Proceedings of The Physiological Society
King's College London (2011) Proc Physiol Soc 22, C19
Molecular mechanisms mediating dietary modulation of adult hippocampal neurogenesis and associated behaviour
D. Stangl1, B. Morisse1, S. Ahmet1, S. Thuret1
1. Neuroscience, King's college London, London, United Kingdom.
It is now well established that during adulthood, new neurons are generated from adult neural stem cells residing in the dentate gyrus of the hippocampus, a region important for memory and learning function as well as mood in rodents and humans (1). In the rodent, an increase of neurogenesis in the hippocampus is associated with improved learning/memory abilities (2), whereas a decrease is associated with symptoms of depression (3). The level of adult hippocampal neurogenesis can be regulated by factors such as enriched environment, physical activity, aging and stress but also by diet (4). We first present dietary parameters responsible for adult hippocampal neurogenesis and memory and learning as well as mood regulation. We show, in the mouse animal model (mus musculus, strain C57BL/6) that meal frequency, independently of calorie intake, affects adult neurogenesis, learning/memory and mood. We next identified possible molecular mechanisms mediating the effects of diet on adult hippocampal neurogenesis. We show that the gene Klotho is highly expressed in the hippocampus and its expression is up-regulated by 2 fold upon intermittent fasting-induced increased adult hippocampal neurogenesis (n=3, p<0.05). Klotho is also known as the ‘ageing suppressor gene’, due to the symptoms of a knockout mouse resembling human aging. In turn in a mouse model over-expressing Klotho lifespan is extended up to 30% (5). Up to date, the role of Klotho in the central nervous system has not been investigated. To further examine the role of Klotho on cellular and molecular mechanisms underlying the influence of food intake on hippocampal neurogenesis, we used a human embryonic hippocampal progenitor cell line. Threshold analysis in the dentate gyrus of mice maintained on an intermittent fasting diet (fed ad libitum every other day) for 3 months shows an increase of Klotho protein compared to ad libitum fed mice (p<0.0297, n=5) but no increase in the number of Klotho positive cells. Immunocytochemical analysis of the cells upon Klotho knockdown showed a decrease in proliferation, differentiation, gliogenesis while apoptosis is increased. Markers used were BrdU and Ki67 for proliferation, Dcx and MAP2 for differentiation, s100beta (p=0.0363) for glial cells and cleaved Caspase 3 (p=0.0290) for apoptosis. Our data suggest that diet modulates adult hippocampal neurogenesis through Klotho regulation, and underline a central role for Klotho in regulating hippocampal neurogenesis. Data are presented as mean ± SEM. All statistical analyses were performed with GraphPad Prism5 on independent biological replicates (indicated as n=3). One-Way ANOVA with Newman-Keuls post hoc test was used for multiple comparisons among treatment groups. Student’s t-test was used to compare means of two independent treatment groups. P-values <0.05 were considered significant.
Where applicable, experiments conform with Society ethical requirements