Responses of the central nervous system to high linear energy transfer radiation: NSCOR project highlights

• Published in: Journal of radiation research 2014-03, Vol.55 (suppl_1), p.i22-i23
• Main Authors: Nelson, Gregory, Fike, John, Limoli, Charles, Obenaus, André, Raber, Jacob, Soltesz, Ivan, Vlkolinský, Roman
• Format: Article
• Language: English
• Subjects: Analysis; Catalase; Central nervous system; Communications protocols; Exposure; Firing; Gene expression; Genetic engineering; Hippocampus; House mouse; Mathematical models; Networks; Neurons; Protons; Radiation (Physics); Stem cells; Three dimensional
• ISSN: 0449-3060; 1349-9157
• DOI: 10.1093/jrr/rrt214

Overview: The five-university NSCOR project investigates the responses of the central nervous system to space-like charged particle exposure by evaluating: synaptic function, in vitro and in vivo neurogenesis, behavior and behaviorally induced gene expression, and oxidative stress of the mouse hippocampus and cultured neural precursor cells. To test the role of reactive oxygen species in mediating the effects of radiation exposure, we compare responses in a catalase overexpressing transgenic mouse strain to wild type. We also use computational models of the hippocampus in three dimensions, informed by experimental measurements, to provide insight into network behavior. Radiation exposure protocols include single, acute whole-body exposures to 1H, 28Si and 56Fe ions and mixed field exposures using 1H + 56Fe ions (24 h later). The animal models are 10-week-old C57BL/6J and MCATtg males which are evaluated at 30 and 90 days postirradiation. In vitro models are cultured murine and human neural stem cells irradiated with 1H, 16O, 28Si and 56Fe ions at multiple energies and are evaluated at times from days to weeks. Highlights: Neural stem cells organized into neurospheres were irradiated with several ions at doses as low as 0.75 cGy. Data show that significant oxidative stress occurs that alters survival, proliferation and differentiation. Overall trends indicate that changes in oxidative stress (persisting for weeks) correlate with particle linear energy transfer (LET). 56Fe ions elicited the largest and most persistent changes in stress markers, including antioxidant enzyme expression levels. The hippocampus-dependent contextual fear conditioning (CFC) and novel object recognition (NOR) paradigms were used to assess cognition and showed cognitive deficits after irradiation with the NOR paradigm more sensitive than CFC. Analysis of neurogenesis indicates that overall neurogenesis is inhibited at doses ≥1 Gy, but newly born activated microglia are significantly elevated at ≥0.1 Gy. High LET radiation affects all lineages of neural precursor cells and elicits a U-shaped dose-response for cells exhibiting the astrocyte marker GFAP. In a mixed field irradiation regimen (0.1 Gy 1H, then 0.5 Gy 56Fe 24 h later), NOR was impaired with 0.1 Gy 1H or 0.1 Gy 1H + 0.5 Gy 56Fe but not with 0.5 Gy 56Fe alone. A negative correlation between newly born activated microglia and NOR or behaviorally activated Arc gene expression was observed for exposures using protons and iron i