measured by open-field, rotorod, or acoustic startle habituation. radiation-induced changes in conditioned taste aversion there is evidence that deficits in conditioned taste aversion (cta) are induced by low doses of heavy ions. the cta test is a classical conditioning paradigm that assesses the avoidance behavior that occurs when the ingestion of a normally acceptable food item is associated with illness. this is considered a standard behavioral test of drug toxicity. ncrp report no. 153 notes that: “the role of the dopaminergic system in radiation-induced changes in cta is suggested by the fact that amphetamine-induced cta, which depends on the dopaminergic system, is affected by radiation, whereas lithium chloride-induced cta, which does not involve the dopaminergic system, is not affected by radiation. it was established that the degree of cta due to radiation is let-dependent () and that 56fe-ions are the most effective of the various low and high let radiation types that have been tested. doses as low as ~0.2 gy of 56fe-ions appear to have an effect on cta.” the rbe of different types of heavy particles on cns function and cognitive/behavioral performance was studied in sprague-dawley rats. the relationship between the thresholds for the hze particle-induced disruption of amphetamine-induced cta learning is shown in figure 6-4; and for the disruption of operant responding is shown in figure 6-5. these figures show a similar pattern of responsiveness to the disruptive effects of exposure to either 56fe or 28si particles on both cta learning and operant responding. these results suggest that the rbe of different particles for neurobehavioral dysfunction cannot be predicted solely on the basis of the let of the specific particle. figure 6-3. ed50 for cta as a function of let for the following radiation sources: 40ar = argon ions, 60co = cobalt-60 gamma rays, e− = electrons, 56fe = iron ions, 4he = helium ions, n0 = neutrons, 20ne = neon ions. figure 6-4. radiation-induced disruption in cta. this figure shows the relationship between exposure to different energies of 56fe and 28si particles and the threshold dose for the disruption of amphetamine-induced cta learning. only a single energy of 48ti particles was tested. the threshold dose (cgy) for the disruption of the response is plotted against particle let (kev/μm). figure 6-5.jpg high-let radiation effects on operant response. this figure shows the relationship between the exposure to different energies of 56fe and 28si particles and the threshold dose for the disruption of performance on a food-reinforced operant response. only a single energy of 48ti particles was tested. the threshold dose (cgy) for the disruption of the response is plotted against particle let (kev/μm). radiation effect on operant conditioning operant conditioning uses several consequences to modify a voluntary behavior. recent studies by rabin et al. have examined the ability of rats to perform an operant order to obtain food reinforcement using an ascending fixed ratio (fr) schedule. they found that 56fe-ion doses that are above 2 gy affect the appropriate responses of rats to increasing work requirements. ncrp report no. 153 notes that "the disruption of operant response in rats was tested 5 and 8 months after exposure, but maintaining the rats on a diet containing strawberry, but not blueberry, extract were shown to prevent the disruption. when tested 13 and 18 months after irradiation, there were no differences in performance between the irradiated rats maintained on control, strawberry or blueberry diets. these observations suggest that the beneficial effects of antioxidant diets may be age dependent." spatial learning and memory the effects of exposure to hze nuclei on spatial learning, memory behavior, and neuronal signaling have been tested, and threshold doses have also been considered for such effects. it will be important to understand the mechanisms that are involved in these deficits to extrapolate the results to other dose regimes, particle types, and, eventually, astronauts. studies on rats were performed using the morris water maze test 1 month after whole-body irradiation with 1.5 gy of 1 gev/u 56fe-ions. irradiated rats demonstrated cognitive impairment that was similar to that seen in aged rats. this leads to the possibility that an increase in the amount of ros may be responsible for the induction of both radiation- and age-related cognitive deficits. ncrp report no. 153 notes that: “denisova et al. exposed rats to 1.5 gy of 1 gev/u56feions and tested their spatial memory in an eight-arm radial maze. radiation exposure impaired the rats’ cognitive behavior, since they committed more errors than control rats in the radial maze and were unable to adopt a spatial strategy to solve the maze. to determine whether these findings related to brain-region specific alterations in sensitivity to oxidative stress, inflammation or neuronal plasticity, three regions of the brain, the striatum, hippocampus and frontal cortex that are linked to behavior, were isolated and compared to controls. those that were irradiated were adversely affected as reflected through the levels of dichlorofluorescein, heat shock, and synaptic proteins (for example, synaptobrevin and synaptophysin). changes in these factors consequently altered cellular signaling (for example, calciumdependent protein kinase c and protein kinase a). these changes in brain responses significantly correlated with working memory errors in the radial maze. the results show differential brain-region-specific sensitivity induced by 56fe irradiation (). these findings are similar to those seen in aged rats, suggesting that increased oxidative stress and inflammation may be responsible for the induction of both radiation and age-related cognitive deficits.” figure 6-6. brain-region-specific calcium-dependent protein kinase c expression was assessed in control and irradiated rats using standard western blotting procedures. values are means ± sem (standard error of mean). acute central nervous system risks in addition to the possible in-flight performance and motor skill changes that were described above, the immediate cns effects (i.e., within 24 hours following exposure to low-let radiation) are anorexia and nausea. these prodromal risks are dose-dependent and, as such, can provide an indicator of the exposure dose. estimates are ed50 = 1.08 gy for anorexia, ed50 = 1.58 gy for nausea, and ed50=2.40 gy for emesis. the relative effectiveness of different radiation types in producing emesis was studied in ferrets and is illustrated in figure 6-7. high-let radiation at doses that are below 0.5 gy show greater relative biological effectiveness compared to low-let radiation. the acute effects on the cns, which are associated with increases in cytokines and chemokines, may lead to disruption in the proliferation of stem cells or memory loss that may contribute to other degenerative diseases. figure 6-7. let dependence of rbe of radiation in producing emesis or retching in a ferret. b = bremsstrahlung; e− = electrons; p = protons; 60co = cobalt gamma rays; n0 = neutrons; and 56fe = iron. computer models and systems biology analysis of central nervous system risks since human epidemiology and experimental data for cns risks from space radiation are limited, mammalian models are essential tools for understanding the uncertainties of human risks. cellular, tissue, and genetic animal models have been used in biological studies on the cns using simulated space radiation. new technologies, such as three-dimensional cell cultures, microarrays, proteomics, and brain imaging, are used in systematic studies on cns risks from different radiation types. according to biological data, mathematical models can be used to estimate the risks from space radiation. systems biology approaches to alzheimer's disease that consider the biochemical pathways that are important in cns disease evolution have been developed by research that was funded outside nasa. figure 6-8 shows a schematic of the biochemical pathways that are important in the development of alzheimer's disease. the description of the interaction of space radiation within these pathways would be one approach to developing predictive models of space radiation risks. for example, if the pathways that were studied in animal models could be correlated with studies in humans who are suffering from alzheimer's disease, an approach to describe risk that uses biochemical degrees-of-freedom could be pursued. edelstein-keshet and spiros have developed an in silico model of senile plaques that are related to alzheimer's disease. in this model, the biochemical interactions among tnf, il-1b, and il-6 are described within several important cell populations, including astrocytes, microglia, and neurons. further, in this model soluble amyloid causes microglial chemotaxis and activates il-1b secretion. figure 6-9 shows the results of the edelstein-keshet and spiros model simulating plaque formation and neuronal death. establishing links between space radiation-induced changes to the changes that are described in this approach can be pursued to develop an in silico model of alzheimer's disease that results from space radiation. figure 6-8.molecular pathways important in alzheimer's disease. from kyoto encyclopedia of genes and genomes. copyrighted image located at http://www.genome.jp/kegg/pathway/hsa/hsa05010.html figure 6-9. model of plaque formation and neuronal death in alzheimer's disease. from edelstein-keshet and spiros, 2002: top row: formation of a plaque and death of neurons in the absence of glial cells, when fibrous amyloid is the only injurious influence. the simulation was run with no astrocytes or microglia, and the health of neurons was determined solely by the local fibrous amyloid. shown above is a time sequence (left to right) of three stages in plaque development, at early, intermediate, and advanced stages. density of fibrous deposit is represented by small dots and neuronal health by shading from white (healthy) to black (dead). note radial symmetry due to simple diffusion. bottom row: effect of microglial removal of amyloid on plaque morphology. note that microglia (small star-like shapes) are seen approaching the plaque (via chemotaxis to soluble amyloid, not shown). at a later stage, they have congregated at the plaque center, where they adhere to fibers. as a result of the removal of soluble and fibrous amyloid, the microglia lead to irregular plaque morphology. size scale: in this figure, the distance between the small single dots (representing low-fiber deposits) is 10 mm. similar results were obtained for a 10-fold scaling in the time scale of neuronal health dynamics. other interesting candidate pathways that may be important in the regulation of radiation-induced degenerative cns changes are signal transduction pathways that are regulated by cdk5. cdk5 is a kinase that plays a key role in neural development; its aberrant expression and activation are associated with neurodegenerative processes, including alzheimer's disease. this kinase is up-regulated in neural cells following ionizing radiation exposure. risks in context of exploration mission operational scenarios projections for space missions reliable projections of cns risks for space missions cannot be made from the available data. animal behavior studies indicate that high-hze radiation has a high rbe, but the data are not consistent. other uncertainties include: age at exposure, radiation quality, and dose-rate effects, as well as issues regarding genetic susceptibility to cns risk from space radiation exposure. more research is required before cns risk can be estimated. potential for biological countermeasures the goal of space radiation research is to estimate and reduce uncertainties in risk projection models and, if necessary, develop countermeasures and technologies to monitor and treat adverse outcomes to human health and performance that are relevant to space radiation for short-term and career exposures, including acute or late cns effects from radiation exposure. the need for the development of countermeasures to cns risks is dependent on further understanding of cns risks, especially issues that are related to a possible dose threshold, and if so, which nasa missions would likely exceed threshold doses. as a result of animal experimental studies, antioxidant and anti-inflammation are expected to be effective countermeasures for cns risks from space radiation. diets of blueberries and strawberries were shown to reduce cns risks after heavy-ion exposure. estimating the effects of diet and nutritional supplementation will be a primary goal of cns research on countermeasures. a diet that is rich in fruit and vegetables significantly reduces the risk of several diseases. retinoids and vitamins a, c, and e are probably the most well-known and studied natural radioprotectors, but hormones (e.g., melatonin), glutathione, superoxide dismutase, and phytochemicals from plant extracts (including green tea and cruciferous vegetables), as well as metals (especially selenium, zinc, and copper salts) are also under study as dietary supplements for individuals, including astronauts, who have been overexposed to radiation. antioxidants should provide reduced or no protection against the initial damage from densely ionizing radiation such as hze nuclei, because the direct effect is more important than the free-radical-mediated indirect radiation damage at high let. however, there is an expectation that some