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Title: Molecular mechanisms underlying dietary modulation of adult hippocampal neurogenesis
Author: Stangl, Doris
Awarding Body: King's College London (University of London)
Current Institution: King's College London (University of London)
Date of Award: 2012
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The studies described in this thesis explore the molecular mechanisms by which nutrition modulates Adult Hippocamapal Neurogenesis (AHN) using a human hippocampal progenitor cell line (HPC). AHN has been shown to be important for cognition and mood regulation. Interestingly, diet in the form of the Omega-3 fatty acids Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DMA) is known to have beneficial effects on cognition and mood; these effects are hypothesised to be mediated via modulating AHN. My studies show that in an in vitro model of stress, EPA (10uM) and DHA (10uM) prevent the detrimental effects of Cortisol on proliferation and neurogenesis by increasing the percentage of dividing cells and neurogenesis while decreasing apoptosis mainly by promoting survival. Resveratrol (1uM), a stilbenoid present in the skin of red fruit, prevents the Cortisol induced changes by increasing the percentage of dividing cells and neurogenesis but has no effect on apoptosis. Intermittent fasting (IF), shown to promote AHN, increases the expression of Klotho, the longevity gene. Klotho over expression increases neurogenesis. Whereas Klotho knock down decreases neurogenesis by diminishing survival. To further investigate the molecular pathways downstream of Resveratrol as mimetic of IF and Klotho expression, I focused on PPARy (Peroxisome proliferator-activated receptor) a nuclear receptor transcription factor which is known to activate Klotho transcription and is activated by Resveratrol. My results show that Resveratrol partly requires PPARy to activate Klotho and that Klotho is partly required during proliferation for Resveratrol to exert its effect. Whereas, Resveratrol partly requires both Klotho and PPARy to increase neurogenesis and PPARy requires Klotho to increase the proportion of mature neurons. These experiments provide evidence that PPARy and Klotho are two of the neurogenic effectors of Resveratrol. This thesis provides for the first time evidence in a human in vitro model of neurogenesis and stress that EPA, DHA and Resveratrol can modulate neurogenesis and prevent its decrease induced by stress. This study also provides the first identification of Klotho and PPARy as downstream effectors of Resveratrol on neurogenesis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available