Effects of social isolation and galactic cosmic radiation on fine motor skills and behavioral performance.

Future NASA missions will require astronauts to travel farther and spend longer durations in space than ever before. This will also expose astronauts to longer periods of several physical and psychological challenges, including exposure to space radiation (SR) and periods of social isolation (SI), which could have unknown negative effects on physical and mental health. Each also has the potential to negatively impact sleep which can reduce the ability to cope with stressful experiences and lead to sensorimotor, neurocognitive, and physical deficits. The effects of SI and SR on gross motor performance has been shown to vary, and depend on, individual differences in stress resilience and vulnerability based on our established animal model in which stress produces different effects on sleep. In this study, the impact that SI and SR, either alone or together, had on fine motor skill performance (bilateral tactile adhesive removal task (BTAR)) was assessed in male rats. We also examined emotional, exploratory, and other off-task behavioral responses during testing and assessed whether sensorimotor performance and emotion varied with individual differences in resilience and vulnerability. BTAR task performance was differentially impacted by SI and SR, and were further influenced by the stress resilience/vulnerability phenotype of the rats. These findings further demonstrate that identifying individual responses to stressors that can impact sensorimotor ability and behavior necessary to perform mission-related tasks will be of particular importance for astronauts and future missions. Should similar effects occur in humans, there may be considerable inter-individual variability in the impact that inflight stressors have on astronauts and their ability to perform mission-related tasks.

Loss of Cognitive Flexibility Practice Effects in Female Rats Exposed to Simulated Space Radiation.

During the planned missions to Mars, astronauts will be faced with many potential health hazards including prolonged exposure to space radiation. Ground-based studies have shown that exposure to space radiation impairs the performance of male rats in cognitive flexibility tasks which involve processes that are essential to rapidly and efficiently adapting to different situations. However, there is presently a paucity of information on the effects of space radiation on cognitive flexibility in female rodents. This study has determined the impact that exposure to a low (10 cGy) dose of ions from the simplified 5-ion galactic cosmic ray simulation [https://www.bnl.gov/nsrl/userguide/SimGCRSim.php (07/2023)] (GCRSim) beam or 250 MeV/n 4He ions has on the ability of female Wistar rats to perform in constrained [attentional set shifting (ATSET)] and unconstrained cognitive flexibility (UCFlex) tasks. Female rats exposed to GCRSim exhibited multiple decrements in ATSET performance. Firstly, GCRSim exposure impaired performance in the compound discrimination (CD) stage of the ATSET task. While the ability of rats to identify the rewarded cue was not compromised, the time the rats required to do so significantly increased. Secondly, both 4He and GCRSim exposure reduced the ability of rats to reach criterion in the compound discrimination reversal (CDR) stage. Approximately 20% of the irradiated rats were unable to complete the CDR task; furthermore, the irradiated rats that did reach criterion took more attempts to do so than did the sham-treated animals. Radiation exposure also altered the magnitude and/or nature of practice effects. A comparison of performance metrics from the pre-screen and post-exposure ATSET task revealed that while the sham-treated rats completed the post-exposure CD stage of the ATSET task in 30% less time than for completion of the pre-screen ATSET task, the irradiated rats took 30-50% longer to do so. Similarly, while sham-treated rats completed the CDR stage in ∼10% fewer attempts in the post-exposure task compared to the pre-screen task, in contrast, the 4He- and GCRSim-exposed cohorts took more (∼2-fold) attempts to reach criterion in the post-exposure task than in the pre-screen task. In conclusion, this study demonstrates that female rats are susceptible to radiation-induced loss of performance in the constrained ATSET cognitive flexibility task. Moreover, exposure to radiation leads to multiple performance decrements, including loss of practice effects, an increase in anterograde interference and reduced ability or unwillingness to switch attention. Should similar effects occur in humans, astronauts may have a compromised ability to perform complex tasks.

New Radiobiological Principles for the CNS Arising from Space Radiation Research.

Traditionally, the brain has been regarded as a relatively insensitive late-reacting tissue, with radiologically detectable damage not being reported at doses < 60 Gy. When NASA proposed interplanetary exploration missions, it was required to conduct an intensive health and safety evaluation of cancer, cardiovascular, and cognitive risks associated with exposure to deep space radiation (SR). The SR dose that astronauts on a mission to Mars are predicted to receive is ~300 mGy. Even after correcting for the higher RBE of the SR particles, the biologically effective SR dose (<1 Gy) would still be 60-fold lower than the threshold dose for clinically detectable neurological damage. Unexpectedly, the NASA-funded research program has consistently reported that low (<250 mGy) doses of SR induce deficits in multiple cognitive functions. This review will discuss these findings and the radical paradigm shifts in radiobiological principles for the brain that were required in light of these findings. These included a shift from cell killing to loss of function models, an expansion of the critical brain regions for radiation-induced cognitive impediments, and the concept that the neuron may not be the sole critical target for neurocognitive impairment. The accrued information on how SR exposure impacts neurocognitive performance may provide new opportunities to reduce neurocognitive impairment in brain cancer patients.

Multiple decrements in switch task performance in female rats exposed to space radiation.

Astronauts on the Artemis missions to the Moon and Mars will be exposed to unavoidable Galactic Cosmic Radiation (GCR). Studies using male rats suggest that GCR exposure impairs several processes required for cognitive flexibility performance, including attention and task switching. Currently no comparable studies have been conducted with female rats. Given that both males and females will travel into deep space, this study determined whether simulated GCR (GCRsim) exposure impairs task switching performance in female rats. Female Wistar rats exposed to 10 cGy GCRsim (n = 12) and shams (n = 14) were trained to perform a touchscreen-based switch task that mimics a switch task used to evaluate pilots' response times. In comparison to sham rats, three-fold more GCRsim-exposed rats failed to complete the stimulus response stage of training, a high cognitive loading task. In the switch task, 50% of the GCRsim-exposed rats failed to consistently transition between the repeated and switch blocks of stimuli, which they completed during lower cognitive loading training stages. The GCRsim-exposed rats that completed the switch task only performed at 65% of the accuracy of shams. Female rats exposed to GCRsim thus exhibit multiple decrements in the switch task under high, but not low, cognitive loading conditions. While the operational significance of this performance decrement is unknown, if GCRSim exposure was to induce similar effects in astronauts, our data suggests there may be a reduced ability to execute task switching under high cognitive loading situations.

Sleep and Core Body Temperature Alterations Induced by Space Radiation in Rats.

Sleep problems in astronauts can arise from mission demands and stress and can impact both their health and ability to accomplish mission objectives. In addition to mission-related physical and psychological stressors, the long durations of the proposed Mars missions will expose astronauts to space radiation (SR), which has a significant impact on the brain and may also alter sleep and physiological functions. Therefore, in this study, we assessed sleep, EEG spectra, activity, and core body temperature (CBT) in rats exposed to SR and compared them to age-matched nonirradiated rats. Male outbred Wistar rats (8-9 months old at the time of the study) received SR (15 cGy GCRsim, n = 15) or served as age- and time-matched controls (CTRL, n = 15) without irradiation. At least 90 days after SR and 3 weeks prior to recording, all rats were implanted with telemetry transmitters for recording EEG, activity, and CBT. Sleep, EEG spectra (delta, 0.5-4 Hz; theta, 4-8 Hz; alpha, 8-12 Hz; sigma, 12-16 Hz; beta, 16-24 Hz), activity, and CBT were examined during light and dark periods and during waking and sleeping states. When compared to the CTRLs, SR produced significant reductions in the amounts of dark period total sleep time, total nonrapid eye movement sleep (NREM), and total rapid eye movement sleep (REM), with significant decreases in light and dark period NREM deltas and dark period REM thetas as well as increases in alpha and sigma in NREM and REM during either light or dark periods. The SR animals showed modest increases in some measures of activity. CBT was significantly reduced during waking and sleeping in the light period. These data demonstrate that SR alone can produce alterations to sleep and temperature control that could have consequences for astronauts and their ability to meet mission demands.

Differential Impact of Social Isolation and Space Radiation on Behavior and Motor Learning in Rats.

Future missions to Mars will expose astronauts to several physical and psychological challenges, including exposure to space radiation (SR) and periods of social isolation (SI). Each of these stressors, in addition to mission demands, can affect physical and mental health and potentially negatively impact sleep. The effects of inflight stressors may vary with duration and time course, may be additive or compounding, and may vary with individual differences in stress resilience and vulnerability. Determining how individual differences in resilient and vulnerable phenotypes respond to these mission-related stressors and their interactions with sleep will be crucial for understanding and mitigating factors that can impair performance and damage health. Here, we examined the single and compound effects of ground-based analogs of SI and SR on sensorimotor performance on the balance beam (BB) in rats. We also assessed emotional responses during testing on the BB and assessed whether sensorimotor performance and emotion varied with individual differences in stress resiliency using our established animal model in which stress produces different effects on sleep. Results showed differential motor performance and emotion in the BB task between SI and SR, and these varied based on resilient and vulnerable phenotypes. These findings demonstrate that identifying individual responses to stressors that can impact sensorimotor ability and behavior necessary to perform mission-related tasks will be of particular importance for astronauts and future missions. Should similar effects occur in humans, there may be considerable inter-individual variability in the impact that flight stressors have on the mental health of astronauts and their ability to perform mission-related tasks.

Galactic cosmic ray simulation at the NASA space radiation laboratory - Progress, challenges and recommendations on mixed-field effects.

For missions beyond low Earth orbit to the moon or Mars, space explorers will encounter a complex radiation field composed of various ion species with a broad range of energies. Such missions pose significant radiation protection challenges that need to be solved in order to minimize exposures and associated health risks. An innovative galactic cosmic ray simulator (GCRsim) was recently developed at the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory (BNL). The GCRsim technology is intended to represent major components of the space radiation environment in a ground analog laboratory setting where it can be used to improve understanding of biological risks and serve as a testbed for countermeasure development and validation. The current GCRsim consists of 33 energetic ion beams that collectively simulate the primary and secondary GCR field encountered by humans in space over the broad range of particle types, energies, and linear energy transfer (LET) of interest to health effects. A virtual workshop was held in December 2020 to assess the status of the NASA baseline GCRsim. Workshop attendees examined various aspects of simulator design, with a particular emphasis on beam selection strategies. Experimental results, modeling approaches, areas of consensus, and questions of concern were also discussed in detail. This report includes a summary of the GCRsim workshop and a description of the current status of the GCRsim. This information is important for future advancements and applications in space radiobiology.

Fine motor deficits exhibited in rat string-pulling behavior following exposure to sleep fragmentation and deep space radiation.

Deep space flight missions will expose astronauts to multiple stressors, including sleep fragmentation and space radiation. There is debate over whether sleep disruptions are an issue in deep space. While these stressors independently impair sensorimotor function, the combined effects on performance are currently unknown. String-pulling behavior involves highly organized bimanual reach-to-grasp and withdraw movements. This behavior was examined under rested wakeful conditions and immediately following one session of sleep fragmentation in Sham and irradiated rats 3 months after exposure (10 cGy 4Helium or 5-ion simulated Galactic Cosmic Radiation). Sleep fragmentation disrupted several aspects of string-pulling behavior, such that rats' ability to grasp the string was reduced, reach endpoint concentration was more variable, and distance traveled by the nose increased in the Y-range compared to rested wakeful performance. Overall, irradiated rats missed the string more than Sham rats 3 months post-exposure. Irradiated rats also exhibited differential impairments at 3 months, with additional deficits unveiled after sleep fragmentation. 4Helium-exposed rats took longer to approach the string after sleep fragmentation. Further, rats exposed to 4Helium traveled shorter withdraw distances 3 months after irradiation, while this only emerged in the other irradiated group after sleep fragmentation. These findings identify sleep fragmentation as a risk for fine motor dysfunction in Sham and irradiated conditions, in addition to radiation exposure. There may be complex temporal alterations in performance that are stressor- and ion-dependent. Thus, it is critical to implement appropriate models of multi-flight stressors and performance assessments in preparation for future deep space flight missions.

Radiation and CNS effects: summary of evidence from a recent symposium of the Radiation Research Society.

This article summarizes a Symposium on 'Radiation risks of the central nervous system' held virtually at the 67th Annual Meeting of the Radiation Research Society, 3-6 October 2021. Repeated low-dose radiation exposure over a certain period could lead to reduced neuronal proliferation, altered neurogenesis, neuroinflammation and various neurological complications, including psychological consequences, necessitating further research in these areas. Four speakers from radiation biology, genetics and epidemiology presented the latest data from their studies seeking insights into this important topic. This symposium highlighted new and important directions for further research on mental health disorders, neurodegenerative conditions and cognitive impairment. Future studies will examine risks of mental and behavioral disorders and neurodegenerative diseases following protracted radiation exposures to better understand risks of occupational exposures as well as provide insights into risks from exposures to galactic cosmic rays.

Similar Loss of Executive Function Performance after Exposure to Low (10 cGy) Doses of Single (4He) Ions and the Multi-Ion GCRSim Beam.

While astronauts are trained to deal with multiple issues that they are likely to encounter during a mission, it is likely that some problems will arise that astronauts have no direct experience in resolving. During International Space Station (ISS) missions, astronauts can rely on Mission Control to help resolve complex problems, however during the long-duration space missions planned to the Moon and Mars, astronauts will have to act more autonomously, thus the ability of astronauts to conduct executive function will be critical for problem solving during deep space missions. Several studies have shown that exposure to space radiation results in decreased executive function performance. However, to date these studies have used single ions, whereas there is a complex mixture of ion species and energies within the space-radiation spectrum that astronauts will be exposed to. Thus, there is some concern that the neurocognitive impairments reported from single ion studies will not be representative of the severity, frequency or nature of cognitive deficits that arise following exposure to more complex space-radiation spectra. The current study has determined the relative impact that isodoses of He ions or the simplified 6-ion-galactic cosmic ray simulation (GCRSim) beams had on the performance of male Wistar rats in executive function tasks, attentional set shifting (ATSET) task and unconstrained cognitive flexibility (UCFlex). Exposure to 10 cGy GCRSim induced performance deficits in the simple discrimination (SD) stage of the ATSET task, which appears to be universally impacted by all space-radiation ions studied to date. The magnitude of the SD performance decrements in the GCRSim-irradiated rats were comparable to those observed in He-irradiated rats. Importantly, space-radiation exposure does not appear to decrease the ability of rats to identify the key cues in the ATSET task, but increased the time/number of iterations required to successfully find the solution. Practice effect (PE) analysis (comparing prescreen to the postirradiation SD performance) revealed that while the sham-treated rats completed the second ATSET task in 30% less time than they did the prescreen ATSET test (despite the perceptual domain of the relevant (rewarded) cue being changed), the space-radiation-exposed rats took 50% longer to do so. The space-radiation-induced delay in problem solving was not confined to the ATSET task, but was also observed when rats were screened for UCFlex performance. Should similar changes occur in astronauts, these data raise the possibility that space-radiation exposure would reduce in-flight improvement in performance in repetitive tasks (PE) and may lead to a reduced ability to utilize transitive inference from "similar" problems to solve issues that have not been previously encountered.

Quantitative proteomic analytic approaches to identify metabolic changes in the medial prefrontal cortex of rats exposed to space radiation.

NASA's planned mission to Mars will result in astronauts being exposed to ∼350 mSv/yr of Galactic Cosmic Radiation (GCR). A growing body of data from ground-based experiments indicates that exposure to space radiation doses (approximating those that astronauts will be exposed to on a mission to Mars) impairs a variety of cognitive processes, including cognitive flexibility tasks. Some studies report that 33% of individuals may experience severe cognitive impairment. Translating the results from ground-based rodent studies into tangible risk estimates for astronauts is an enormous challenge, but it would be germane for NASA to use the vast body of data from the rodent studies to start developing appropriate countermeasures, in the expectation that some level of space radiation (SR) -induced cognitive impairment could occur in astronauts. While some targeted studies have reported radiation-induced changes in the neurotransmission properties and/or increased neuroinflammation within space radiation exposed brains, there remains little information that can be used to start the development of a mechanism-based countermeasure strategy. In this study, we have employed a robust label-free mass spectrometry (MS) -based untargeted quantitative proteomic profiling approach to characterize the composition of the medial prefrontal cortex (mPFC) proteome in rats that have been exposed to 15 cGy of 600 MeV/n28Si ions. A variety of analytical techniques were used to mine the generated expression data, which in such studies is typically hampered by low and variable sample size. We have identified several pathways and proteins whose expression alters as a result of space radiation exposure, including decreased mitochondrial function, and a further subset of proteins differs in rats that have a high level of cognitive performance after SR exposure in comparison with those that have low performance levels. While this study has provided further insight into how SR impacts upon neurophysiology, and what adaptive responses can be invoked to prevent the emergence of SR-induced cognitive impairment, the main objective of this paper is to outline strategies that can be used by others to analyze sub-optimal data sets and to identify new information.

Similar Loss of Executive Function Performance after Exposure to Low (10 cGy) Doses of Single (4He) Ions and the Multi-Ion GCRSim Beam.

While astronauts are trained to deal with multiple issues that they are likely to encounter during a mission, it is likely that some problems will arise that astronauts have no direct experience in resolving. During International Space Station (ISS) missions, astronauts can rely on Mission Control to help resolve complex problems, however during the long-duration space missions planned to the Moon and Mars, astronauts will have to act more autonomously, thus the ability of astronauts to conduct executive function will be critical for problem solving during deep space missions. Several studies have shown that exposure to space radiation results in decreased executive function performance. However, to date these studies have used single ions, whereas there is a complex mixture of ion species and energies within the space-radiation spectrum that astronauts will be exposed to. Thus, there is some concern that the neurocognitive impairments reported from single ion studies will not be representative of the severity, frequency or nature of cognitive deficits that arise following exposure to more complex space-radiation spectra. The current study has determined the relative impact that isodoses of He ions or the simplified 6-ion-galactic cosmic ray simulation (GCRSim) beams had on the performance of male Wistar rats in executive function tasks, attentional set shifting (ATSET) task and unconstrained cognitive flexibility (UCFlex). Exposure to 10 cGy GCRSim induced performance deficits in the simple discrimination (SD) stage of the ATSET task, which appears to be universally impacted by all space-radiation ions studied to date. The magnitude of the SD performance decrements in the GCRSim-irradiated rats were comparable to those observed in He-irradiated rats. Importantly, space-radiation exposure does not appear to decrease the ability of rats to identify the key cues in the ATSET task, but increased the time/number of iterations required to successfully find the solution. Practice effect (PE) analysis (comparing prescreen to the postirradiation SD performance) revealed that while the sham-treated rats completed the second ATSET task in 30% less time than they did the prescreen ATSET test (despite the perceptual domain of the relevant (rewarded) cue being changed), the space-radiation-exposed rats took 50% longer to do so. The space-radiation-induced delay in problem solving was not confined to the ATSET task, but was also observed when rats were screened for UCFlex performance. Should similar changes occur in astronauts, these data raise the possibility that space-radiation exposure would reduce in-flight improvement in performance in repetitive tasks (PE) and may lead to a reduced ability to utilize transitive inference from "similar" problems to solve issues that have not been previously encountered.

Rapid loss of fine motor skills after low dose space radiation exposure.

Sensorimotor function, motivation, and attentional processes are fundamental aspects of behavioral organization during skilled tasks. NASA's planned expedition to Mars will expose astronauts to space radiation (SR) that has the potential to impair performance in mission critical tasks. Impairments in task accuracy and movement kinematics have been previously reported during string-pulling behavior ~7 months after SR exposure. If similar SR-induced sensorimotor deficits emerge at earlier times, then astronauts may have compromised in-flight performance disruptions while performing skilled tasks in critical situations, such as when manipulating controls or performing seat egress. Due to the possibility that such performance losses may compromise mission success, it is critical to determine if sensorimotor, motivation, or attentional deficits occur acutely after SR exposure at a time point that corresponds to in-flight performance. Male Wistar rats were thus exposed to either 10 cGy simplified galactic cosmic radiation (GCRsim), 10 cGy 4Helium (4He), or no radiation at all (Sham), and string-pulling behavior was assessed approximately 72 h later. Following exposure to SR, rats (4He) took more time to approach the string to initiate string-pulling behavior and to pull in the string to reach the Cheerio (4He and GCRsim) relative to Sham rats. 4He-exposed rats also exhibited a greater number of misses and less contacts relative to both Sham and GCRsim-exposed rats. Further, rats exposed to 4He demonstrated less concentrated reach endpoints with both the left and right hands compared to GCR-exposed rats. This work suggests that sensorimotor function and motivation and/or attentional processes were impaired 72 h after 4He-radiation exposure.

Exposure to 5 cGy 28Si Particles Induces Long-Term Microglial Activation in the Striatum and Subventricular Zone and Concomitant Neurogenic Suppression.

The proposed mission to Mars will expose astronauts to space radiation that is known to adversely affect cognition and tasks that rely on fine sensorimotor function. Space radiation has also been shown to affect the microglial and neurogenic responses in the central nervous system (CNS). We recently reported that a low dose of 5 cGy 600 MeV/n 28Si results in impaired cognition and skilled motor behavior in adult rats. Since these tasks rely at least in part on the proper functioning of the striatum, we examined striatal microglial cells in these same subjects. Using morphometric analysis, we found that 28Si exposure increased activated microglial cells in the striatum. The majority of these striatal Iba1+ microglia were ED1-, indicating that they were in an alternatively activated state, where microglia do not have phagocytic activity but may be releasing cytokines that could negatively impact neuronal function. In the other areas studied, Iba1+ microglial cells were increased in the subventricular zone (SVZ), but not in the dentate gyrus (DG). Additionally, we examined the relationship between the microglial response and neurogenesis. An analysis of new neurons in the DG revealed an increase in doublecortin-positive (DCX+) hilar ectopic granule cells (hEGC) which correlated with Iba1+ cells, suggesting that microglial cells contributed to this aberrant distribution which may adversely affect hippocampal function. Taken together, these results indicate that a single dose of 28Si radiation results in persistent cellular effects in the CNS that may impact astronauts both in the short and long-term following deep space missions.

Dissecting Differential Complex Behavioral Responses to Simulated Space Radiation Exposures.

This study has established the impact that space radiation exposure has on the capability of rats to successfully negotiate behavioral tasks of increasing complexity. Rats previously exposed to a low dose (10 cGy) of either 4He ions or a cocktail of 6 ions that simulates the galactic cosmic ray spectrum (GCRSim) were screened initially on an attentional set shifting (ATSET) task that provides a measure of executive function. Rats that exhibited superior ATSET performance were then selected for follow up behavioral assessments designed to evaluate how the cohort of "good performers" would fare when presented with a novel behavioral paradigm termed the Associative Recognition Memory and Interference Touchscreen (ARMIT) task. Central to this approach was to discriminate if/how adaptive problem solving would be impacted by changing the options of associative cues presented over several learning sessions to obtain a reward under time constraints using this newly designed touch screen-based task. Data from these studies indicated that when faced with an increased cognitive load, possibly due to interference from prior associative recognition memories, rats exhibited impairments in their capability to negotiate task dynamics and efficiently engage abstract reasoning. Interestingly, while exposure to the GCRSim adversely impacted problem-solving capabilities, single ion exposure did not, pointing to the nuances of space radiation exposure on CNS functionality. Since the selected behavioral paradigms exhibit strong cross-species correlates, data suggest that rodents succumb to increased task rigor as observed in humans, and make similar mistakes when challenged with the interference of overlapping associative memories. Furthermore, data clearly points to the limitations of over-reliance on a single cognitive endpoint that may underestimate global neurocognitive risk due to space radiation exposure.

Predicting Space Radiation Single Ion Exposure in Rodents: A Machine Learning Approach.

This study presents a data-driven machine learning approach to predict individual Galactic Cosmic Radiation (GCR) ion exposure for 4He, 16O, 28Si, 48Ti, or 56Fe up to 150 mGy, based on Attentional Set-shifting (ATSET) experimental tests. The ATSET assay consists of a series of cognitive performance tasks on irradiated male Wistar rats. The GCR ion doses represent the expected cumulative radiation astronauts may receive during a Mars mission on an individual ion basis. The primary objective is to synthesize and assess predictive models on a per-subject level through Machine Learning (ML) classifiers. The raw cognitive performance data from individual rodent subjects are used as features to train the models and to explore the capabilities of three different ML techniques for elucidating a range of correlations between received radiation on rodents and their performance outcomes. The analysis employs scores of selected input features and different normalization approaches which yield varying degrees of model performance. The current study shows that support vector machine, Gaussian naive Bayes, and random forest models are capable of predicting individual ion exposure using ATSET scores where corresponding Matthews correlation coefficients and F1 scores reflect model performance exceeding random chance. The study suggests a decremental effect on cognitive performance in rodents due to ≤150 mGy of single ion exposure, inasmuch as the models can discriminate between 0 mGy and any exposure level in the performance score feature space. A number of observations about the utility and limitations in specific normalization routines and evaluation scores are examined as well as best practices for ML with imbalanced datasets observed.

Machine Learning Models to Predict Cognitive Impairment of Rodents Subjected to Space Radiation.

This research uses machine-learned computational analyses to predict the cognitive performance impairment of rats induced by irradiation. The experimental data in the analyses is from a rodent model exposed to ≤15 cGy of individual galactic cosmic radiation (GCR) ions: 4He, 16O, 28Si, 48Ti, or 56Fe, expected for a Lunar or Mars mission. This work investigates rats at a subject-based level and uses performance scores taken before irradiation to predict impairment in attentional set-shifting (ATSET) data post-irradiation. Here, the worst performing rats of the control group define the impairment thresholds based on population analyses via cumulative distribution functions, leading to the labeling of impairment for each subject. A significant finding is the exhibition of a dose-dependent increasing probability of impairment for 1 to 10 cGy of 28Si or 56Fe in the simple discrimination (SD) stage of the ATSET, and for 1 to 10 cGy of 56Fe in the compound discrimination (CD) stage. On a subject-based level, implementing machine learning (ML) classifiers such as the Gaussian naïve Bayes, support vector machine, and artificial neural networks identifies rats that have a higher tendency for impairment after GCR exposure. The algorithms employ the experimental prescreen performance scores as multidimensional input features to predict each rodent's susceptibility to cognitive impairment due to space radiation exposure. The receiver operating characteristic and the precision-recall curves of the ML models show a better prediction of impairment when 56Fe is the ion in question in both SD and CD stages. They, however, do not depict impairment due to 4He in SD and 28Si in CD, suggesting no dose-dependent impairment response in these cases. One key finding of our study is that prescreen performance scores can be used to predict the ATSET performance impairments. This result is significant to crewed space missions as it supports the potential of predicting an astronaut's impairment in a specific task before spaceflight through the implementation of appropriately trained ML tools. Future research can focus on constructing ML ensemble methods to integrate the findings from the methodologies implemented in this study for more robust predictions of cognitive decrements due to space radiation exposure.

Exposure to Low (≤10 cGy) Doses of 4He Particles Leads to Increased Social Withdrawal and Loss of Executive Function Performance.

Astronauts on the planned mission to Mars will be exposed to galactic cosmic radiation (GCR), with proton and He particles accounting (in approximately equal amounts) for ∼75% of the equivalent dose. Exposure to ≤15 cGy of space radiation ions with Z ≥ 15 particles has been shown to impair various executive functions, including attentional set shifting and creative problem-solving in rats. Executive functions also regulate social interactions and mood. Should space radiation exposure alter these executive functions as it does cognitive flexibility, there is the possibility of altered interactions among crew members and team cooperativity during prolonged space exploration. This study characterized the effects of ≤10 cGy 400 MeV/n of 4He particles on cognitive flexibility and social interaction (within freely interacting dyads) in male Wistar rats. Exposure to ≥1 cGy 4He ions induced deficits in the SD and/or CD stages of the attentional set shifting (ATSET) task, as reported after exposure to Z ≥ 15 space radiation ions. Should similar effects occur in astronauts, these data suggest that they would have a reduced ability to identify key events in a new situation and would be more easily distracted by extraneous variables. The irradiated rats were also screened for performance in a task for unconstrained cognitive flexibility (UCFlex), often referred to as creative problem-solving. There was a marked dose-dependent change in UCFlex performance with ∼30% of rats exposed to 10 cGy being unable to solve the problem, while the remaining rats took longer than the sham-irradiated animals to resolve the problem. Importantly, performance in the ATSET test was not indicative of UCFlex performance. From a risk assessment perspective, these findings suggest that a value based on a single behavioral end point may not fully represent the cognitive deficits induced by space radiation, even within the cognitive flexibility domain. Rats that received 5 cGy 4He ion irradiation had a significantly lower level of interaction toward their sham-irradiated partners in a non-anxiogenic (uncaged) dyad interactions study. This is consistent with the social withdrawal previously observed in space radiation-exposed male mice in a three-chamber test. 4He-irradiated rats exhibited a significantly higher incidence and duration of self-grooming, which is even more concerning, given that their dyad partners were able to physically interact with the irradiated rats (i.e., touching/climbing over them). This study has established that exposure of male rats to "light" ions such as He affects multiple executive functions resulting in deficits in both sociability and cognitive flexibility, and possibly affective behavior (reward valuation). Further studies are needed to determine if these space radiation-induced co-morbidities are concomitantly induced within individual rats.

Space Radiation-Induced Alterations in the Hippocampal Ubiquitin-Proteome System.

Exposure of rodents to <20 cGy Space Radiation (SR) impairs performance in several hippocampus-dependent cognitive tasks, including spatial memory. However, there is considerable inter-individual susceptibility to develop SR-induced spatial memory impairment. In this study, a robust label-free mass spectrometry (MS)-based unbiased proteomic profiling approach was used to characterize the composition of the hippocampal proteome in adult male Wistar rats exposed to 15 cGy of 1 GeV/n 48Ti and their sham counterparts. Unique protein signatures were identified 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. Approximately 14% (159) of the proteins detected in hippocampal proteome of sham rats were not detected in the Ti-exposed rats. We explored the possibility that the loss of the Sham-only proteins may arise as a result of SR-induced changes in protein homeostasis. SR-exposure was associated with a switch towards increased pro-ubiquitination proteins from that seen in Sham. 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.

Chronic Low Dose Neutron Exposure Results in Altered Neurotransmission Properties of the Hippocampus-Prefrontal Cortex Axis in Both Mice and Rats.

The proposed deep space exploration to the moon and later to Mars will result in astronauts receiving significant chronic exposures to space radiation (SR). SR exposure results in multiple neurocognitive impairments. Recently, our cross-species (mouse/rat) studies reported impaired associative memory formation in both species following a chronic 6-month low dose exposure to a mixed field of neutrons (1 mGy/day for a total dose pf 18 cGy). In the present study, we report neutron exposure induced synaptic plasticity in the medial prefrontal cortex, accompanied by microglial activation and significant synaptic loss in the hippocampus. In a parallel study, neutron exposure was also found to alter fluorescence assisted single synaptosome LTP (FASS-LTP) in the hippocampus of rats, that may be related to a reduced ability to insert AMPAR into the post-synaptic membrane, which may arise from increased phosphorylation of the serine 845 residue of the GluA1 subunit. Thus, we demonstrate for the first time, that low dose chronic neutron irradiation impacts homeostatic synaptic plasticity in the hippocampal-cortical circuit in two rodent species, and that the ability to successfully encode associative recognition memory is a dynamic, multicircuit process, possibly involving compensatory changes in AMPAR density on the synaptic surface.