Travel outside the Earth's protective atmosphere, magnetosphere, and gravitational field can harm human health, and understanding such harm is essential for successful manned spaceflight. Potential<unk>  on the<unk><unk><unk>  (CNS) are particularly important. A vigorous ground-based cellular and animal model research program will help quantify the risk to the CNS from space<unk><unk>  on future long distance space missions and promote the development of optimized countermeasures. Possible acute and late risks to the CNS from galactic cosmic rays (GCRs) and solar proton events (SPEs) are a documented concern for human exploration of the Solar<unk> . In the past, the risks to the CNS of adults who were exposed to low to moderate doses of ionizing<unk>  (0 to 2 Gy (Gray) (Gy = 100 rad)) have not been a major consideration. However, the heavy ion component of space<unk>  presents distinct biophysical challenges to cells and tissues as compared to the physical challenges that are presented by terrestrial forms of<unk> . Soon after the discovery of cosmic rays, the concern for CNS risks originated with the prediction of the light flash phenomenon from single HZE nuclei traversals of the retina; this phenomenon was confirmed by the Apollo astronauts in 1970 and 1973. HZE nuclei are capable of producing a column of heavily damaged cells, or a microlesion, along their path through tissues, thereby raising concern over serious impacts on the CNS. In recent years, other concerns have arisen with the discovery of neurogenesis and its impact by HZE nuclei, which have been observed in experimental models of the CNS. Human epidemiology is used as a basis for risk estimation for cancer, acute<unk>  risks, and cataracts. This approach is not viable for estimating CNS risks from space<unk> , however. At doses above a few Gy, detrimental CNS changes occur in humans who are treated with<unk>  (e.g., gamma rays and protons) for cancer. Treatment doses of 50 Gy are typical, which is well above the<unk> s in space even if a large SPE were to occur. Thus, of the four categories of space<unk>  risks (cancer, CNS, degenerative, and acute<unk>  syndromes), the CNS risk relies most extensively on experimental data with animals for its evidence base. Understanding and mitigating CNS risks requires a vigorous research program that will draw on the basic understanding that is gained from cellular and animal models, and on the development of approaches to extrapolate risks and the potential benefits of countermeasures for astronauts. Several experimental studies, which use heavy ion beams simulating space<unk> , provide constructive evidence of the CNS risks from space<unk> . First,<unk>  to HZE nuclei at low doses (<50 cGy) significantly induces neurocognitive deficits, such as learning and behavioral changes as well as operant reactions in the mouse and rat.<unk> s to equal or higher doses of low-LET<unk>  (e.g., gamma or X rays) do not show similar<unk> . The threshold of performance deficit following<unk>  to HZE nuclei depends on both the physical characteristics of the particles, such as linear energy transfer (LET), and the animal age at<unk> . A performance deficit has been shown to occur at doses that are similar to the ones that will occur on a Mars mission (<0.5 Gy). The neurocognitive deficits with the dopaminergic<unk><unk>  are similar to aging and appear to be unique to space<unk> . Second,<unk>  to HZE disrupts neurogenesis in mice at low doses (<1 Gy), showing a significant dose-related reduction of new neurons and oligodendrocytes in the subgranular zone (SGZ) of the hippocampal dentate gyrus. Third, reactive oxygen species (ROS) in neuronal precursor cells arise following<unk>  to HZE nuclei and protons at low dose, and can persist for several months. Antioxidants and anti-inflammatory agents can possibly reduce these changes. Fourth, neuroinflammation arises from the CNS following<unk>  to HZE nuclei and protons. In addition, age-related genetic changes increase the sensitivity of the CNS to<unk> . Research with animal models that are irradiated with HZE nuclei has shown that important changes to the CNS occur with the dose levels that are of concern to NASA. However, the significance of these results on the morbidity to astronauts has not been elucidated. One model of late tissue<unk>  suggests that significant<unk>  will occur at lower doses, but with increased latency. It is to be noted that the studies that have been conducted to date have been carried out with relatively small numbers of animals (<10 per dose group); therefore, testing of dose threshold<unk>  at lower doses (< 0.5 Gy) has not been carried out sufficiently at this time. As the problem of extrapolating space<unk> <unk>  in animals to humans will be a challenge for space<unk>  research, such research could become limited by the population size that is used in animal studies. Furthermore, the role of dose protraction has not been studied to date. An approach to extrapolate existing observations to possible cognitive changes, performance degradation, or late CNS<unk>  in astronauts has not been discovered. New approaches in<unk> s biology offer an exciting tool to tackle this challenge. Recently, eight gaps were identified for projecting CNS risks. Research on new approaches to risk assessment may be needed to provide the necessary data and knowledge to develop risk projection models of the CNS from space<unk> .
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