Effects of Proton and Combined Proton and 56Fe Radiation on the Hippocampus

Abstract

The space radiation environment contains protons and (56)Fe, which could pose a significant hazard to space flight crews during and after missions. The space environment involves complex radiation exposures, thus, the effects of a dose of protons might be modulated by a dose of heavy-ion radiation. The brain, and particularly the hippocampus, may be susceptible to space radiation-induced changes. In this study, we first determined the dose-response effect of proton radiation (150 MeV) on hippocampus-dependent cognition 1 and 3 months after exposure. Based on those results, we subsequently exposed mice to protons alone (150 MeV, 0.1 Gy), (56)Fe alone (600 MeV/n, 0.5 Gy) or combined proton and (56)Fe radiations (protons first) with the two exposures separated by 24 h. At one month postirradiation, all animal groups showed novel object recognition. However, at three months postirradiation, mice exposed to either protons or combined proton and (56)Fe radiations showed impaired novel object recognition, which was not observed in mice irradiated with (56)Fe alone. The mechanisms in these impairments might involve inflammation. In mice irradiated with protons alone or (56)Fe alone three months earlier, there was a negative correlation between a measure of novel object recognition and the number of newly born activated microglia in the dentate gyrus. Next, cytokine and chemokine levels were assessed in the hippocampus. At one month after exposure the levels of IL-12 were higher in mice exposed to combined radiations compared with sham-irradiated mice, while the levels of IFN-γ were lower in mice exposed to (56)Fe radiation alone or combined radiations. In addition, IL-4 levels were lower in (56)Fe-irradiated mice compared with proton-irradiated mice and TNF-α levels were lower in proton-irradiated mice than in mice receiving combined radiations. At three months after exposure, macrophage-derived chemokine (MDC) and eotaxin levels were lower in mice receiving combined radiations. The levels of MDC and eotaxin correlated and the levels of MDC, but not eotaxin, correlated with the percentage of newly born activated microglia in the blades of the dentate gyrus. Finally, hippocampal IL-6 levels were higher in mice receiving combined radiations compared with mice receiving (56)Fe radiation alone. These data demonstrate the sensitivity of novel object recognition for detecting cognitive injury three months after exposure to proton radiation alone, and combined exposure to proton and (56)Fe radiations, and that newly-born activated microglia and inflammation might be involved in this injury.

Whole-Body Exposure to28Si-Radiation Dose-Dependently Disrupts Dentate Gyrus Neurogenesis and Proliferation in the Short Term and New Neuron Survival and Contextual Fear Conditioning in the Long Term

“…Only a few studies have examined CFC in young adult mice after HZE-particle exposure, and it is challenging to compare these to our work. For example, young adult mice exposed to protons (150 MeV) have shown increased freezing at low dose (0.1 Gy) with no change at higher doses (0.5, 1 Gy) at 1 month postirradiation, and no change in any group at 3 months postirradiation (27). However, cued FC was not reported as being assessed, so it remains possible that increased freezing at 0.1 Gy proton irradiation was due to anxiety, not improved memory.…”

“…Another way to answer this question is to widen the comparison to all studies investigating HZE-induced behavioral changes in young adult mice after exposure to mission-relevant doses (<1 Gy and ideally <0.2 Gy). From this perspective, there is increasing evidence that lower doses of 56 Fe (as low as 0.2 Gy), 28 Si (0.005 Gy), 16 O (0.01 Gy), 12 C (0.05 Gy), protons (0.1 Gy) or combined exposure (e.g., protons and 56 Fe) impede hippocampal, striatal and executive function in young adult rats and mice (9, 27, 91–100) in an energy-dependent manner. Although there is a relative paucity of behavioral studies using 28 Si radiation, our data show that exposure to 0.2 Gy 28 Si radiation induces deficits in hippocampal function even at 3 months postirradiation.…”

“…As for CNS function, there is an ion-specific effect on the hippocampal-based learning task, contextual fear conditioning (CFC), where mice learn that a context is associated with a foot shock (25). For example, it has been reported that 2-month-old C57BL/6J mice exposed to 56 Fe (0.1–0.5 Gy) freeze as much as nonirradiated mice in a shock-associated context (26, 27). 56 Fe-exposed mice also freeze similarly to nonirradiated mice in a companion test to CFC, cued fear conditioning (FC), which is both hippocampal-and amygdalar-dependent and whose results can reflect anxiety-like behaviors (26).…”

Densely ionizing radiation affects DNA methylation of selective LINE-1 elements

“…Sham irradiated mice served as controls and were placed into the same enclosures and for the same amount of time, since previous studies reported no effect of sham irradiation on molecular end-points (Miousse et al, 2014). One week after irradiation, the mice were shipped to Oregon Health and Science University (OHSU) where they underwent behavioral testing reported elsewhere (Raber et al, 2015). Food (PicoLab Rodent Diet 20, no.…”

The impact of high and low dose ionising radiation on the central nervous system

“…It is now recognised that sufficient doses of ionising radiation can induce microglial activation and pro-inflammatory derived factors which can propagate radiation-induced brain injury [90], [91]. Correspondingly, radiation-induced neuroinflammation can inhibit adult neurogenesis in the hippocampus [92], [93], [94], [95], with longer term cognitive deficits in patients persisting from months to decades after initial exposure [96]. Interestingly, the finding of reversible inhibition of the proliferative capacity of progenitor cells in the dentate gyrus 1 week after 4 Gy X-radiation exposure, with an absence of microglial activation [97], suggests there is a requirement of neuroinflammatory processes to cause persistent and deleterious effects to cells [98].…”