DEFINITION PHASE ONLY. EVIDENCE HAS ACCUMULATED FROM ANIMAL STUDIES THAT THE CENTRAL NERVOUS SYSTEM UNDERGOES DELETERIOUS CHANGES AFTER EXPOSURE TO CHARGED PARTICLE RADIATION SUCH AS PROTONS AND HIGH ATOMIC NUMBER ATOMIC NUCLEI THAT ARE FOUND IN SPACE AS GALACTIC COSMIC RAYS AND SOLAR PARTICLE EVENTS. OBSERVED CHANGES INCLUDE INFLAMMATION OXIDATIVE STRESS LOSS OF NEURON (DENDRITE) BRANCHES AND CONNECTIONS (SYNAPSES) ALTERED SIGNALING MOLECULES ALTERED ELECTRICAL PROPERTIES LOSS OF BLOOD VESSELS AND IMPAIRED BEHAVIORAL PERFORMANCE. IF HUMANS RESPOND TO CHARGED PARTICLES IN THE SAME WAY AS ANIMALS THEN IT IS POSSIBLE THAT DELETERIOUS CHANGES MAY BE SUFFICIENT TO CAUSE COGNITIVE AND OTHER BEHAVIORAL IMPAIRMENTS THAT COULD COMPROMISE SPACEFLIGHT MISSIONS AND ASTRONAUT HEALTH. THE CURRENT EVIDENCE IS BASED PRIMARILY ON SHORT EXPOSURES TO SINGLE RADIATION TYPES. HOWEVER SPACE RADIATION IS A COMPLEX MIXTURE OF THESE PARTICLES AND EXPOSURES ACCUMULATE GRADUALLY OVER THE COURSE OF MISSIONS. IT IS WELL ESTABLISHED IN RADIATION BIOLOGY THAT REDUCTION OF THE DOSE RATE CAN HAVE A PROFOUND EFFECT ON THE OUTCOME. THEREFORE TO BETTER SIMULATE THE SPACE ENVIRONMENT WE PROPOSE TO EXPOSE ADULT MICE TO EITHER 0.5 GY PROTONS OR 0.25 AND 0.5 GY MIXTURES OF HELIUM OXYGEN AND SILICON PARTICLES IN 2:1:1 RATIOS AS THEY ARE FOUND IN SPACE. THEN WE WILL DELIVER THE EXPOSURES OVER LONG TIME PERIODS (UP TO 6 WEEKS) IN MULTIPLE SHORT EXPOSURES (FRACTIONS) COMPATIBLE WITH PARTICLE ACCELERATOR OPERATIONS. THESE RESULTS WOULD BE COMPARED TO RESULTS FROM ACUTE EXPOSURES TO ESTABLISH THE DOSE RATE EFFECTIVENESS FACTORS (DREFS) WHICH ARE NEEDED FOR RISK ESTIMATION FOR ASTRONAUT HEALTH. WE PREDICT THAT THE HIGH NUMBERS (FLUENCE) OF PROTONS WILL RESULT IN MULTIPLE TRAVERSALS OF CELLS WITHIN SHORT TIMES THAT MAY ELICIT INTERACTING BIOLOGICAL RESPONSES WHEREAS THE LOWER FLUENCE OF HIGHER CHARGED IONS WILL RESULT IN RARE INDEPENDENT EVENTS. DREFS>1 ARE PREDICTED FOR PROTONS AND DREFS ~1 ARE PREDICTED FOR HIGH Z PARTICLES. WE WILL ALSO COMPARE THE "PROTRACTED" EXPOSURES OF CHARGED PARTICLE MIXTURES TO GAMMA RAYS TO DETERMINE WHETHER THEY HAVE EQUIVALENT DOSE EFFECTS OR ARE MORE EFFECTIVE. THE RELATIVE BIOLOGICAL EFFECTIVENESS FACTOR (RBES) WILL BE DERIVED. THESE RBES ARE UTILIZED IN PREDICTING DENSELY IONIZING RADIATION EFFECTS IN HUMANS FOR WHOM ONLY GAMMA RAY AND X-RAY DATA ARE AVAILABLE WITH THE ASSUMPTION THAT THE RATIOS OBTAINED IN ANIMAL MODELS ARE REALISTIC SURROGATES FOR HUMANS. WE WILL TEST BOTH MALE AND FEMALE ANIMALS AS THEIR RESPONSES ARE NOT IDENTICAL AND THE ASTRONAUT POPULATION IS OF MIXED GENDER. FOR EACH OF THE EXPOSURE REGIMENS WE WILL CONDUCT A BATTERY OF BEHAVIOR TESTS MEASURE ELECTROPHYSIOLOGICAL PROPERTIES IN TISSUE SLICES AND QUANTIFY CHANGES IN THE STRUCTURE AND COMPOSITION OF THE TISSUE USING STATE OF THE ART BIOCHEMICAL HISTOCHEMICAL AND MICROSCOPY METHODS. THIS WILL ALLOW US TO IDENTIFY THE UNDERLYING PHYSIOLOGICAL CHANGES MOST SENSITIVE TO DOSE RATE AND RADIATION QUALITY AND HOW THEY COMBINE TO PRODUCE BEHAVIORS THAT ARE ADAPTIVE OR MALADAPTIVE. TOGETHER THE DATA GENERATED BY THE PROJECT WILL ENHANCE NASAS ABILITY TO TRANSLATE ANIMAL ASSESSMENTS OF CNS STRUCTURE AND FUNCTION TO HUMANS AND TO UPDATE RISK ESTIMATES BASED ON SINGLE RADIATION SPECIES HIGH DOSE RATE IRRADIATION PROTOCOLS TO HIGHER FIDELITY SPACE-LIKE EXPOSURES OF CHARGED PARTICLE MIXTURES DELIVERED AT DOSE RATES APPROACHING THOSE OBSERVED IN SPACE.