BACKGROUND: GALACTIC COSMIC RADIATION (GCR) IS AN UNAVOIDABLE FACTOR IN DEEP SPACE THAT MAY AFFECT ASTRONAUT HEALTH AND MISSION SUCCESS. TO DATE GROUND-BASED STUDIES ON THE COGNITIVE IMPACT OF GCR HAVE EXPOSED RODENTS TO A SINGLE HIGH-ENERGY PARTICLE OR A COMBINATION OF A FEW PARTICLES. IT IS UNKNOWN HOW A COMPLEX MULTIPLE-ION GCR SPECTRUM - AS WILL BE ENCOUNTERED DURING A MARS MISSION - INFLUENCES RODENT COGNITION. IT IS ALSO IMPORTANT TO IDENTIFY COUNTERMEASURES THAT CAN REDUCE RISK TO CREW HEALTH OR PERFORMANCE. PRECLINICAL AND CLINICAL STUDIES SUGGEST THE ANTI-INFLAMMATORY COMPOUND CDDO-EA MEDIATES ITS THERAPEUTIC EFFECTS IN COMBATING LUNG DISEASE BY UPREGULATING THE KEY ANTIOXIDANT TRANSCRIPTION FACTOR NRF2. NOTABLY IN MOUSE MODELS OF NEUROLOGICAL DISORDERS CDDO-EA AMELIORATES STRIATAL- AND HIPPOCAMPAL-DEPENDENT COGNITIVE AND CELLULAR DEFICITS. THUS IT IS TIMELY AND URGENT TO ASSESS IF A COMPLEX GCR SPECTRUM DECREASES RODENT COGNITION AND IF CDDO-EA MITIGATES SUCH CHANGES. HYPOTHESIS: EXPOSURE TO A COMPLEX GCR MIXTURE WILL DECREASE TRANSLATIONALLY RELEVANT COGNITIVE FUNCTION AND NEGATIVELY-IMPACT ASSOCIATED CELLULAR AND MOLECULAR PROCESSES IN FEMALE AND MALE MICE AND CDDO-EA WILL MITIGATE THESE CHANGES. AIM 1. WE WILL DETERMINE THE EFFECTS OF (1A) 33-PARTICLE GCR (33-GCR) ON HIPPOCAMPAL DENTATE GYRUS (DG) FUNCTION (PATTERN SEPARATION) AND PREFRONTAL CORTEX (PFC) FUNCTIONS (COGNITIVE FLEXIBILITY EXTINCTION OF STIMULUS-RESPONSE) IN 6-MONTH-OLD MATURE MALE C57BL/6J MICE AND (1B) CDDO-EA ON 33-GCR-INDUCED COGNITIVE CHANGES. AIM 2. WE WILL ALSO DEFINE DG NEUROGENESIS AND DG AND PFC INFLAMMATION IN FEMALE AND MALE MICE EXPOSED TO 33-GCR OR SHAM WITH AND WITHOUT CDDO-EA. METHODS: MATURE C57BL/6J MALE AND FEMALE MICE WILL RECEIVE CDDO-EA (400 MG/KG N80) OR CONTROL CHOW (CONTROL N80) FOR 5 DAYS (3 DAYS BEFORE DURING AND 1 DAY AFTER 33-GCR). MICE WILL RECEIVE EITHER SHAM OR WHOLE-BODY 33-GCR (~73% 1H 18% 4HE 2.4% 12C 3.1% 16O 1.6% 28SI 0.9% 48TI 0.8% 56FE 750MGY) WITH THE 4 GROUPS BEING CONTROL/SHAM CONTROL/33-GCR CDDOEA/ SHAM CDDO-EA/33-GCR (N16/GROUP). TO COMPLEMENT PILOT DATA WITH FEMALE MICE IN AIM 1 2-MON POST-IRRADIATION MALE MICE WILL UNDERGO GENERAL TOUCHSCREEN TRAINING LOCATION DISCRIMINATION (LD) AND ACQUISITION AND EXTINCTION OF STIMULUS-RESPONSE. IN AIM 2 BRAINS WILL BE COLLECTED FROM MALE AND FEMALE MICE AT THREE TIMEPOINTS POST-33-GCR: 3 DAYS 2-MON AND 11-MON. 2- AND 11-MON GROUPS WILL BE GIVEN BROMODEOXYURIDINE (BRDU I.P. 180 MG/KG) 2 HRS PRIOR TO PERFUSION AND INDICES OF NEUROGENESIS AND INFLAMMATION WILL BE QUANTIFIED VIA UNBIASED STEREOLOGY. IN THE 3-DAY GROUP PROTEIN EXPRESSION OF NRF2/ARE SIGNALING TARGETS WILL BE QUANTIFIED IN THE DG AND PFC. AIM 1 DELIVERABLES INCLUDE MEASURES OF LD (SESSION LENGTH # TRIALS % CORRECT ETC.) AND ACQUISITION AND EXTINCTION (SESSION LENGTH # RESPONSES # OMISSIONS DAYS TO COMPLETION) IN MALE MICE AND THE IMPACT OF 33-GCR VS. SHAM AND CDDO-EA VS. CONTROL CHOW ON THESE MEASURES. AIM 2 DELIVERABLES INCLUDE INDICES OF DG NEUROGENESIS (# OF KI67- DCX- BRDU-IMMUNOREACTIVE [+] CELLS) AND DG AND PFC INFLAMMATION (# OF IBA-1+ GFAP+ CELLS) AND PROTEIN EXPRESSION OF SIGNALING MEDIATORS DOWNSTREAM FROM NRF2/ARE. SIGNIFICANCE: IT IS IMPERATIVE TO UNDERSTAND HOW A MISSION RELEVANT GCR MIXTURE INFLUENCES COGNITION AND DETERMINATION OF GCRINDUCED CELLULAR AND MOLECULAR CHANGES ENABLES IDENTIFICATION OF APPROPRIATE COUNTERMEASURES. THE PROPOSED WORK IN MALE AND FEMALE MICE WILL COMPLEMENT OUR ALREADY-COMPLETED COGNITIVE STUDY IN FEMALE MICE (MANUSCRIPT IN PREPARATION). GIVEN THE SIMILARITY BETWEEN COGNITIVE FUNCTION IN MICE AND HUMANS THE RESULTING DATA WILL ALLOW MORE ACCURATE ESTIMATION OF SPACE-RADIATION RISKS TO BOTH MALE AND FEMALE ASTRONAUTS. HRP GAPS ADDRESSED: CBS-CNS1 CNS4 CNS5 CNS6 BMED1. IN BRIEF WHAT ARE THE ACUTE AND LATE CNS RISKS AT THE MOLECULAR CELLULAR AND BEHAVIORAL LEVELS FOR ASTRONAUTS EXPOSED TO GCR?