Project Objectives
1. Identify the lowest dose of space radiation (SR) that results in Attentional Set Shifting (ATSET) impairment; 2. Determine if there are LET-specific mechanisms of ATSET impairment; 3. Identify changes in the neuroproteome that reflect the cognitive performance status of SR-exposed animals.
Supplemental studies
4. Establish the impact that that re-irradiation with 10 cGy of simplified (5-ion) CGRsim beam has on the ATSET performance of male and female Wistar rats that maintained a functional ATSET performance after exposure to 10 cGy of either He or GCRsim.
Project Approach
To better simulate the “clinical reality”, adult rats that have been pre-selected for good ATSET performance and who have been maintained on an exercise regimen are used in this study. The first radiation exposures will occur when the rats are ~7 months old. While the biological equivalent age of these 7-month-old rats is closer to that of a 30-year-old human, which is currently younger than most astronauts, the use of such rats allows for the long-term monitoring of cognitive decline, which is less likely to be impacted by age-related cognitive decline.
Rats are exposed to 10 cGy of SR ions (incident energy <1000 MeV/n) and ATSET performance re-established at 3 months post exposure. After completion of the ATSET test, the rats are then tested in the Unconstrained Cognitive flexibility (UCFlex) assay, which requires the rats to complete a new task, where the food reward is no longer present in either reward bowl, as it was for all seven stages of the ATSET; instead the reward is located in a third location that the rat had limited experience with that requires the rats to develop a novel solution to obtain the food reward. Thus, the UCFlex version of the ATSET task interrogates both constrained and unconstrained cognitive flexibility performance within individual rats. Importantly both cognitive flexibility tasks are homologs of tasks used in clinical testing of humans.
Executive functions also regulate social interactions and mood; should SR-exposure alter these executive functions as it does cognitive flexibility, there is the possibility of altered inter-crew interactions and team cooperativity during prolonged space exploration. We have previously reported that exposure to 5 cGy He ions leads to social withdrawal (within freely interacting dyads) in male Wistar rats (Burket et al., 2021). Dr. Burket and her students will determine the relative impact that GCRSim and He ions have on social withdrawal.
We have shown that rats that have no significant loss of ATSET performance after SR (Si) exposure can have significant loss of fine motor skills (Blackwell et al., 2021). Dr. Blackwell has now joined the Britten laboratory and will characterize the impact that He and GCRsim exposure has on fine motor skill performance. Importantly, these studies will be conducted in close temporal proximity (2-3 days) to radiation exposure as well as our traditional 3 month time point.
Brain regions (that regulated certain paradigms within the ATSET and UCFlex tasks) are recovered and subjected to proteomic analysis to identify some of the processes that may be responsible for the SR-induced impairment of cognitive and sensorimotor function.
The supplemental studies involve returning the rats that have maintained good ATSET performance after SR (10 cGy 4He ions or the 6-ion GCRsim beam) to Brookhaven National Laboratory (BNL) where they receive a second dose of 10 cGy of the 6-ion GCRsim. Cognitive and sensorimotor performance is then reassessed at 3 months after the second exposure.
Research Highlights from this reporting period.
• Low doses (10 cGy) of simplified GCRSim significantly impairs ATSET performance, specifically in the Simple Discrimination task. These data extend the range of space radiation ions that have a significant impact upon SD performance to include He (Burket et al., 2021), Si (Britten et al., 2020), Ti (Parihar et al., 2016), Fe (Jewell et al., 2018), protracted mixed neutrons (Britten et al., 2021), and now GCRSim. Impairment of SD performance would thus appear to be the common consequence of exposure to every SR ion studied to date. SR-exposed rats take between 1.5 (Si (Britten et al., 2020)) to 2.6 (neutron (Britten et al., 2021))-fold more attempts to reach criterion (Impairment ratio) than sham rats.
• An assessment of performance savings (a concept widely used in many fields to define the faster response to a situation that has been previously encountered than when it was initially encountered) revealed that both He and GCRSim exposure eliminated performance savings in the ATSET task.
• Low doses (10 cGy) of simplified GCRSim significantly impair UCFlex (creative problem solving) performance.
• We conducted a robust (akin to a phase III clinical trial) concurrent validation of the effect of a single dose of 10 cGy simplified 6-ion GCRSim versus a single dose of 10 cGy 250 MeV/n He ions on ATSET/UCFlex performance using the same batch of rats, laboratory personal, transport, and environmental conditions. While both He ions and GCRsim significantly impaired ATSET performance, there was no obvious difference in the incidence nor severity of the ATSET performance. Similarly, there were no obvious differences in the severity of UCFlex impairment induced by He and GCRSim.
• Exposure to low (10 cGy) doses of He ions led to significant impairment of string pulling (fine motor skill) performance within 72 hours of exposure. He-exposed rats took longer to approach the string and to start the recovery of the string, indicating disruptions in motivation, attention, or sensorimotor function. By 3 months both He and GCRSim exposed rats exhibited longer approach and recovery times.
• Both He and GCRSim exposed rats had significant problems in completing a high cognitive task load assay. When the task was compartmentalized, so that the rats were presented with incremental changes instead of simultaneous changes, over 90% of the SR-exposed rats that previously failed the high cognitive task load assay were able to complete it after the incremental “remedial” training.
• GCRSim-exposed, but not He-exposed rats that completed the high cognitive task load assay, had a significantly decreased ability to switch attention (higher switch cost) in a task that mimics those used to assess pilot response times. The magnitude of this deficit would nearly double the rate of errors in flight simulator exercises.
• The doubly irradiated rat study has shown that there are further decrements in ATSET and UCFlex performance induced in rats that retained a high level of performance after a single SR exposure. The most notable feature of the performance decrements induced after the second exposure is the lack of any performance savings. While it is reassuring that no further losses in performance (completion percentage) occurred, the inability to improve performance with practice (MCL) is problematic.
• We identified unique protein signatures in the hippocampal proteome of: 1) sham rats, 2) Ti-exposed rats, 3) Ti-exposed rats that had sham-like spatial memory performance, and 4) Ti-exposed rats that impaired spatial memory performance (Tidmore et al., 2021). SR-exposure was also associated with a switch towards increased pro-ubiquitination proteins from that seen in shams. These data suggest that the role of the ubiquitin-proteome system as a determinant of SR-induced neurocognitive deficits needs to be more thoroughly investigated.
References
Burket JA, Matar M, Fesshaye A, Pickle JC, Britten RA. Exposure to low (=10 cGy) doses of 4He particles leads to increased social withdrawal and loss of executive function performance. Radiat Res. 2021, 196:345-354.
Blackwell AA, Schell BR, Osterlund Oltmanns JR, Whishaw IQ, Ton ST, Adamczyk NS, Kartje GL, Britten RA, Wallace DG. Skilled movement and posture deficits in rat string-pulling behavior following low dose space radiation (28Si) exposure. Behav Brain Res. 2021;400:113010.
Britten RA, Duncan VD, Fesshaye A, Rudobek E, Nelson GA, Vlkolinsky R. Altered cognitive flexibility and synaptic plasticity in the rat prefrontal cortex after exposure to low (< or =15 cGy) doses of 28Si radiation. Radiat Res. 2020 Mar;193(3):223-35.
Parihar V, Allen B, Caressi C, Kwok S, Chu E, Tran K, Chmielewski N, Giedzinski E, Acharya M, Britten RA, Baulch J, Limoli CL. Cosmic radiation exposure and persistent cognitive dysfunction. Sci Reports 2016, 6: 34774.
Jewell JS, Duncan VD, Fesshaye A, Tondin A, Macadat E, Britten RA. Exposure to <15 cGy of 600 MeV/n 56Fe particles impairs rule acquisition but not long-term memory in the attentional set-shifting assay. Radiat Res. 2018, 190:565-575.
Britten RA, Duncan VD, Fesshaye AS, Wellman LL, Fallgren CM, Sanford LD. Sleep fragmentation exacerbates executive function impairments induced by protracted low dose rate neutron exposure. Int J Radiat Biol. 2021;97(8):1077-1087.
Tidmore A, Dutta SM, Fesshaye AS, Russell W, Duncan VD, Britten RA. Space radiation induced alterations in the hippocampal ubiquitin-proteome system. Int J Mol Sciences 2021;22: 7713.
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