light flash phenomenon caused by single hze nuclei traversals of the retina. light flashes, such as those described by tobias, were observed by the astronauts during the early apollo missions as well as in dedicated experiments that were subsequently performed on apollo and skylab missions. more recently, studies of light flashes were made on the russian mir space station and the iss. a 1973 report by the nas considered these effects in detail. this phenomenon, which is known as a phosphene, is the visual perception of flickering light. it is considered a subjective sensation of light since it can be caused by simply applying pressure on the eyeball. the traversal of a single, highly charged particle through the occipital cortex or the retina was estimated to be able to cause a light flash. possible mechanisms for hze-induced light flashes include direction ionization and cerenkov radiation within the retina. the observation of light flashes by the astronauts brought attention to the possible effects of hze nuclei on brain function. the microlesion concept, which considered the effects of the column of damaged cells surrounding the path of an hze nucleus traversing critical regions of the brain, originated at this time. an important task that still remains is to determine whether and to what extent such particle traversals contribute to functional degradation within the cns. the possible observation of cns effects in astronauts who were participating in past nasa missions is highly unlikely for several reasons. first, the lengths of past missions are relatively short and the population sizes of astronauts are small. second, when astronauts are traveling in leo, they are partially protected by the magnetic field and the solid body of the earth, which together reduce the gcr dose-rate by about two-thirds from its free space values. furthermore, the gcr in leo has lower let components compared to the gcr that will be encountered in transit to mars or on the lunar surface because the magnetic field of the earth repels nuclei with energies that are below about 1,000 mev/u, which are of higher let. for these reasons, the cns risks are a greater concern for long-duration lunar missions or for a mars mission than for missions on the iss. radiobiology studies of central nervous system risks for protons, neutrons, and high-z high-energy nuclei both gcr and spe could possibly contribute to acute and late cns risks to astronaut health and performance. this section presents a description of the studies that have been performed on the effects of space radiation in cell, tissue, and animal models. neurogenesis the cns consists of neurons, astrocytes, and oligodendrocytes that are generated from multipotent stem cells. ncrp report no. 153 provides the following excellent and short introduction to the composition and cell types of interest for radiation studies of the cns: “the cns consists of neurons differing markedly in size and number per unit area. there are several nuclei or centers that consist of closely packed neuron cell bodies (e.g., the respiratory and cardiac centers in the floor of the fourth ventricle). in the cerebral cortex the large neuron cell bodies, such as betz cells, are separated by a considerable distance. of additional importance are the neuroglia which are the supporting cells and consist of astrocytes, oligodendroglia, and microglia. these cells permeate and support the nervous tissue of the cns, binding it together like a scaffold that also supports the vasculature. the most numerous of the neuroglia are type i astrocytes, which make up about half the brain, greatly outnumbering the neurons. neuroglia retain the capability of cell division in contrast to neurons and, therefore, the responses to radiation differ between the cell types. a third type of tissue in the brain is the vasculature which exhibits a comparable vulnerability for radiation damage to that found elsewhere in the body. radiation-induced damage to oligodendrocytes and endothelial cells of the vasculature accounts for major aspects of the pathogenesis of brain damage that can occur after high doses of low-let radiation.” based on studies with low-let radiation, the cns is considered a radioresistant tissue. for example: in radiotherapy, early brain complications in adults usually do not develop if daily fractions of 2 gy or less are administered with a total dose of up to 50 gy. the tolerance dose in the cns, as with other tissues, depends on the volume and the specific anatomical location in the human brain that is irradiated. in recent years, studies with stem cells uncovered that neurogenesis still occurs in the adult hippocampus, where cognitive actions such as memory and learning are determined. this discovery provides an approach to understand mechanistically the cns risk of space radiation. accumulating data indicate that radiation not only affects differentiated neural cells, but also the proliferation and differentiation of neuronal precursor cells and even adult stem cells. recent evidence points out that neuronal progenitor cells are sensitive to radiation. studies on low-let radiation show that radiation stops not only the generation of neuronal progenitor cells, but also their differentiation into neurons and other neural cells. ncrp report no. 153 notes that cells in the sgz of the dentate gyrus undergo dose-dependent apoptosis above 2 gy of x-ray irradiation, and the production of new neurons in young adult male mice is significantly reduced by relatively low (>2 gy) doses of x rays. ncrp report no. 153 also notes that: “these changes are observed to be dose dependent. in contrast there were no apparent effects on the production of new astrocytes or oligodendrocytes. measurements of activated microglia indicated that changes in neurogenesis were associated with a significant dose-dependent inflammatory response even 2 months after irradiation. this suggests that the pathogenesis of long-recognized radiation-induced cognitive injury may involve loss of neural precursor cells from the sgz of the hippocampal dentate gyrus and alterations in neurogenesis.” recent studies provide evidence of the pathogenesis of hze nuclei in the cns. the authors of one of these studies were the first to suggest neurodegeneration with hze nuclei, as shown in figure 6-1(a). these studies demonstrate that hze radiation led to the progressive loss of neuronal progenitor cells in the sgz at doses of 1 to 3 gy in a dosedependent manner. ncrp report no. 153 notes that “mice were irradiated with 1 to 3 gy of 12c or 56fe-ions and 9 months later proliferating cells and immature neurons in the dentate sgz were quantified. the results showed that reductions in these cells were dependent on the dose and let. loss of precursor cells was also associated with altered neurogenesis and a robust inflammatory response, as shown in figures 6-1(a) and 6-1(b). these results indicate that high-let radiation has a significant and long-lasting effect on the neurogenic population in the hippocampus that involves cell loss and changes in the microenvironment. the work has been confirmed by other studies. these investigators noted that these changes are consistent with those found in aged subjects, indicating that heavy-particle irradiation is a possible model for the study of aging.” figure 6-1(a). (panel a) expression of polysialic acid form of neural cell adhesion molecule (psa-ncam) in the hippocampus of rats that were irradiated (ir) with 2.5 gy of 56fe high-energy radiation and control subjects as measured by % density/field area measured. (panel b) psa-ncam staining in the dentate gyrus of representative irradiated (ir) and control (c) subjects at 5x magnification. figure 6-1(b). numbers of proliferating cells (left panel) and immature neurons (right panel) in the dentate sgz are significantly decreased 48 hours after irradiation. antibodies against ki-67 and doublecortin (dcx) were used to detect proliferating cells and immature neurons, respectively. doses from 2 to 10 gy significantly (p < 0.05) reduced the numbers of proliferating cells. immature neurons were also reduced in a dose-dependent fashion (p<0.001). each bar represents an average of four animals; error bars, and standard error. oxidative damage recent studies indicate that adult rat neural precursor cells from the hippocampus show an acute, dose-dependent apoptotic response that was accompanied by an increase in ros. low-let protons are also used in clinical proton beam radiation therapy, at an rbe of 1.1 relative to megavoltage x rays at a high dose. ncrp report no. 153 notes that: “relative ros levels were increased at nearly all doses (1 to 10 gy) of bragg-peak 250 mev protons at post-irradiation times (6 to 24 hours) compared to unirradiated controls. the increase in ros after proton irradiation was more rapid than that observed with x rays and showed a well-defined dose response at 6 and 24 hours, increasing about 10-fold over controls at a rate of 3% per gy. however, by 48 hours post-irradiation, ros levels fell below controls and coincided with minor reductions in mitochondrial content. use of the antioxidant alpha-lipoic acid (before or after irradiation) was shown to eliminate the radiation-induced rise in ros levels. these results corroborate the earlier studies using x rays and provide further evidence that elevated ros are integral to the radioresponse of neural precursor cells.” furthermore, high-let radiation led to significantly higher levels of oxidative stress in hippocampal precursor cells as compared to lower-let radiations (x rays, protons) at lower doses (≤1 gy) (figure 6-2). the use of the antioxidant lipoic acid was able to reduce ros levels below background levels when added before or after 56fe-ion irradiation. these results conclusively show that low doses of 56fe-ions can elicit significant levels of oxidative stress in neural precursor cells at a low dose. figure 6-2. dose response for oxidative stress after 56fe-ion irradiation. hippocampal precursors that are subjected to 56fe-ion irradiation were analyzed for oxidative stress 6 hours after exposure. at doses ≤1 gy a linear dose response for the induction of oxidative stress was observed. at higher 56fe doses, oxidative stress fell to values that were found using lower-let irradiations (x rays, protons). experiments, which represent a minimum of three independent measurements (±se), were normalized against unirradiated controls set to unity. ros levels induced after 56fe irradiation were significantly (p < 0.05) higher than controls. neuroinflammation neuroinflammation, which is a fundamental reaction to brain injury, is characterized by the activation of resident microglia and astrocytes and local expression of a wide range of inflammatory mediators. acute and chronic neuroinflammation has been studied in the mouse brain following exposure to hze. the acute effect of hze is detectable at 6 and 9 gy; no studies are available at lower doses. myeloid cell recruitment appears by 6 months following exposure. the estimated rbe value of hze irradiation for induction of an acute neuroinflammatory response is three compared to that of gamma irradiation. cox-2 pathways are implicated in neuroinflammatory processes that are caused by low-let radiation. cox-2 up-regulation in irradiated microglia cells leads to prostaglandin e2 production, which appears to be responsible for radiation-induced gliosis (overproliferation of astrocytes in damaged areas of the cns). behavioral effects as behavioral effects are difficult to quantitate, they consequently are one of the most uncertain of the space radiation risks. ncrp report no. 153 notes that: “the behavioral neurosciences literature is replete with examples of major differences in behavioral outcome depending on the animal species, strain, or measurement method used. for example, compared to unirradiated controls, x-irradiated mice show hippocampal-dependent spatial learning and memory impairments in the barnes maze, but not in the morris water maze which, however, can be used to demonstrate deficits in rats. particle radiation studies of behavior have been accomplished with rats and mice, but with some differences in the outcome depending on the endpoint measured.” the following studies provide evidence that space radiation affects the cns behavior of animals in a somewhat dose- and let-dependent manner. sensorimotor effects sensorimotor deficits and neurochemical changes were observed in rats that were exposed to low doses of 56fe-ions. doses that are below 1 gy reduce performance, as tested by the wire suspension test. behavioral changes were observed as early as 3 days after radiation exposure and lasted up to 8 months. biochemical studies showed that the k+-evoked release of dopamine was significantly reduced in the irradiated group, together with an alteration of the nerve signaling pathways. a negative result was reported by pecaut et al., in which no behavioral effects were seen in female c57/bl6 mice in a 2- to 8-week period following their exposure to 0, 0.1, 0.5 or 2 gy accelerated 56fe-ions (1 gev/u56fe) as