disturbances in the neuroendocrine stress system, the hypothalamic- pituitary-adrenal (HPA) axis, including disregulation of its end-hormone cortisol. Cortisol normally stimulates emotional, cognitive and behavioral processes in order to cope with a stressor and promotes recovery, learning and memory. This thesis describes the identification of a specific genetic variant of the mineralocorticoid receptor (MR), one of the two receptors for cortisol, which protects 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...Show moreDepression involves multiple mental problems, including low mood, inability to experience pleasure and emotional, cognitive and behavioral problems. It has a lifetime prevalence of ~15% in the Dutch population, striking women twice as often as men. The disorder often comprises persisting disturbances in the neuroendocrine stress system, the hypothalamic- pituitary-adrenal (HPA) axis, including disregulation of its end-hormone cortisol. Cortisol normally stimulates emotional, cognitive and behavioral processes in order to cope with a stressor and promotes recovery, learning and memory. This thesis describes the identification of a specific genetic variant of the mineralocorticoid receptor (MR), one of the two receptors for cortisol, which protects 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 same variant was found to associate with personality characteristics that predict the risk of depression later in life and with a lower risk of depression itself. All associations were found only in women and not in men. To conclude, the MR is an important determinant of resilience; increased MR expression seems to be protective against depression.Show less
Stress
Optimism
Mineralocorticoid receptor
Gene variants
Depression
Cortisol
All authors
Klok, M.D.
Supervisor
Kloet, E.R. de; Zitman, F.G.
Co-supervisor
Rijk, R.H. de
Qualification
Doctor (dr.)
Awarding Institution
Leiden University Medical Center (LUMC), Leiden University
Date
2011-12-15
ISBN (print)
9789088913532

Funding

Sponsorship
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