Studies on radiation induced impairment of hippocampal neurogenesis

• Applicant: Dr. Annegret Glasow
• Subject Area: Developmental Neurobiology ; Nuclear Medicine, Radiotherapy, Radiobiology
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 251521705

The most severe late effect of whole brain irradiation in childhood is a long-term decline in neurocognition. The hippocampal neurogenesis is probably the most important basis for neurocognitive abilities. Single time exposure to high radiation doses inhibits hippocampal neurogenesis irreversibly, whereas after exposure to moderate doses regeneration takes place. Until now it has been failed to investigate the effects of fractionation of higher radiation doses on hippocampal neurogenesis, although in clinical routine fractionated radiotherapy regimens possess outstanding importance. The canonical WNT signaling pathway controls many processes in embryonic development and all steps of postnatal neurogenesis. It has been shown, that by its pharmacological activation the radioresistance of extra-cerebral stem cells, e.g. in the parotid gland, can be increased. Modulation of the canonical WNT signaling may therefore be an innovative approach to develop neuro-protective drugs. First of all we will investigate the cell type-specific (neural progenitor cells, mature neurons, microglia, astrocytes) dose-effect relationships with respect to proliferation, cell survival and DNA repair capacity in irradiated tissue slices of a murine hippocampus.In a second step we will examine the regenerative capacity of hippocampal neurogenesis in more detail. For this purpose the pool of neural progenitor cells in irradiated hippocampal tissue sections of transgenic nestin-GFP mice will be observed using live imaging microscopy.Our primary goal is to increase the radioresistance of neural progenitor cells.For this, the influence of different fractionation schemes will be studied. Furthermore, we will test the neurogenesis-protective potential of different drugs, e.g. lithium, an activator of the canonical WNT signaling pathway.

• DFG Programme: Research Grants