Biol Psychiatry. 2010 Feb 2;
Arabadzisz D, Diaz-Heitjz R, Knuesel I, Weber E, Pilloud S, Dettling AC, Feldon J, Law AJ, Harrison PJ, Pryce CR
BACKGROUND: Expression of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) genes are moderately reduced in several brain regions in depression.
These reductions could be partly due to early life stress (ELS), which predicts emotional disorders.
Controlled primate studies are important to test whether ELS sufficient to induce long-term emotional changes also induces long-term altered MR and/or GR brain expression.
METHODS: In the common marmoset, ELS of daily 30-120-min social isolation across month-1 resulted in some long-term changes in homeostasis and emotional behavior. In some of these same subjects, the aim of this study was to use marmoset-specific riboprobes to determine whether ELS produced long-term effects on brain MR and GR gene expression.
RESULTS: At adolescence, relative to control subjects, ELS marmosets exhibited mildly reduced messenger RNA signal for both MR (-15%, p = .05) and GR (-13%, p = .02) in hippocampus-primarily CA1-2-but not in prefrontal cortex, other cortical regions, or hypothalamus.
CONCLUSIONS: In adolescent marmoset monkey brains, reduced hippocampal expression of MR and GR are consistent chronic-indicators of ELS. It is unlikely that these chronic, mild, specific reductions were acute-mediators of the observed long-term emotional effects of ELS. However, they do suggest involvement of hippocampal MR/GR in the neurodevelopmental effects of ELS.
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In major depressive disorder, hippocampal mass loss occurs. This is thought to be one mechanism by which memory impairment occurs in depression. It is thought that high cortisol levels were the cause of this mass loss, given petri dish evidence that supraphysiologic massive doses of cortisol has toxic effects on hippocampal cells.
The problem I have is that in real life, low cortisol levels are what I almost universally see in patients presenting with major depressive disorder. I almost never see high cortisol levels in such patients.
This study points to a different cause of hippocampal mass loss. A reduction in cortisol sensitivity in the hippocampus under stress means a reduction to the anti-inflammatory effects of cortisol. And instead, there is an increase in susceptibility to pro-inflammatory cytokine signaling. This leads to a cellular inflammatory response in hippocampal cells and either tissue destruction or loss of mass.
Inflammatory signaling is a well-known cause of cell death – apoptosis. Cellular apoptosis during inflammation is a known defense mechanism against the spread of infection within a multicellular organism.
I would propose that pro-inflammatory cytokine signaling, increased in major depressive disorder, is the actual cause of hippocampal mass loss. Cortisol has a protective effect at physiologic levels against inflammation and is not the cause of hippocampal mass loss.