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Paul Lucassen "Stress and hippocampal structural plasticity; possible mechanisms".

Abstract :

tress is an important risk factor for the development of depression(1,2,3). One of the brain regions particularly sensitive to stress, is the hippocampus as it is richly endowed with glucocorticoid receptors (GR). Indeed, the hypothalamic-pituitary-adrenal (HPA) hyperdrive in depressed individuals is commonly accompanied by memory deficits and by significant hippocampal volume reductions. This suggests that structural changes are expected to occur in this region after stress. We therefore studied effects of stress on structural plasticity markers like new cell birth, neurogenesis, apoptosis, cell number and volume in the chronically stressed rat hippocampus.
In rats, chronic unpredictable, but also acute stress decreased the numbers of adult-generated cells. The reduced proliferation rate after acute stress, however, normalized again already within 24 hrs, whereas most of the structural dynamic changes after chronic stress were at least partly recovered after 3 week of recovery, indicating that the stress mediated reduction in adult cytogenesis is transient and reversible. Apoptosis on the other hand, increased after acute, but was decreased after chronic stress, while the significant reduction in CA3 volume after chronic stress had not yet normalized after an additional 3 weeks recovery period (4). Recent clinical studies that blocked the effects of stress by treating depressed patients with high doses of the GR antagonist RU486, proved very promising as a strong reduction was found in their depressive symptoms (1). Our preliminary data on stressed rats treated with high doses of RU486 for the last 4 days, indicate this clinical effect is mediated through rapid normalization of hippocampal neurogenesis.
Subsequently, we questioned which mechanims underlie the stress mediated reductions in hippocampal neurogenesis (5,6). Recent evidence has shown that adult proliferation takes place near the local microvasculature of the hippocampus while both angiogenesis and neurogenesis are modulated by similar stimuli, suggesting that regulatory signals for adult proliferation are at least partially derived from the endothelium. We studied vascular endothelial growth factor (VEGF), a major angiogenic factor that can exert neuroprotective effects. Our results show that 32% of the proliferating cells in the rat hippocampus is vascular associated. Chronic stress affected this population of newborn cells to a significantly larger extent than the non-associated cells. After chronic stress, protein levels of both VEGF and its receptor, i.e. Flk-1, were significantly decreased, but again recovered after 3 weeks (6). This demonstrates that changes in angiogenic factors are implicated in the decreased adult proliferation after chronic stress.

Selected publications

Heine VM, Zareno J, S Maslam, M Joëls and d PJ Lucassen.
Chronic stress in the adult dentate gyrus reduces cell proliferation near the vasculature and VEGF and Flk-1 protein expression.
Europ J Neurosci, 21 (2005) 1304-1314.
Heine VM, S Maslam, M Joëls and PJ Lucassen. Increased P27Kip1 protein expression in the dentate gyrus of chronically stressed rats indicates G1 arrest involvement.
Neuroscience 129 (2004c) 593–601.
Heine VM, S Maslam, J Zareno, M Joëls, PJ Lucassen. Suppressed proliferation and apoptotic changes in the rat dentate gyrus after acute and chronic stress are reversible.
Eur. J. Neurosci., 19; 131-144, 2004b.
PJ Lucassen, E Fuchs and B Czéh:
Biol Psychiatry 55: 789–796, 2004.

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