Multi-domain cognitive assessment of male mice shows space radiation is not harmful to high-level cognition and actually improves pattern separation.

Astronauts on interplanetary missions - such as to Mars - will be exposed to space radiation, a spectrum of highly-charged, fast-moving particles that includes 56Fe and 28Si. Earth-based preclinical studies show space radiation decreases rodent performance in low- and some high-level cognitive tasks. Given astronaut use of touchscreen platforms during training and space flight and given the ability of rodent touchscreen tasks to assess functional integrity of brain circuits and multiple cognitive domains in a non-aversive way, here we exposed 6-month-old C57BL/6J male mice to whole-body space radiation and subsequently assessed them on a touchscreen battery. Relative to Sham treatment, 56Fe irradiation did not overtly change performance on tasks of visual discrimination, reversal learning, rule-based, or object-spatial paired associates learning, suggesting preserved functional integrity of supporting brain circuits. Surprisingly, 56Fe irradiation improved performance on a dentate gyrus-reliant pattern separation task; irradiated mice learned faster and were more accurate than controls. Improved pattern separation performance did not appear to be touchscreen-, radiation particle-, or neurogenesis-dependent, as 56Fe and 28Si irradiation led to faster context discrimination in a non-touchscreen task and 56Fe decreased new dentate gyrus neurons relative to Sham. These data urge revisitation of the broadly-held view that space radiation is detrimental to cognition.

Whole-Body 12C Irradiation Transiently Decreases Mouse Hippocampal Dentate Gyrus Proliferation and Immature Neuron Number, but Does Not Change New Neuron Survival Rate.

High-charge and -energy (HZE) particles comprise space radiation and they pose a challenge to astronauts on deep space missions. While exposure to most HZE particles decreases neurogenesis in the hippocampus-a brain structure important in memory-prior work suggests that 12C does not. However, much about 12C's influence on neurogenesis remains unknown, including the time course of its impact on neurogenesis. To address this knowledge gap, male mice (9⁻11 weeks of age) were exposed to whole-body 12C irradiation 100 cGy (IRR; 1000 MeV/n; 8 kEV/µm) or Sham treatment. To birthdate dividing cells, mice received BrdU i.p. 22 h post-irradiation and brains were harvested 2 h (Short-Term) or three months (Long-Term) later for stereological analysis indices of dentate gyrus neurogenesis. For the Short-Term time point, IRR mice had fewer Ki67, BrdU, and doublecortin (DCX) immunoreactive (+) cells versus Sham mice, indicating decreased proliferation (Ki67, BrdU) and immature neurons (DCX). For the Long-Term time point, IRR and Sham mice had similar Ki67+ and DCX+ cell numbers, suggesting restoration of proliferation and immature neurons 3 months post-12C irradiation. IRR mice had fewer surviving BrdU+ cells versus Sham mice, suggesting decreased cell survival, but there was no difference in BrdU+ cell survival rate when compared within treatment and across time point. These data underscore the ability of neurogenesis in the mouse brain to recover from the detrimental effect of 12C exposure.

Whole-Body Exposure to 28Si-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.

Astronauts traveling to Mars will be exposed to chronic low doses of galactic cosmic space radiation, which contains highly charged, high-energy (HZE) particles. 56Fe-HZE-particle exposure decreases hippocampal dentate gyrus (DG) neurogenesis and disrupts hippocampal function in young adult rodents, raising the possibility of impaired astronaut cognition and risk of mission failure. However, far less is known about how exposure to other HZE particles, such as 28Si, influences hippocampal neurogenesis and function. To compare the influence of 28Si exposure on indices of neurogenesis and hippocampal function with previous studies on 56Fe exposure, 9-week-old C57BL/6J and Nestin-GFP mice (NGFP; made and maintained for 10 or more generations on a C57BL/6J background) received whole-body 28Si-particle-radiation exposure (0, 0.2 and 1 Gy, 300 MeV/n, LET 67 KeV/µ, dose rate 1 Gy/min). For neurogenesis assessment, the NGFP mice were injected with the mitotic marker BrdU at 22 h postirradiation and brains were examined for indices of hippocampal proliferation and neurogenesis, including Ki67+, BrdU+, BrdU+NeuN+ and DCX+ cell numbers at short- and long-term time points (24 h and 3 months postirradiation, respectively). In the short-term group, stereology revealed fewer Ki67+, BrdU+ and DCX+ cells in 1-Gy-irradiated group relative to nonirradiated control mice, fewer Ki67+ and DCX+ cells in 0.2 Gy group relative to control group and fewer BrdU+ and DCX+ cells in 1 Gy group relative to 0.2 Gy group. In contrast to the clearly observed radiation-induced, dose-dependent reductions in the short-term group across all markers, only a few neurogenesis indices were changed in the long-term irradiated groups. Notably, there were fewer surviving BrdU+ cells in the 1 Gy group relative to 0- and 0.2-Gy-irradiated mice in the long-term group. When the short- and long-term groups were analyzed by sex, exposure to radiation had a similar effect on neurogenesis indices in male and female mice, although only male mice showed fewer surviving BrdU+ cells in the long-term group. Fluorescent immunolabeling and confocal phenotypic analysis revealed that most surviving BrdU+ cells in the long-term group expressed the neuronal marker NeuN, definitively confirming that exposure to 1 Gy 28Si radiation decreased the number of surviving adult-generated neurons in male mice relative to both 0- and 0.2-Gy-irradiated mice. For hippocampal function assessment, 9-week-old male C57BL/6J mice received whole-body 28Si-particle exposure and were then assessed long-term for performance on contextual and cued fear conditioning. In the context test the animals that received 0.2 Gy froze less relative to control animals, suggesting decreased hippocampal-dependent function. However, in the cued fear conditioning test, animals that received 1 Gy froze more during the pretone portion of the test, relative to controls and 0.2-Gy-irradiated mice, suggesting enhanced anxiety. Compared to previously reported studies, these data suggest that 28Si-radiation exposure damages neurogenesis, but to a lesser extent than 56Fe radiation and that low-dose 28Si exposure induces abnormalities in hippocampal function, disrupting fear memory but also inducing anxiety-like behavior. Furthermore, exposure to 28Si radiation decreased new neuron survival in long-term male groups but not females suggests that sex may be an important factor when performing brain health risk assessment for astronauts traveling in space.

Acute and fractionated exposure to high-LET (56)Fe HZE-particle radiation both result in similar long-term deficits in adult hippocampal neurogenesis.

Astronauts on multi-year interplanetary missions will be exposed to a low, chronic dose of high-energy, high-charge particles. Studies in rodents show acute, nonfractionated exposure to these particles causes brain changes such as fewer adult-generated hippocampal neurons and stem cells that may be detrimental to cognition and mood regulation and thus compromise mission success. However, the influence of a low, chronic dose of these particles on neurogenesis and stem cells is unknown. To examine the influence of galactic cosmic radiation on neurogenesis, adult-generated stem and progenitor cells in Nestin-CreER(T2)/R26R-YFP transgenic mice were inducibly labeled to allow fate tracking. Mice were then sham exposed or given one acute 100 cGy (56)Fe-particle exposure or five fractionated 20 cGy (56)Fe-particle exposures. Adult-generated hippocampal neurons and stem cells were quantified 24 h or 3 months later. Both acute and fractionated exposure decreased the amount of proliferating cells and immature neurons relative to sham exposure. Unexpectedly, neither acute nor fractionated exposure decreased the number of adult neural stem cells relative to sham expsoure. Our findings show that single and fractionated exposures of (56)Fe-particle irradiation are similarly detrimental to adult-generated neurons. Implications for future missions and ground-based studies in space radiation are discussed.

Running reduces stress and enhances cell genesis in aged mice.

Cell proliferation and neurogenesis are diminished in the aging mouse dentate gyrus. However, it is not known whether isolated or social living affects cell genesis and stress levels in old animals. To address this question, aged (17-18 months old) female C57Bl/6 mice were single or group housed, under sedentary or running conditions. We demonstrate that both individual and socially housed aged C57Bl/6 mice have comparable basal cell proliferation levels and demonstrate increased running-induced cell genesis. To assess stress levels in young and aged mice, corticosterone (CORT) was measured at the onset of the active/dark cycle and 4h later. In young mice, no differences in CORT levels were observed as a result of physical activity or housing conditions. However, a significant increase in stress in socially housed, aged sedentary animals was observed at the onset of the dark cycle; CORT returned to basal levels 4h later. Together, these results indicate that voluntary exercise reduces stress in group housed aged animals and enhances hippocampal cell proliferation.

Plant-derived flavanol (-)epicatechin enhances angiogenesis and retention of spatial memory in mice.

Diet and exercise have a profound impact on brain function. In particular, natural nutrients found in plants may influence neuronal survival and plasticity. Here, we tested whether consumption of a plant-derived flavanol, (-)epicatechin, enhances cognition in sedentary or wheel-running female C57BL/6 mice. Retention of spatial memory in the water maze was enhanced by ingestion of (-)epicatechin, especially in combination with exercise. Improved spatial memory was associated with increased angiogenesis and neuronal spine density, but not newborn cell survival, in the dentate gyrus of the hippocampus. Moreover, microarray analysis showed upregulation of genes associated with learning and downregulation of markers of neurodegeneration in the hippocampus. Together, our data show that ingestion of a single flavanol improves spatial memory retention in adult mammals.