Acquired deficit of forebrain glucocorticoid receptor produces depression-like changes in adrenal axis regulation and behavior

PNAS, VOLUME 102, 473~478, 2005

Speaker: 陳澤思                               Date: 15:00~16:00; 2005/03/09

Commentator: 黃朝慶 老師                     Place: Room 601

Abstract:

  What is a depressive disorder? A depressive disorder is an illness that involves the body, mood, and thoughts. It affects the way a person eats and sleeps, the way one feels about oneself, and the way one thinks about things.¹  A major component of stress responsiveness in mammals is the hypothalamic-pituitary-adrenal(HPA) axis which, when activated, leads to the synthesis and release of the corticosteroid hormones-cortisol in humans and corticosterone in rodents.²  In this paper, the authors show in mice that a targeted disruption of the glucocorticoid receptor(GR) in the forebrain leads to behavioral and neuroendocrine changes that are parallel to human depression. To test the hypothesis that acquired disruption of GR action will lead to dysregulation of the HPA axis and depression-like behavior, they used the Cre/LoxP system to generate forebrain-specific GR knockout (FBGRKO) mice.  This Cre transgene is not active until ~3 weeks of age, allowing them to avoid deletion during early brain development. Deletion of forebrain GR is not complete in the FBGRKO mice until ~4–6 months of age. This time course is highly relevant to the natural progression of depression in humans, which is most commonly diagnosed between the ages of 25 and 35 years.³  For the treatment, the present study have shown that antidepressant ~imipramine,inhibit the corticosterone -induced gene transcription in a concentration- and a time-dependent manner. This has been suggested to be a mechanism through which antidepressants reverse the HPA axis phenotype associated with depression and lead to recovery of both the HPA axis and normal behavior.⁴

References:

1.            http://www.nimh.nih.gov/healthinformation/depressionmenu.cfm

2.            Huda Akil, Nature Medicine, 11, 116(2005).

3.            Maureen P. Boyle, et al., PNAS, 102, 473(2005).

4.            Budziszewska B, et al., Br. J. Pharmacol., 130, 1385(2000)