22nd Annual NASA Space Radiation Investigators' Workshop (2011)
7051.pdf
Effect of 56Fe Particle Irradiation on Adult Hippocampal Neurogenesis In Vivo
1
B.P. Chen1, E. Shih1, M. G. Cole2, J. L. LeBlanc2, S. Zhang1, P. D. Rivera2, A. J. Eisch2
Department of Radiation Oncology, 2Department of Psychiatry, University of Texas Southwestern Medical Center
at Dallas, Dallas, Texas 75390
The high-LET HZE particles from galactic cosmic radiation pose tremendous health risks to astronauts including
risks to the central nervous system (CNS) and potential cognitive impairment. One CNS cell population that
warrants close analysis for their response to radiation is adult neural stem cells, as these pluripotent cells may play a
key role in cellular and cognitive recovery after brain injury. The long-term goal of this project is to provide a
comprehensive analysis of the impact of low- and high-LET irradiation on adult neural stem cells at hippocampal
subgranular zone (SGZ). Our studies rely on two transgenic mouse models, nestin-GFP and nestinCreERT2/R26RYFP mice, to label and track adult neural stem cells respectively. In this study, nestin-GFP and nestinCreERT2/R26R-YFP mice were subjected to 1 Gy Fe whole body irradiation under fractioned and non-fractioned
condition (300 MeV, 0.2Gyx5days vs 1Gy). The brains of sham and irradiated mice were harvested 24 hours and 3
months later with BrdU injection (150 mg/kg) given 2 hours prior to sacrifice to allow examination of rapidly
dividing progenitors in the SGZ. We find that Fe particle irradiation causes long-term changes in overall adult
hippocampal neurogenesis: The number of SGZ proliferating (BrdU+) cells was significantly decreased at 24 hours
and 3 months in both mouse models, and the number of immature neuron (DCX+) and total YFP+ cells were
significantly decreased at both time in nestin-CreERT2/R26R-YFP mice. However, Fe particle irradiation did not
cause a significant change in the number of Type-1 stem cells. This suggests that the slow-proliferating Type-1 cells
are more resilient than the fast-proliferating progenitor cells. Interestingly, while non-fractioned and fractionated Fe
irradiation generally produced similar changes in adult hippocampal neurogenesis, we also find evidence that these
irradiation paradigms differ importantly with time (e.g. fractionated leads to greater loss of immature neurons at 24
hrs, but non-fractionated leads to a greater loss of immature neurons at 3 months). Additionally, we analyzed the
recovery of adult neural stem cells in nestin-CreERT2/R26R-YFP mice after previous exposure to Fe particle (300
MeV, 0.1Gy or 0.5Gy). Tamoxifen injection was given to all mice at 7 days post-irradiation to track adult neural
stem cells and their progeny. At 30 days post-Tamoxifen, mice were given BrdU and brains were harvested 2 hours
later. We find that the number of BrdU+ proliferating cells and DCX+ immature neurons decreases significantly in
0.5Gy group but not in 0.1Gy group. However, analyses of the number of total YFP+ cells and the Type-1 stem cells
revealed no difference between sham and irradiated mice. Taken together, these data show that Fe particle
irradiation above 0.5Gy is sufficient to cause a long-term impairment in adult hippocampal neurogenesis.
Importantly, these changes in neurogenesis do not appear to result from influencing the number of nestin-expressing
Type-1 neural stem cells, but rather by influencing the ability of these neural stem cells to generate progeny and
proliferate, and likely the influence of their progeny to differentiate.