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Project Title:  Changes in the Neuroproteome Associated with HZE-Induced Impairment of Cognition Reduce
Images: icon  Fiscal Year: FY 2022 
Division: Human Research 
Research Discipline/Element:
HRP HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Start Date: 02/27/2014  
End Date: 04/30/2023  
Task Last Updated: 12/29/2021 
Download report in PDF pdf
Principal Investigator/Affiliation:   Britten, Richard  Ph.D. / Eastern Virginia Medical School 
Address:  Radiation Oncology 
700 W Olney Rd 
Norfolk , VA 23507-1607 
Email: Brittera@evms.edu 
Phone: 757-446-5038  
Congressional District:
Web:  
Organization Type: NON-PROFIT 
Organization Name: Eastern Virginia Medical School 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Wallace, Douglas  Ph.D. Northern Illinois University 
Blackwell, Ashley  Ph.D. Eastern Virginia Medical School 
Burket, Jessica  Ph.D. Christopher Newport University 
Key Personnel Changes / Previous PI: December 2021 report: Dr. Jessica Burket at Christopher Newport University has been added to the project to conduct the social interaction studies. Dr Ashley Blackwell at Eastern Virginia Medical School has been added to the project to conduct the string pulling and neural network cohesiveness studies. December 2019 report: Dr. Douglas Wallace at Northern Illinois University (NIU) is now a CoInvestigator. Dec 2016: Drs. Semmes and Dutta were removed from the project; proteomic analysis is now being conducted at UTMB (University of Texas Medical Branch) as contract work.
Project Information: Grant/Contract No. NNX14AE73G 
Responsible Center: NASA JSC 
Grant Monitor: Whitmire, Alexandra  
Center Contact:  
alexandra.m.whitmire@nasa.gov 
Solicitation / Funding Source: 2013 Space Radiobiology NNJ13ZSA001N 
Grant/Contract No.: NNX14AE73G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Human Research Program Risks: (1) HFBP Bmed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders (IRP Rev J)
(2) Sensorimotor:Risk of Altered Sensorimotor/Vestibular Function Impacting Critical Mission Tasks (Revised as of IRP Rev M)
Human Research Program Gaps: (1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-103:What are the validated, efficacious treatments (individual or Team-based) and/or countermeasures to prevent adverse behavioral conditions, CNS/neurological, and/or psychiatric disorders caused by either single and/or integrated exposures to spaceflight hazards during exploration class missions? (IRP Rev L)
(3) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
(4) BMed-108:Given each crewmember will experience multiple spaceflight hazards simultaneously, we need to identify and characterize the potential additive, antagonistic, or synergistic impacts of multiple stressors (e.g., space radiation, altered gravity, isolation, altered immune, altered sleep) on crew health and/or CNS/ cognitive functioning to develop threshold limits and validate countermeasures for any identified adverse crew health and/or operationally-relevant performance outcomes (IRP Rev L)
(5) SM-104:Evaluate how weightlessness-induced changes in sensorimotor/vestibular function relate to and/or interact with changes in other brain functions (sleep, cognition, attention) (IRP Rev M)
Flight Assignment/Project Notes: NOTE: Element change from SR to HFBP per Human Research Roadmap information dtd July 2019 (Ed., 1/6/2020)

NOTE: Extended to 4/30/2023 per NSSC information (Ed., 12/30/2020)

NOTE: Extended to 12/31/2020 per NSSC information (Ed., 3/12/19)

NOTE: Extended to 12/31/2018 per S. Monk/SR/LaRC (Ed., 1/11/18)

Task Description: One of NASA's biggest concerns about the long-term health of astronauts who go on deep space missions is the impact that High Z, High Energy (HZE) particles have on brain function (neurocognition). Data from our laboratory and others suggests that there is significant impairment of certain neurocognitive tasks (spatial memory and Executive function-attentional set shifting) following exposure to low HZE doses. The goal of this application is to determine the Threshold dose for the induction of HZE-induced spatial memory impairments (HISMI) or Attentional Set Shifting Impairments (HIASSI) following exposure to 56Fe, 48Ti, and 28Si particles. The proposed studies will also identify the changes in the proteome of the brain (neuroproteome) of rats that differ in their susceptibility to HISMI and HIASSI, which will provide further insight into the factors that lead to HISMI/HIASSI and perhaps more importantly, that prevent its emergence. Our underlying hypothesis is that HISMI and HIASSI arise as the direct result of HZE-induced changes in the neuroproteome. We also hypothesize that exposure to HZE species that have different track structures will result in different mechanisms of HZE-induced cognitive impairment (HICI). Collectively, these studies will give some insight into the underlying cause for HISMI and HIASSI.

Our studies will thus address CNS (Central Nervous System) Gaps 1, 2, and 6, [Ed. note February 2022: Human Research Program risks and gaps have changed since this project was initiated--see Human Research Roadmap for updated gaps: https://humanresearchroadmap.nasa.gov/ ] and we shall specifically focus on the following aims:

Aim 1. Determine the Threshold dose for the induction of HISMI and HIASSI following exposure to 56Fe, 48Ti, and 28Si particles when delivered as a single dose.

Aim 2. Identify changes in the neuroproteome that are associated with susceptibility or resistance to developing HISMI and HIASSI following exposure to 56Fe particles.

Aim 3. Determine the mechanism of HISMI and HIASSI induced by HZE particles of differing LET (linear energy transfer).

In Aim 1, socially mature (~6 month old) male Wistar rats will be irradiated with 56Fe, 48Ti, and 28Si particles (with incident energies of 600 MeV/nucleon). Rats will receive whole body HZE irradiation (< 15 cGy), and HISMI and HIASSI will be assessed at 3 months post irradiation.

In Aim 2 and 3, the composition of the neuroproteome (hippocampus and selected regions of the prefrontal cortex) of irradiated rats that have “normal” cognitive performance or have developed HISMI or HIASSI will be established using an unbiased proteomic profiling approach. We shall use a label free differential protein profiling workflow on the Q-Exactive Orbitrap mass spectrometer.

These studies will give considerable insight into the underlying cause for HZE-induced neurocognitive failure. The proposed studies will continue to define the minimum dose of HZE particles that will induce HISMI and HIASSI. Moreover, our studies will provide considerable insight into the underlying mechanism of HICI, and will identify prognostic biomarkers that could be translated to human studies to monitor the emergence of HICI. These studies may also help to develop appropriate countermeasures and help identify sensitive individuals, so that NASA’s medical staff can implement appropriate countermeasures to protect these at risk individuals.

Supplemental studies (in December 2019 report)

This study will provide information on the robustness of single-exposure experiments to predict the impact of repeated episodic radiation exposures (such as will be encountered on the mission to Mars) on neurocognition. This study will test the hypothesis that episodic SR exposure will result in more severe neurocognitive deficits than single, or multiple daily SR doses. In addition, this study will be 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. This study will utilize both male and female rats, and two different radiation regimens incorporating 4He ions and the 6-ion GCRsim beam. Executive function performance (ATSET) will be assessed after a single exposure (He or GCRsim) and after a second exposure (~6 months later) to the 6-ion GCRsim beam. To maximize the amount of data obtained from these expensive studies, where possible (dependent upon volunteers in the Britten lab) the impact of these radiations on sensorimotor (string pulling activity), social interaction and switch task performance will also be established.

Research Impact/Earth Benefits: These studies will give considerable insight into the underlying cause for Space radiation (SR)-induced neurocognitive impairment (SICI).

The proposed studies will continue to define the minimum dose of SR particles that will impair cognitive flexibility (Attentional Set shifting and Unconstrained cognitive flexibility) performance. Importantly both of our cognitive flexibility tasks are homologs of tasks used in clinical testing of humans. Our studies will model the impact that single and repeated episodic exposure to SR has on neurocognitive performance and fine motor skills.

Moreover, our studies will provide considerable insight into the underlying mechanism of SICI, and will identify prognostic biomarkers that could be translated to human studies to monitor the emergence of SICI. These studies may also help to develop appropriate countermeasures and help identify sensitive individuals, so that NASA’s medical staff can implement appropriate countermeasures to protect these at risk individuals.

Task Progress & Bibliography Information FY2022 
Task Progress: 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.

Bibliography Type: Description: (Last Updated: 02/15/2022) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Britten RA, Wellman LL, Sanford LD. "Progressive increase in the complexity and translatability of rodent testing to assess space-radiation induced cognitive impairment." Neurosci Biobehav Rev. 2021 Jul;126:159-74. Review. https://doi.org/10.1016/j.neubiorev.2021.01.027 ; PMID: 33766676 , Jul-2021
Articles in Peer-reviewed Journals Willey JS, Britten RA, Blaber E, Tahimic CGT, Chancellor J, Mortreux M, Sanford LD, Kubik AJ, Delp MD, Mao XW. "The individual and combined effects of spaceflight radiation and microgravity on biologic systems and functional outcomes." J Environ Sci Health C Toxicol Carcinog. 2021 Apr 27;39(2):129-79. https://doi.org/10.1080/26896583.2021.1885283 ; PMID: 33902391; PMCID: PMC8274610 , Apr-2021
Articles in Peer-reviewed Journals Tidmore A, Dutta SM, Fesshaye AS, Russell WK, Duncan VD, Britten RA. "Space radiation-induced alterations in the hippocampal ubiquitin-proteome system." Int J Mol Sci. 2021 Jul 19;22(14):7713. https://doi.org/10.3390/ijms22147713 ; PMID: 34299332; PMCID: PMC8304141 , Jul-2021
Articles in Peer-reviewed Journals Matar M, Gokoglu SA, Prelich MT, Gallo CA, Iqbal AK, Britten RA, Prabhu RK, Myers JG Jr. "Machine learning models to predict cognitive impairment of rodents subjected to space radiation." Front Syst Neurosci. 2021 Sep 13;15:713131. https://doi.org/10.3389/fnsys.2021.713131 ; PMID: 34588962; PMCID: PMC8473791 , Sep-2021
Articles in Peer-reviewed Journals Prelich MT, Matar M, Gokoglu SA, Gallo CA, Schepelmann A, Iqbal AK, Lewandowski BE, Britten RA, Prabhu RK, Myers JG Jr. "Predicting space radiation single ion exposure in rodents: A machine learning approach." Front Syst Neurosci. 2021 Oct 15;15:715433. https://doi.org/10.3389/fnsys.2021.715433 ; PMID: 34720896; PMCID: PMC8555470 , Oct-2021
Articles in Peer-reviewed Journals Burket JA, Matar M, Fesshaye A, Pickle JC, Britten RA. "Exposure to low (< or =10 cGy) doses of 4He particles leads to increased social withdrawal and loss of executive function performance." Radiat Res. 2021 Oct 1;196(4):345-54. https://doi.org/10.1667/RADE-20-00251.1 ; PMID: 34270762 , Oct-2021
Articles in Peer-reviewed Journals Britten RA, Fesshaye A, Ihle P, Wheeler A, Baulch JE, Limoli CL, Stark CE. "Dissecting differential complex behavioral responses to simulated space radiation exposures." Radiat Res. 2021 Dec 17. Online ahead of print. https://doi.org/10.1667/RADE-21-00068.1 , Dec-2021
Project Title:  Changes in the Neuroproteome Associated with HZE-Induced Impairment of Cognition Reduce
Images: icon  Fiscal Year: FY 2021 
Division: Human Research 
Research Discipline/Element:
HRP HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Start Date: 02/27/2014  
End Date: 04/30/2023  
Task Last Updated: 12/22/2020 
Download report in PDF pdf
Principal Investigator/Affiliation:   Britten, Richard  Ph.D. / Eastern Virginia Medical School 
Address:  Radiation Oncology 
700 W Olney Rd 
Norfolk , VA 23507-1607 
Email: Brittera@evms.edu 
Phone: 757-446-5038  
Congressional District:
Web:  
Organization Type: NON-PROFIT 
Organization Name: Eastern Virginia Medical School 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Wallace, Douglas  Ph.D. Northern Illinois University 
Key Personnel Changes / Previous PI: December 2019 report: Dr. Douglas Wallace at Northern Illinois University (NIU) is now a CoInvestigator. Dec 2016: Drs. Semmes and Dutta were removed from the project; proteomic analysis is now being conducted at UTMB (University of Texas Medical Branch) as contract work.
Project Information: Grant/Contract No. NNX14AE73G 
Responsible Center: NASA JSC 
Grant Monitor: Whitmire, Alexandra  
Center Contact:  
alexandra.m.whitmire@nasa.gov 
Solicitation / Funding Source: 2013 Space Radiobiology NNJ13ZSA001N 
Grant/Contract No.: NNX14AE73G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Human Research Program Risks: (1) HFBP Bmed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders (IRP Rev J)
(2) Sensorimotor:Risk of Altered Sensorimotor/Vestibular Function Impacting Critical Mission Tasks (Revised as of IRP Rev M)
Human Research Program Gaps: (1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-103:What are the validated, efficacious treatments (individual or Team-based) and/or countermeasures to prevent adverse behavioral conditions, CNS/neurological, and/or psychiatric disorders caused by either single and/or integrated exposures to spaceflight hazards during exploration class missions? (IRP Rev L)
(3) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
(4) BMed-108:Given each crewmember will experience multiple spaceflight hazards simultaneously, we need to identify and characterize the potential additive, antagonistic, or synergistic impacts of multiple stressors (e.g., space radiation, altered gravity, isolation, altered immune, altered sleep) on crew health and/or CNS/ cognitive functioning to develop threshold limits and validate countermeasures for any identified adverse crew health and/or operationally-relevant performance outcomes (IRP Rev L)
(5) SM-104:Evaluate how weightlessness-induced changes in sensorimotor/vestibular function relate to and/or interact with changes in other brain functions (sleep, cognition, attention) (IRP Rev M)
Flight Assignment/Project Notes: NOTE: Element change from SR to HFBP per Human Research Roadmap information dtd July 2019 (Ed., 1/6/2020)

NOTE: Extended to 4/30/2023 per NSSC information (Ed., 12/30/2020)

NOTE: Extended to 12/31/2020 per NSSC information (Ed., 3/12/19)

NOTE: Extended to 12/31/2018 per S. Monk/SR/LaRC (Ed., 1/11/18)

Task Description: One of NASA's biggest concerns about the long-term health of astronauts who go on deep space missions is the impact that High Z, High Energy (HZE) particles have on brain function (neurocognition). Data from our laboratory and others suggests that there is significant impairment of certain neurocognitive tasks (spatial memory and Executive function-attentional set shifting) following exposure to low HZE doses. The goal of this application is to determine the Threshold dose for the induction of HZE-induced spatial memory impairments (HISMI) or Attentional Set Shifting Impairments (HIASSI) following exposure to 56Fe, 48Ti, and 28Si particles. The proposed studies will also identify the changes in the proteome of the brain (neuroproteome) of rats that differ in their susceptibility to HISMI and HIASSI, which will provide further insight into the factors that lead to HISMI/HIASSI and perhaps more importantly, that prevent its emergence. Our underlying hypothesis is that HISMI and HIASSI arise as the direct result of HZE-induced changes in the neuroproteome. We also hypothesize that exposure to HZE species that have different track structures will result in different mechanisms of HZE-induced cognitive impairment (HICI). Collectively, these studies will give some insight into the underlying cause for HISMI and HIASSI.

Our studies will thus address CNS (Central Nervous System) Gaps 1, 2, and 6, and we shall specifically focus on the following aims:

Aim 1. Determine the Threshold dose for the induction of HISMI and HIASSI following exposure to 56Fe, 48Ti, and 28Si particles when delivered as a single dose.

Aim 2. Identify changes in the neuroproteome that are associated with susceptibility or resistance to developing HISMI and HIASSI following exposure to 56Fe particles.

Aim 3. Determine the mechanism of HISMI and HIASSI induced by HZE particles of differing LET (linear energy transfer).

In Aim 1, socially mature (~6 month old) male Wistar rats will be irradiated with 56Fe, 48Ti, and 28Si particles (with incident energies of 600 MeV/nucleon). Rats will receive whole body HZE irradiation (< 15 cGy), and HISMI and HIASSI will be assessed at 3 months post irradiation.

In Aim 2 and 3, the composition of the neuroproteome (hippocampus and selected regions of the prefrontal cortex) of irradiated rats that have “normal” cognitive performance or have developed HISMI or HIASSI will be established using an unbiased proteomic profiling approach. We shall use a label free differential protein profiling workflow on the Q-Exactive Orbitrap mass spectrometer.

These studies will give considerable insight into the underlying cause for HZE-induced neurocognitive failure. The proposed studies will continue to define the minimum dose of HZE particles that will induce HISMI and HIASSI. Moreover, our studies will provide considerable insight into the underlying mechanism of HICI, and will identify prognostic biomarkers that could be translated to human studies to monitor the emergence of HICI. These studies may also help to develop appropriate countermeasures and help identify sensitive individuals, so that NASA’s medical staff can implement appropriate countermeasures to protect these at risk individuals.

Supplemental studies (in December 2019 report)

This study will provide information on the robustness of single-exposure experiments to predict the impact of repeated episodic radiation exposures (such as will be encountered on the mission to Mars) on neurocognition. This study will test the hypothesis that episodic space radiation (SR) exposure will result in more severe neurocognitive deficits than single, or multiple daily SR doses. This study will utilize both male and female rats, and two different radiation regimens incorporating 4He ions and the 5-ion galactic cosmic ray simulation (GCRsim) beam. Performance in one executive function task (Attentional Set shifting-ATSET) will be assessed after a single exposure (He or GCRsim) and after a second exposure (~6 months later) to the 5-ion GCRsim beam.

Research Impact/Earth Benefits: These studies will give considerable insight into the underlying cause for Space radiation (SR)-induced neurocognitive impairment (SICI).

The proposed studies will continue to define the minimum dose of SR particles that will impair cognitive flexibility (Attentional Set shifting and Unconstrained cognitive flexibility) performance. Importantly both of our cognitive flexibility tasks are homologs of tasks used in clinical testing of humans. Our studies will model the impact that single and repeated episodic exposure to SR has on neurocognitive performance and fine motor skills.

Moreover, our studies will provide considerable insight into the underlying mechanism of SICI, and will identify prognostic biomarkers that could be translated to human studies to monitor the emergence of SICI. These studies may also help to develop appropriate countermeasures and help identify sensitive individuals, so that NASA’s medical staff can implement appropriate countermeasures to protect these at risk individuals.

Task Progress & Bibliography Information FY2021 
Task Progress: 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 (proven breeder) rats that have been pre-selected for good attentional set shifting (ATSET) performance, and who have been maintained on an exercise regimen are used in this study.

Rats are exposed (primarily a single exposure) to <15 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 Unrestrained Cognitive flexibility (UCFlex) assay, which requires the rats to complete a new task (where the food reward is no longer present in either reward pot, 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 rat to develop a novel solution to obtain the food reward. Thus, the UCFlex version of the ATSET provides the ability to measure both constrained and unconstrained cognitive flexibility within individual rats. Importantly both cognitive flexibility tasks are homologs of tasks used in clinical testing of humans.

Through a new collaboration with Dr. Wallace at Northern Illinois University, we have shipped our rats to NIU, where Dr. Wallace’s team has determined whether there are sensorimotor defects induced by SR, and if any observed changes are co-incidental with changes in ATSET/UCF performance. Specifically, fine motor skills have been assessed using the string-pull assay.

Regions of the cortex, basal forebrain, hippocampus (that regulated certain paradigms with the ATSET test), and temporal lobe (that probably regulates UCFlex performance) are recovered and subjected to proteomic analysis to identify some of the processes that may be responsible for the SR-induced impairment of ATSET.

The supplemental studies involve returning the rats that have maintained good ATSET performance after SR (10 cGy 4He ions or the 5-ion GCRsim beam) to Brookhaven National Laboratory (BNL) where they receive a second dose of 10 cGy of the 5-ion GCRsim. ATSET performance is then reassessed at 3 months after the second exposure.

Research Highlights from this reporting period.

• The COVID pandemic severely interrupted work on this project for the majority of this reporting period; however, progress was made in several areas.

• We published the first study to report that exposure to mission relevant space radiation doses (5 cGy of Si) results in fine motor skill loss, as measured using the string pull assay (Blackwell et al., 2020). The loss of performance in the string pull assay was evident at 3 months post exposure, in rats that had no obvious loss of neurocognitive performance. Ongoing studies are determining how rapidly the impairment of fine motor skills occurs after radiation exposure.

• We have determined that exposure to =1 cGy 400 MeV/n 4He ions results in a significant loss of ATSET performance, and also social withdrawal in male rats. This is the first study to demonstrate space radiation-induced social withdrawal in freely-interacting rodents. Some individuals in confinement studies such as the Mars 500 study (Basner et al., 2014) did socially withdraw, so there is a possibility that SR exposure could exacerbate such withdrawals.

• We have demonstrated for the first time that there is a marked dose responsiveness of UCFlex impairment following He exposure, in stark contrast to other previous studies with neutrons and Si ions. Once again there is no concomitant loss of ATSET and UCFlex performance in individual rats.

• We have demonstrated that exposure to 10 cGy GCRsim results in impaired ATSET performance in female rats. These data suggest that there is no panoramic resilience of female rodents to the impact of SR on neurocognition, as implicated by the mouse/ NOR studies.

• We have demonstrated that exposure to 10 cGy GCRsim leads to a significant reduction in the ability of female to perform pattern separation and avoid anterograde interference in rats that had no obvious loss of ATSET performance. These studies provide further evidence that reliance on a sole measure of neurocognitive performance may lead to significant underestimate of the impact of SR on cognition, and suggest that as task complexity (cognitive loading) increases so does the likelihood of SR-induced performance impairment.

• In collaboration with NASA GeneLab we have determined that exposure to 5 cGy Si results in significant changes in the proteomic composition of the prefrontal cortex, i.e., identified protein biomarkers for space radiation exposure and further subset that dissociated rats that have impaired ATSET performance from those that have apparently normal performance, e.g., the mitochondrial oxidative phosphorylation pathway.

Reference: Basner M, Dinges DF, Mollicone DJ, Savelev I, Ecker AJ, Di Antonio A, Jones CW, Hyder EC, Kan K, Morukov BV, Sutton JP. "Psychological and behavioral changes during confinement in a 520-day simulated interplanetary mission to Mars." PLoS One. 2014 Mar 27;9(3):e93298.

Bibliography Type: Description: (Last Updated: 02/15/2022) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals 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. https://doi.org/10.1667/RR15458.1 ; PMID: 32011211 , Mar-2020
Articles in Peer-reviewed Journals Britten RA, Fesshaye A, Duncan VD, Wellman LL, Sanford LD. "Sleep fragmentation exacerbates executive function impairments induced by low doses of Si ions." Radiat Res. 2020 Aug 1;194(2):116-23. https://doi.org/10.1667/RADE-20-00080.1 ; PMID: 32845991 , Aug-2020
Articles in Peer-reviewed Journals Blackwell AA, Schell BD, 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 Feb 26;400:113010. Epub 2020 Nov 10. https://doi.org/10.1016/j.bbr.2020.113010 ; PMID: 33181183 , Feb-2021
Project Title:  Changes in the Neuroproteome Associated with HZE-Induced Impairment of Cognition Reduce
Images: icon  Fiscal Year: FY 2020 
Division: Human Research 
Research Discipline/Element:
HRP HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Start Date: 02/27/2014  
End Date: 12/31/2020  
Task Last Updated: 12/30/2019 
Download report in PDF pdf
Principal Investigator/Affiliation:   Britten, Richard  Ph.D. / Eastern Virginia Medical School 
Address:  Radiation Oncology 
700 W Olney Rd 
Norfolk , VA 23507-1607 
Email: Brittera@evms.edu 
Phone: 757-446-5038  
Congressional District:
Web:  
Organization Type: NON-PROFIT 
Organization Name: Eastern Virginia Medical School 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Wallace, Douglas  Ph.D. Northern Illinois University 
Key Personnel Changes / Previous PI: December 2019 report: Dr. Douglas Wallace at Northern Illinois University (NIU) is now a CoInvestigator. Dec 2016: Drs. Semmes and Dutta were removed from the project; proteomic analysis is now being conducted at UTMB (University of Texas Medical Branch) as contract work.
Project Information: Grant/Contract No. NNX14AE73G 
Responsible Center: NASA JSC 
Grant Monitor: Williams, Thomas  
Center Contact: 281-483-8773 
thomas.j.will1@nasa.gov 
Solicitation / Funding Source: 2013 Space Radiobiology NNJ13ZSA001N 
Grant/Contract No.: NNX14AE73G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Human Research Program Risks: (1) HFBP Bmed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders (IRP Rev J)
(2) Sensorimotor:Risk of Altered Sensorimotor/Vestibular Function Impacting Critical Mission Tasks (Revised as of IRP Rev M)
Human Research Program Gaps: (1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-103:What are the validated, efficacious treatments (individual or Team-based) and/or countermeasures to prevent adverse behavioral conditions, CNS/neurological, and/or psychiatric disorders caused by either single and/or integrated exposures to spaceflight hazards during exploration class missions? (IRP Rev L)
(3) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
(4) BMed-108:Given each crewmember will experience multiple spaceflight hazards simultaneously, we need to identify and characterize the potential additive, antagonistic, or synergistic impacts of multiple stressors (e.g., space radiation, altered gravity, isolation, altered immune, altered sleep) on crew health and/or CNS/ cognitive functioning to develop threshold limits and validate countermeasures for any identified adverse crew health and/or operationally-relevant performance outcomes (IRP Rev L)
(5) SM-104:Evaluate how weightlessness-induced changes in sensorimotor/vestibular function relate to and/or interact with changes in other brain functions (sleep, cognition, attention) (IRP Rev M)
Flight Assignment/Project Notes: NOTE: Element change from SR to HFBP per Human Research Roadmap information dtd July 2019 (Ed., 1/6/2020)

NOTE: Extended to 12/31/2020 per NSSC information (Ed., 3/12/19)

NOTE: Extended to 12/31/2018 per S. Monk/SR/LaRC (Ed., 1/11/18)

Task Description: One of NASA's biggest concerns about the long-term health of astronauts who go on deep space missions is the impact that High Z, High Energy (HZE) particles have on brain function (neurocognition). Data from our laboratory and others suggests that there is significant impairment of certain neurocognitive tasks (spatial memory and Executive function-attentional set shifting) following exposure to low HZE doses. The goal of this application is to determine the Threshold dose for the induction of HZE-induced spatial memory impairments (HISMI) or Attentional Set Shifting Impairments (HIASSI) following exposure to 56Fe, 48Ti, and 28Si particles. The proposed studies will also identify the changes in the proteome of the brain (neuroproteome) of rats that differ in their susceptibility to HISMI and HIASSI, which will provide further insight into the factors that lead to HISMI/HIASSI and perhaps more importantly, that prevent its emergence. Our underlying hypothesis is that HISMI and HIASSI arise as the direct result of HZE-induced changes in the neuroproteome. We also hypothesize that exposure to HZE species that have different track structures will result in different mechanisms of HZE-induced cognitive impairment (HICI). Collectively, these studies will give some insight into the underlying cause for HISMI and HIASSI.

Our studies will thus address CNS (Central Nervous System) Gaps 1, 2, and 6, and we shall specifically focus on the following aims:

Aim 1. Determine the Threshold dose for the induction of HISMI and HIASSI following exposure to 56Fe, 48Ti, and 28Si particles when delivered as a single dose.

Aim 2. Identify changes in the neuroproteome that are associated with susceptibility or resistance to developing HISMI and HIASSI following exposure to 56Fe particles.

Aim 3. Determine the mechanism of HISMI and HIASSI induced by HZE particles of differing LET (linear energy transfer).

In Aim 1, socially mature (~6 month old) male Wistar rats will be irradiated with 56Fe, 48Ti, and 28Si particles (with incident energies of 600 MeV/nucleon). Rats will receive whole body HZE irradiation (< 15 cGy), and HISMI and HIASSI will be assessed at 3 months post irradiation.

In Aim 2 and 3, the composition of the neuroproteome (hippocampus and selected regions of the prefrontal cortex) of irradiated rats that have “normal” cognitive performance or have developed HISMI or HIASSI will be established using an unbiased proteomic profiling approach. We shall use a label free differential protein profiling workflow on the Q-Exactive Orbitrap mass spectrometer.

These studies will give considerable insight into the underlying cause for HZE-induced neurocognitive failure. The proposed studies will continue to define the minimum dose of HZE particles that will induce HISMI and HIASSI. Moreover, our studies will provide considerable insight into the underlying mechanism of HICI, and will identify prognostic biomarkers that could be translated to human studies to monitor the emergence of HICI. These studies may also help to develop appropriate countermeasures and help identify sensitive individuals, so that NASA’s medical staff can implement appropriate countermeasures to protect these at risk individuals.

Supplemental studies (in December 2019 report)

This study will provide information on the robustness of single-exposure experiments to predict the impact of repeated episodic radiation exposures (such as will be encountered on the mission to Mars) on neurocognition. This study will test the hypothesis that episodic space radiation (SR) exposure will result in more severe neurocognitive deficits than single, or multiple daily SR doses. This study will utilize both male and female rats, and two different radiation regimens incorporating 4He ions and the 5-ion GCRsim beam. Performance in one executive function task (Attentional Set shifting-ATSET) will be assessed after a single exposure (He or GCRsim) and after a second exposure (~6 months later) to the 5-ion GCRsim beam.

Research Impact/Earth Benefits: These studies will give considerable insight into the underlying cause for Space radiation (SR)-induced neurocognitive impairment (SICI).

The proposed studies will continue to define the minimum dose of SR particles that will impair cognitive flexibility (Attentional Set shifting and Unconstrained cognitive flexibility) performance. Importantly both of our cognitive flexibility tasks are homologs of tasks used in clinical testing of humans. Our studies will model the impact that single and repeated episodic exposure to SR has on neurocognitive performance and fine motor skills.

Moreover, our studies will provide considerable insight into the underlying mechanism of SICI, and will identify prognostic biomarkers that could be translated to human studies to monitor the emergence of SICI. These studies may also help to develop appropriate countermeasures and help identify sensitive individuals, so that NASA’s medical staff can implement appropriate countermeasures to protect these at risk individuals.

Task Progress & Bibliography Information FY2020 
Task Progress: 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 (proven breeder) rats that have been pre-selected for good attentional set shifting (ATSET) performance, and who have been maintained on an exercise regimen are used in this study.

Rats are exposed (primarily a single exposure) to <15 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 Unrestrained Cognitive flexibility (UCFlex) assay, that requires the rats to complete a new task (where the food reward is no longer present in either reward pot, 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 rat to develop a novel solution to obtain the food reward. Thus, the UCFlex version of the ATSET provides the ability to measure both constrained and unconstrained cognitive flexibility within individual rats. Importantly, both of our cognitive flexibility tasks are homologs of tasks used in clinical testing of humans.

Through a new collaboration with Dr. Wallace at Northern Illinois University (NIU), we have shipped our rats to NIU, where Dr. Wallace’s team has determined whether there are sensorimotor defects induced by SR, and if any observed changes are co-incidental with changes in ATSET/UCF performance. Specifically, fine motor skills have been assessed using the string-pull assay.

Regions of the cortex, basal forebrain, hippocampus (that regulated certain paradigms with the ATSET test), and temporal lobe (that probably regulates UCFlex performance) are recovered and subjected to proteomic analysis to identify some of the processes that may be responsible for the SR-induced impairment of ATSET.

The supplemental studies involve returning the rats that have maintained good ATSET performance after SR (10 cGy 4He ions or the 5-ion GCRsim beam) to Brookhaven National Laboratory (BNL) where they receive a second dose of 10 cGy of the 5-ion GCRsim. ATSET performance is then reassessed at 3 months after the second exposure.

Research Highlights

• SR doses as low as 1 cGy lead to the impairment of ATSET performance, particularly in the tasks regulated by the mPFC and perirhinal regions.

• However, imprinted memories are preserved following SR exposure, suggesting that highly “entrained” skill sets may not be affected by SR exposure [Jewell et al., 2018].

• The addition of the UCFlex test not only increases the spectrum of executive functions studied, but provides information on the impact of SR exposure on insightful problem solving, and by default on the functionality of the temporal lobe.

• SR doses as low as 1 cGy impair insightful problem solving.

• SR doses as low as 5 cGy impair fine motor skills, even when the rats have no apparent loss of ATSET performance.

• These data suggest that a wide range of executive functions are impaired by mission pertinent SR doses, which raises concerns about whether other executive functions that regulate risk decision making and impulsivity are also affected.

• The use of Kernel Density Estimation to interrogate the distribution of ATSET performance metrics in sham and irradiated rats facilitates the quantification of severely impaired individuals. Substitution of the percentage of severely impaired individuals into the Numbers Needed to Harm (NNH) algorithm provides an estimation of the absolute risk increase on cognitive performance by SR: 34% following 3 cGy Fe, 36% following 18 cGy protracted neutron (data from NSCOR--NASA Specialized Center of Research--studies).

Brain regions impacted by SR exposure.

The tasks most frequently impaired after SR exposure were Simple Discrimination (SD) and Compound Discrimination (CD). SD is regulated by the mPFC; CD is probably regulated by perirhinal cortical region, and requires optimal dopamine D2 receptor activation in pre-frontal cortex. The impairment of UCFlex performance is indicative of changes in the functionality of the temporal lobe.

Changes in the Neuroproteome associated with changes in ATSET performance.

The first batch of pre-frontal cortex samples were run over the summer of 2017, and Dr. Britten has analyzed the vast amount of proteomic data generated. It is clear that there are proteins whose expression changes as a result of radiation exposure, and other proteins whose expression differs in relationship to the ability of the rats to perform ATSET, including GABAergic signaling pathways.

Reference:

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.

Bibliography Type: Description: (Last Updated: 02/15/2022) 

Show Cumulative Bibliography Listing
 
 None in FY 2020
Project Title:  Changes in the Neuroproteome Associated with HZE-Induced Impairment of Cognition Reduce
Images: icon  Fiscal Year: FY 2019 
Division: Human Research 
Research Discipline/Element:
HRP HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Start Date: 02/27/2014  
End Date: 12/31/2020  
Task Last Updated: 12/30/2018 
Download report in PDF pdf
Principal Investigator/Affiliation:   Britten, Richard  Ph.D. / Eastern Virginia Medical School 
Address:  Radiation Oncology 
700 W Olney Rd 
Norfolk , VA 23507-1607 
Email: Brittera@evms.edu 
Phone: 757-446-5038  
Congressional District:
Web:  
Organization Type: NON-PROFIT 
Organization Name: Eastern Virginia Medical School 
Joint Agency:  
Comments:  
Key Personnel Changes / Previous PI: Dec 2016: Drs. Semmes and Dutta were removed from the project; proteomic analysis is now being conducted at UTMB (University of Texas Medical Branch) as contract work.
Project Information: Grant/Contract No. NNX14AE73G 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2013 Space Radiobiology NNJ13ZSA001N 
Grant/Contract No.: NNX14AE73G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Human Research Program Risks: (1) HFBP Bmed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders (IRP Rev J)
(2) Sensorimotor:Risk of Altered Sensorimotor/Vestibular Function Impacting Critical Mission Tasks (Revised as of IRP Rev M)
Human Research Program Gaps: (1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-103:What are the validated, efficacious treatments (individual or Team-based) and/or countermeasures to prevent adverse behavioral conditions, CNS/neurological, and/or psychiatric disorders caused by either single and/or integrated exposures to spaceflight hazards during exploration class missions? (IRP Rev L)
(3) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
(4) BMed-108:Given each crewmember will experience multiple spaceflight hazards simultaneously, we need to identify and characterize the potential additive, antagonistic, or synergistic impacts of multiple stressors (e.g., space radiation, altered gravity, isolation, altered immune, altered sleep) on crew health and/or CNS/ cognitive functioning to develop threshold limits and validate countermeasures for any identified adverse crew health and/or operationally-relevant performance outcomes (IRP Rev L)
(5) SM-104:Evaluate how weightlessness-induced changes in sensorimotor/vestibular function relate to and/or interact with changes in other brain functions (sleep, cognition, attention) (IRP Rev M)
Flight Assignment/Project Notes: NOTE: Extended to 12/31/2020 per NSSC information (Ed., 3/12/19)

NOTE: Extended to 12/31/2018 per S. Monk/SR/LaRC (Ed., 1/11/18)

Task Description: One of NASA's biggest concerns about the long-term health of astronauts who go on deep space missions is the impact that High Z, High Energy (HZE) particles have on brain function (neurocognition). Data from our laboratory and others suggests that there is significant impairment of certain neurocognitive tasks (spatial memory and Executive function-attentional set shifting) following exposure to low HZE doses. The goal of this application is to determine the Threshold dose for the induction of HZE-induced spatial memory impairments (HISMI) or Attentional Set Shifting Impairments (HIASSI) following exposure to 56Fe, 48Ti, and 28Si particles. The proposed studies will also identify the changes in the proteome of the brain (neuroproteome) of rats that differ in their susceptibility to HISMI and HIASSI, which will provide further insight into the factors that lead to HISMI/HIASSI and perhaps more importantly, that prevent its emergence. Our underlying hypothesis is that HISMI and HIASSI arise as the direct result of HZE-induced changes in the neuroproteome. We also hypothesize that exposure to HZE species that have different track structures will result in different mechanisms of HZE-induced cognitive impairment (HICI). Collectively, these studies will give some insight into the underlying cause for HISMI and HIASSI.

Our studies will thus address CNS (Central Nervous System) Gaps 1, 2, and 6, and we shall specifically focus on the following aims:

Aim 1. Determine the Threshold dose for the induction of HISMI and HIASSI following exposure to 56Fe, 48Ti, and 28Si particles when delivered as a single dose.

Aim 2. Identify changes in the neuroproteome that are associated with susceptibility or resistance to developing HISMI and HIASSI following exposure to 56Fe particles.

Aim 3. Determine the mechanism of HISMI and HIASSI induced by HZE particles of differing LET (linear energy transfer).

In Aim 1, socially mature (~6 month old) male Wistar rats will be irradiated with 56Fe, 48Ti, and 28Si particles (with incident energies of 600 MeV/nucleon). Rats will receive whole body HZE irradiation (< 15 cGy), and HISMI and HIASSI will be assessed at 3 months post irradiation.

In Aim 2 and 3, the composition of the neuroproteome (hippocampus and selected regions of the prefrontal cortex) of irradiated rats that have “normal” cognitive performance or have developed HISMI or HIASSI will be established using an unbiased proteomic profiling approach. We shall use a label free differential protein profiling workflow on the Q-Exactive Orbitrap mass spectrometer.

These studies will give considerable insight into the underlying cause for HZE-induced neurocognitive failure. The proposed studies will continue to define the minimum dose of HZE particles that will induce HISMI and HIASSI. Moreover, our studies will provide considerable insight into the underlying mechanism of HICI, and will identify prognostic biomarkers that could be translated to human studies to monitor the emergence of HICI. These studies may also help to develop appropriate countermeasures and help identify sensitive individuals, so that NASA’s medical staff can implement appropriate countermeasures to protect these at risk individuals.

Research Impact/Earth Benefits: These studies will give considerable insight into the underlying cause for HZE-induced neurocognitive failure. The proposed studies will continue to define the minimum dose of HZE particles that will induce HISMI and HIASSI. Moreover, our studies will provide considerable insight into the underlying mechanism of HICI, and will identify prognostic biomarkers that could be translated to human studies to monitor the emergence of HICI. These studies may also help to develop appropriate countermeasures and help identify sensitive individuals, so that NASA’s medical staff can implement appropriate countermeasures to protect these at risk individuals.

Task Progress & Bibliography Information FY2019 
Task Progress: 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.

Project Approach: To better simulate the “clinical reality,” adult (proven breeder) male rats that have been pre-selected for good ATSET performance, and who have been maintained on an exercise regimen are used in this study. These “vetted” rats are exposed (primarily a single exposure) to <15 cGy of SR ions (incident energy <1000 MeV/n) and ATSET performance re-established at 3 months post exposure. Typically the post-exposure ATSET test is reconfigured from the pre-exposure ATSET test, so that the rats have to “relearn” the associative clues, and importantly the post-exposure test uses associative clues in the first six paradigms that are “media”-based and not olfactory-based. These changes eliminate memory retention issues and also SR-induced changes in olfaction. However, in some instances, rats are presented with the pre-screening ATSET protocol to determine if SR exposure impairs the rats’ memory of the test.

After completion of the ATSET test, the rats are then tested in the Unrestrained Cognitive flexibility (UCFlex) assay, which requires that the rats have to complete a new task where the food reward is no longer present in either reward pot (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, requiring the rat to develop a novel solution to obtain the food reward. Thus, the UCFlex version of the ATSET provides the ability to measure both constrained and unconstrained cognitive flexibility within individual rats. Unconstrained cognitive flexibility is frequently used by humans to solve complex problems (insightful problem solving).

Regions of the cortex, basal forebrain, hippocampus (that regulated certain paradigms with the ATSET test), and temporal lobe (that probably regulates UCFlex performance) are recovered and subjected to proteomic analysis to identify some of the processes that may be responsible for the SR-induced impairment of ATSET.

Work conducted to date:

To date ~550 “vetted” rats have been used to assess the ATSET performance after exposure to <10 cGy of 400 MeV/n 4He, 400 MeV/n 16O, 600 MeV/n 28Si, 600 MeV/n 48Ti, and 600 MeV/n 56Fe ions. Approximately 250 of these rats have also been characterized for their performance in the UCFlex assay.

Furthermore, our studies have focused on presenting our data in a format that can be readily used to calculate a Probabilistic Risk Analysis (PRA) for cognitive impairment, i.e., establishing the severity and frequency of severe ATSET impairment.

Research Highlights

• SR doses as low as 1 cGy lead to the impairment of ATSET performance, particularly in the tasks regulated by the mPFC and perirhinal regions.

• However, imprinted memories are preserved following SR exposure, suggesting that highly “entrained” skill sets may not be affected by SR exposure (Jewell et al., 2018).

• The addition of the UCFlex test not only increases the spectrum of executive functions studied, but provides information on the impact of SR exposure on insightful problem solving, and by default on the functionality of the temporal lobe.

• SR doses as low as 1 cGy impair insightful problem solving.

• These data suggest that a wide range of executive functions are impaired by mission pertinent SR doses, which raises concerns about whether other executive functions that regulate risk decision making and impulsivity are also affected.

• The use of Kernel Density Estimation to interrogate the distribution of ATSET performance metrics in sham and irradiated rats facilitates the quantification of severely impaired individuals. Substitution of the percentage of severely impaired individuals into the Numbers Needed to Harm (NNH) algorithm provides an estimation of the absolute risk increase on cognitive performance by SR: 34% following 3 cGy Si, 36% following 18 cGy protracted neutron (data from NSCOR--NASA Specialized Center of Research--studies).

Brain regions impacted by SR exposure. The tasks most frequently impaired after SR exposure were Simple Discrimination (SD) and Compound Discrimination (CD). SD is regulated by the mPFC; CD is probably regulated by perirhinal cortical region, and requires optimal dopamine D2 receptor activation in pre-frontal cortex. The impairment of UCFlex performance is indicative of changes in the functionality of the temporal lobe.

Changes in the Neuroproteome associated with changes in ATSET performance. The first batch of pre-frontal cortex samples were run over the summer of 2017, and Dr. Britten continues to sort through the vast amount of data generated. Preliminary data suggest that SR exposure induces marked differences in the neuroproteome and that Beta-adrenergic signaling and GABAergic signaling pathways may be preferentially altered by SR exposure.

Reference:

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.

Bibliography Type: Description: (Last Updated: 02/15/2022) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Jewell JS, Duncan VD, Fesshaye A, Tondin A, Macadat E, Britten RA. "Exposure to < or =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 Dec;190(6):565-75. Epub 2018 Nov 8. https://doi.org/10.1667/RR15085.1 ; PMID: 30407900 , Dec-2018
Articles in Peer-reviewed Journals Britten RA, Jewell JS, Duncan VD, Hadley MM, Macadat E, Musto AE, La Tessa C. "Impaired attentional set-shifting performance after exposure to 5 cGy of 600 MeV/n (28)Si particles." Radiat Res. 2018 Mar;189(3):273-82. Epub 2018 Jan 8. https://doi.org/10.1667/RR14627.1 ; PubMed PMID: 29309264 , Mar-2018
Articles in Peer-reviewed Journals Dutta SM, Hadley MM, Peterman S, Jewell JS, Duncan VD, Britten RA. "Quantitative proteomic analysis of the hippocampus of rats with GCR-induced spatial memory impairment." Radiat Res. 2018 Feb;189(2):136-45. Epub 2017 Dec 5. https://doi.org/10.1667/RR14822.1 ; PubMed PMID: 29206597 , Feb-2018
Project Title:  Changes in the Neuroproteome Associated with HZE-Induced Impairment of Cognition Reduce
Images: icon  Fiscal Year: FY 2018 
Division: Human Research 
Research Discipline/Element:
HRP HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Start Date: 02/27/2014  
End Date: 12/31/2018  
Task Last Updated: 12/28/2017 
Download report in PDF pdf
Principal Investigator/Affiliation:   Britten, Richard  Ph.D. / Eastern Virginia Medical School 
Address:  Radiation Oncology 
700 W Olney Rd 
Norfolk , VA 23507-1607 
Email: Brittera@evms.edu 
Phone: 757-446-5038  
Congressional District:
Web:  
Organization Type: NON-PROFIT 
Organization Name: Eastern Virginia Medical School 
Joint Agency:  
Comments:  
Key Personnel Changes / Previous PI: Dec 2016: Drs. Semmes and Dutta were removed from the project; proteomic analysis is now being conducted at UTMB (University of Texas Medical Branch) as contract work.
Project Information: Grant/Contract No. NNX14AE73G 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2013 Space Radiobiology NNJ13ZSA001N 
Grant/Contract No.: NNX14AE73G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Human Research Program Risks: (1) HFBP Bmed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders (IRP Rev J)
(2) Sensorimotor:Risk of Altered Sensorimotor/Vestibular Function Impacting Critical Mission Tasks (Revised as of IRP Rev M)
Human Research Program Gaps: (1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-103:What are the validated, efficacious treatments (individual or Team-based) and/or countermeasures to prevent adverse behavioral conditions, CNS/neurological, and/or psychiatric disorders caused by either single and/or integrated exposures to spaceflight hazards during exploration class missions? (IRP Rev L)
(3) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
(4) BMed-108:Given each crewmember will experience multiple spaceflight hazards simultaneously, we need to identify and characterize the potential additive, antagonistic, or synergistic impacts of multiple stressors (e.g., space radiation, altered gravity, isolation, altered immune, altered sleep) on crew health and/or CNS/ cognitive functioning to develop threshold limits and validate countermeasures for any identified adverse crew health and/or operationally-relevant performance outcomes (IRP Rev L)
(5) SM-104:Evaluate how weightlessness-induced changes in sensorimotor/vestibular function relate to and/or interact with changes in other brain functions (sleep, cognition, attention) (IRP Rev M)
Flight Assignment/Project Notes: NOTE: Extended to 12/31/2018 per S. Monk/SR/LaRC (Ed., 1/11/18)

Task Description: One of NASA's biggest concerns about the long-term health of astronauts who go on deep space missions is the impact that High Z, High Energy (HZE) particles have on brain function (neurocognition). Data from our laboratory and others suggests that there is significant impairment of certain neurocognitive tasks (spatial memory and Executive function-attentional set shifting) following exposure to low HZE doses. The goal of this application is to determine the Threshold dose for the induction of HZE-induced spatial memory impairments (HISMI) or Attentional Set Shifting Impairments (HIASSI) following exposure to 56Fe, 48Ti, and 28Si particles. The proposed studies will also identify the changes in the proteome of the brain (neuroproteome) of rats that differ in their susceptibility to HISMI and HIASSI, which will provide further insight into the factors that lead to HISMI/HIASSI and perhaps more importantly, that prevent its emergence. Our underlying hypothesis is that HISMI and HIASSI arise as the direct result of HZE-induced changes in the neuroproteome. We also hypothesize that exposure to HZE species that have different track structures will result in different mechanisms of HZE-induced cognitive impairment (HICI). Collectively, these studies will give some insight into the underlying cause for HISMI and HIASSI.

Our studies will thus address CNS (Central Nervous System) Gaps 1, 2, and 6, and we shall specifically focus on the following aims:

Aim 1. Determine the Threshold dose for the induction of HISMI and HIASSI following exposure to 56Fe, 48Ti, and 28Si particles when delivered as a single dose.

Aim 2. Identify changes in the neuroproteome that are associated with susceptibility or resistance to developing HISMI and HIASSI following exposure to 56Fe particles.

Aim 3. Determine the mechanism of HISMI and HIASSI induced by HZE particles of differing LET (linear energy transfer).

In Aim 1, socially mature (~6 month old) male Wistar rats will be irradiated with 56Fe, 48Ti, and 28Si particles (with incident energies of 600 MeV/nucleon). Rats will receive whole body HZE irradiation (< 15 cGy), and HISMI and HIASSI will be assessed at 3 months post irradiation.

In Aim 2 and 3, the composition of the neuroproteome (hippocampus and selected regions of the prefrontal cortex) of irradiated rats that have “normal” cognitive performance or have developed HISMI or HIASSI will be established using an unbiased proteomic profiling approach. We shall use a label free differential protein profiling workflow on the Q-Exactive Orbitrap mass spectrometer.

These studies will give considerable insight into the underlying cause for HZE-induced neurocognitive failure. The proposed studies will continue to define the minimum dose of HZE particles that will induce HISMI and HIASSI. Moreover, our studies will provide considerable insight into the underlying mechanism of HICI, and will identify prognostic biomarkers that could be translated to human studies to monitor the emergence of HICI. These studies may also help to develop appropriate countermeasures and help identify sensitive individuals, so that NASA’s medical staff can implement appropriate countermeasures to protect these at risk individuals.

Research Impact/Earth Benefits: These studies will give considerable insight into the underlying cause for HZE-induced neurocognitive failure. The proposed studies will continue to define the minimum dose of HZE particles that will induce HISMI and HIASSI. Moreover, our studies will provide considerable insight into the underlying mechanism of HICI, and will identify prognostic biomarkers that could be translated to human studies to monitor the emergence of HICI. These studies may also help to develop appropriate countermeasures and help identify sensitive individuals, so that NASA’s medical staff can implement appropriate countermeasures to protect these at risk individuals.

Task Progress & Bibliography Information FY2018 
Task Progress: Project Objectives

1. Identify the lowest Galactic Cosmic Radiation (GCR) dose 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 GCR-exposed animals.

Project Approach: To better simulate the “clinical reality,” adult (proven breeder) male rats that have been pre-selected for good attentional set shifting (ATSET) performance, and who have been maintained on an exercise regimen are used in this study. Rats are exposed (primarily a single exposure) to <15 cGy of GCR ions (incident energy <600 MeV/n) and ATSET performance re-established at 3 months post exposure. The post-exposure ATSET test is reconfigured from the pre-exposure ATSET test, so that the rats have to “relearn” the associative clues, and importantly the post-exposure test uses associative clues in the first 6 paradigms that are “media”-based and not olfactory-based. These changes eliminate memory retention issues and also GCR-induced changes in olfaction.

Regions of the cortex and basal forebrain (that regulated certain paradigms with the ATSET test) are recovered and subjected to proteomic analysis to identify some of the processes that may be responsible for the GCR-induced impairment of ATSET.

Work conducted to date:

To date ~500 rats that have been selected for good ATSET performance have been used to assess the ATSET performance after exposure to <10 cGy of 400 MeV/n 4He, 400 MeV/n 16O, 600 MeV/n 28Si, 600 MeV/n 48Ti, and 600 MeV/n 56Fe ions.

In addition to accruing data that will help establish the lowest dose of GCR radiation that will impair ATSET, during this reporting period we have also determined whether GCR exposure impacts “established” working memory.

Furthermore, our studies have focused on presenting our data in a format that can be readily used to calculate a Probabilistic Risk Analysis (PRA) for cognitive impairment, i.e., establishing the severity and frequency of severe ATSET impairment.

While the ATSET test provides considerable insight into the problem-solving capacity of rats, it is limited in that it only measures the ability of rats to shift attention between a constrained set of options. Humans also have the ability to conduct creative problem using unconstrained cognitive flexibility. There has been a recent evolution of the ATSET test, the Unconstrained Cognitive flexibility (UCFlex) assay that requires creative problem solving [Hecht et al., 2014]. During this reporting period we have developed our own version of the UCFlex assay and have expanded our studies to include unconstrained cognitive flexibility performance.

Research Highlights

• GCR doses as low as 1 cGy lead to the impairment of ATSET performance, particularly in the tasks regulated by the mPFC and perirhinal regions. (To date we have not seen any measureable ATSET impairment by 16O ions- only 1 batch analyzed, another batch about to be rescreened in Feb 2018.)

• However, imprinted memories are preserved following GCR exposure, suggesting that highly “entrained” skill sets may not be affected by GCR exposure.

• The addition of the UCFlex test not only increases the spectrum of executive functions studied, but also provides information on the impact of GCR exposure on insightful problem solving, and by default on the functionality of the temporal lobe.

• GCR doses as low as 1 cGy impair insightful problem solving.

• These data suggest that a wide range of executive functions are impaired by mission pertinent GCR doses, which raises concerns about whether other executive functions that regulate risk decision making and impulsivity are also effected.

• The use of PRA style analysis in addition to the traditional cohort analysis, suggest that as many as 2/3 of individuals may experience some form of executive function impairment after 5-10 cGy of Z<15 GCR ions.

Brain regions impacted by HZE exposure. The tasks most frequently impaired after GCR exposure were Simple Discrimination (SD) and Compound Discrimination (CD). SD is regulated by the mPFC; CD is probably regulated by perirhinal cortical region, and requires optimal dopamine D2 receptor activation in pre-frontal cortex.

Changes in the Neuroproteome associated with changes in ATSET performance. The first batch of pre-frontal cortex samples were run over the Summer of 2017, and Dr. Britten continues to sort through the vast amount of data generated. It is clear that there are proteins whose expression changes as a result of radiation exposure, other proteins whose expression differs in relationship to the ability of the rats to perform ATSET, including GABAergic signaling pathways. Over the remaining period of this grant, we shall analyze more samples from rats exposed to 600 MeV/n 28Si and 400 MeV/n 4He, and given the observed changes in the UCFlex assay we shall be extending these studies to include the Temporal Lobe.

Project Summary

Over the last year, studies were conducted that determined whether rats exposed to mission-pertinent GCR exposures had compromised cognitive flexibility. The studies have primarily focused on the impact that Z<15 ions had on constrained (ATSET) and unconstrained (creative problem solving) cognitive flexibility. Interestingly, GCR impairment of form of cognitive flexibility was rarely associated with impairment in the other form of cognitive flexibility. These data suggest that risk assessments for cognitive impairment need to be based upon at least two cognitive domains. While some of the observed impairments in executive function could lead to a decreased ability of astronauts to conduct certain tasks, data obtained during this reporting period suggest that “imprinted” memory is not impacted by GCR exposure, so routine procedures will probably be able to be performed during the mission, however, situation requiring novel problem solving could be compromised.

Preliminary data suggest that there are marked differences in the neuroproteome in response to GCR exposure and that Beta-adrenergic signaling and GABAergic signaling pathways may be preferentially altered by GCR exposure.

Reference

Hecht PM, Will MJ, Schachtman TR, Welby LM, Beversdorf DQ. Beta-adrenergic antagonist effects on a novel cognitive flexibility task in rodents. Behav Brain Res, 2014; 260:148-54.

Bibliography Type: Description: (Last Updated: 02/15/2022) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Britten RA, Jewell JS, Duncan VD, Davis LK, Hadley MM, Wyrobek AJ. "Spatial memory performance of socially mature Wistar rats is impaired after exposure to low (5 cGy) doses of 1 GeV/n 48Ti particles." Radiation Research. 2017 Jan;187(1):60-5. https://doi.org/10.1667/RR14550.1 ; PubMed PMID: 28085638 , Jan-2017
Articles in Peer-reviewed Journals Britten RA, Jewell JS, Davis LK, Miller VD, Hadley MM, Semmes OJ, Lonart G, Dutta SM. "Changes in the hippocampal proteome associated with spatial memory impairment after exposure to low (20 cGy) doses of 1 GeV/n 56Fe radiation." Radiation Research. 2017 Mar;187(3):287-297. Epub 2017 Feb 3. https://doi.org/10.1667/RR14067.1 ; PubMed PMID: 28156212 , Mar-2017
Articles in Peer-reviewed Journals Dutta SM, Hadley MM, Peterman S, Jewell JS, Duncan VD, Britten RA. "Quantitative proteomic analysis of the hippocampus of rats with GCR-induced spatial memory impairment." Radiation Research. 2017 Dec 5. [Epub ahead of print] https://doi.org/10.1667/RR14822.1 ; PubMed PMID: 29206597 , Dec-2017
Project Title:  Changes in the Neuroproteome Associated with HZE-Induced Impairment of Cognition Reduce
Images: icon  Fiscal Year: FY 2017 
Division: Human Research 
Research Discipline/Element:
HRP HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Start Date: 02/27/2014  
End Date: 02/26/2018  
Task Last Updated: 01/03/2017 
Download report in PDF pdf
Principal Investigator/Affiliation:   Britten, Richard  Ph.D. / Eastern Virginia Medical School 
Address:  Radiation Oncology 
700 W Olney Rd 
Norfolk , VA 23507-1607 
Email: Brittera@evms.edu 
Phone: 757-446-5038  
Congressional District:
Web:  
Organization Type: NON-PROFIT 
Organization Name: Eastern Virginia Medical School 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Dutta, Sucharita  Eastern Virginia Medical School 
Semmes, Oliver  Eastern Virginia Medical School 
Lonart, Gyorgy  Ph.D. Eastern Virginia Medical School 
Key Personnel Changes / Previous PI: November 2012 report: Dr. Sucharita Dutta, a proteomics expert, has been added to the team.
Project Information: Grant/Contract No. NNX14AE73G 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2013 Space Radiobiology NNJ13ZSA001N 
Grant/Contract No.: NNX14AE73G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Human Research Program Risks: (1) HFBP Bmed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders (IRP Rev J)
(2) Sensorimotor:Risk of Altered Sensorimotor/Vestibular Function Impacting Critical Mission Tasks (Revised as of IRP Rev M)
Human Research Program Gaps: (1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-103:What are the validated, efficacious treatments (individual or Team-based) and/or countermeasures to prevent adverse behavioral conditions, CNS/neurological, and/or psychiatric disorders caused by either single and/or integrated exposures to spaceflight hazards during exploration class missions? (IRP Rev L)
(3) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
(4) BMed-108:Given each crewmember will experience multiple spaceflight hazards simultaneously, we need to identify and characterize the potential additive, antagonistic, or synergistic impacts of multiple stressors (e.g., space radiation, altered gravity, isolation, altered immune, altered sleep) on crew health and/or CNS/ cognitive functioning to develop threshold limits and validate countermeasures for any identified adverse crew health and/or operationally-relevant performance outcomes (IRP Rev L)
(5) SM-104:Evaluate how weightlessness-induced changes in sensorimotor/vestibular function relate to and/or interact with changes in other brain functions (sleep, cognition, attention) (IRP Rev M)
Task Description: One of NASA's biggest concerns about the long-term health of astronauts who go on deep space missions is the impact that High Z, High Energy (HZE) particles have on brain function (neurocognition). Data from our laboratory and others suggests that there is significant impairment of certain neurocognitive tasks (spatial memory and Executive function-attentional set shifting) following exposure to low HZE doses. The goal of this application is to determine the Threshold dose for the induction of HZE-induced spatial memory impairments (HISMI) or Attentional Set Shifting Impairments (HIASSI) following exposure to 56Fe, 48Ti, and 28Si particles. The proposed studies will also identify the changes in the proteome of the brain (neuroproteome) of rats that differ in their susceptibility to HISMI and HIASSI, which will provide further insight into the factors that lead to HISMI/HIASSI and perhaps more importantly, that prevent its emergence. Our underlying hypothesis is that HISMI and HIASSI arise as the direct result of HZE-induced changes in the neuroproteome. We also hypothesize that exposure to HZE species that have different track structures will result in different mechanisms of HZE-induced cognitive impairment (HICI). Collectively, these studies will give some insight into the underlying cause for HISMI and HIASSI.

Our studies will thus address CNS (Central Nervous System) Gaps 1, 2, and 6, and we shall specifically focus on the following aims:

Aim 1. Determine the Threshold dose for the induction of HISMI and HIASSI following exposure to 56Fe, 48Ti, and 28Si particles when delivered as a single dose.

Aim 2. Identify changes in the neuroproteome that are associated with susceptibility or resistance to developing HISMI and HIASSI following exposure to 56Fe particles.

Aim 3. Determine the mechanism of HISMI and HIASSI induced by HZE particles of differing LET (linear energy transfer).

In Aim 1, socially mature (~6 month old) male Wistar rats will be irradiated with 56Fe, 48Ti, and 28Si particles (with incident energies of 600 MeV/nucleon). Rats will receive whole body HZE irradiation (< 15 cGy), and HISMI and HIASSI will be assessed at 3 months post irradiation.

In Aim 2 and 3, the composition of the neuroproteome (hippocampus and selected regions of the prefrontal cortex) of irradiated rats that have “normal” cognitive performance or have developed HISMI or HIASSI will be established using an unbiased proteomic profiling approach. We shall use a label free differential protein profiling workflow on the Q-Exactive Orbitrap mass spectrometer.

These studies will give considerable insight into the underlying cause for HZE-induced neurocognitive failure. The proposed studies will continue to define the minimum dose of HZE particles that will induce HISMI and HIASSI. Moreover, our studies will provide considerable insight into the underlying mechanism of HICI, and will identify prognostic biomarkers that could be translated to human studies to monitor the emergence of HICI. These studies may also help to develop appropriate countermeasures and help identify sensitive individuals, so that NASA’s medical staff can implement appropriate countermeasures to protect these at risk individuals.

Research Impact/Earth Benefits: These studies will give considerable insight into the underlying cause for HZE-induced neurocognitive failure. The proposed studies will continue to define the minimum dose of HZE particles that will induce HISMI and HIASSI. Moreover, our studies will provide considerable insight into the underlying mechanism of HICI, and will identify prognostic biomarkers that could be translated to human studies to monitor the emergence of HICI. These studies may also help to develop appropriate countermeasures and help identify sensitive individuals, so that NASA’s medical staff can implement appropriate countermeasures to protect these at risk individuals.

Task Progress & Bibliography Information FY2017 
Task Progress: Project Objectives

1. Identify the lowest HZE dose 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 HZE-exposed animals.

Project Approach: To better simulate the “clinical reality,” adult (proven breeder) male rats that have been pre-selected for good attentional set shifting (ATSET) performance, and who have been maintained on an exercise regimen are used in this study. Rats are exposed (primarily a single exposure) to <15 cGy of HZE ions (incident energy <600 MeV/n) and ATSET performance re-established at 3 months post exposure. The post-exposure ATSET test is reconfigured from the pre-exposure ATSET test, so that the rats have to “relearn” the associative clues, and importantly the post-exposure test uses associative clues in the first 6 paradigms that are “media”-based and not olfactory-based. These changes eliminate memory retention issues and also HZE-induced changes in olfaction. A novel aspect of the current study is to characterize the “motivational” status of the rats to perform the ATSET test, i.e., whether they are motivated to perform the task, give up easily, etc. Regions of the cortex and basal forebrain (that regulated certain paradigms with the ATSET test) will be recovered and subjected to proteomic analysis to identify some of the processes that may be responsible for the HZE-induced impairment of ATSET.

Work conducted to date:

To date a total of 683 rats have been pre-screened for ATSET performance, and 407 (59.7%) “vetted” rats had adequate ATSET performance to be used to assess the impact of HZE on ATSET performance. These “vetted” rats were exposed to 600 MeV/n 56Fe or 600 MeV/n 28Si during NASA Space Radiation Laboratory (NSRL) 15A, to 600 MeV/n 48Ti, 600 MeV/n 56Fe, 600 MeV/n 28Si, or 400 MeV/n 16O during NSRL15C, and to 600 MeV/n 28Si or 400 MeV/n 4He during NRSRL16C.

Research Highlights

No impairment of ATSET performance was observed in the 1 batch of rats exposed to 400 MeV/n 16O (1.5, 5 and 10 cGy). However, significant impairments in ATSET performance were observed after exposure to the other ions. The lowest dose where ATSET performance was impaired was:

600 MeV/n 48Ti, 5 cGy (lowest studied); 600 MeV/n 56Fe, 3 cGy (NS changes at 1 cGy) 600 MeV/n 28Si, 5 cGy (lowest studied); 400 MeV/n 4He, Rats not screened for ATSET performance yet.

Marked inter-individual differences in level of impairment. Some irradiated individuals retain “normal” ATSET, while others fail the paradigm.

Brain regions impacted by HZE exposure. The paradigms impaired after exposure to 5 cGy (of all ions studied) were Simple Discrimination (SD) and Compound Discrimination (CD). These data suggest that the functionality of multiple brain regions may be impaired by these low HZE doses. SD is regulated by the mPFC; CD is probably regulated by perirhinal cortical region, and requires optimal dopamine D2 receptor activation in pre-frontal cortex.

Probabilistic Risk Assessments: In recent years we have started to present our data in a format that is more amenable to the Probabilistic Risk Assessments that NASA uses to evaluate mission risks. Such data analysis requires that the percentage of individuals impacted as well as the severity of the impairments be considered.

We have established that 5-15% of Sham rats failed to pass the SD and CD paradigms on their first attempt, but <5% of Sham rats could not pass these stages when given 2 attempts to do so. In contrast 15-40% of the irradiated rats had problems completing SD and CD on their first attempt. Many of these rats managed to pass SD on the second attempt, but a significantly higher percentage failed to complete CD even after 2 attempts. Overall, 8% of Sham rats failed (on two occasions) at least one stage of testing; in contrast 43, 41, and 63% of rats irradiated with 5 cGy 600 MeV/n Fe, Si, or Ti ions failed at least one stage.

Re-irradiation studies. As mentioned earlier, some irradiated rats exhibited an ATSET performance that was indistinguishable from that of the Shams. We determined whether these “resistant” individuals maintained their good performance status when exposed to episodic multi-ion exposures. In a pilot study “resistant” (that had good ATSET performance) rats from NSRL14C were returned to Brookhaven National Laboratory (BNL) during NSRL15A (~270 days later) and re-irradiated. In some cases, rats received Si, O, or Ti during NSRL14C and some received Fe. All received 600 MeV/n 56Fe during NSRL15A.

A few conclusions can be drawn from this study:

1. Resistant rats are not always resistant, and that repeated exposures can changed their ATSET performance.

2. The failures in the episodic exposed rats occur in paradigms that are rarely impacted after a single exposure (IDS and IDR) as well as CDR.

Changes in the Neuroproteome associated with changes in ATSET performance. Now that our studies have come close to the lowest dose of HZE particles that resulted in significant impairment of ATSET performance and the regions of the brain most frequently impacted (mPFC, perirhinal and basal forebrain (Reversal behavior), it is appropriate to start establishing how HZE exposures impaired ATSET performance.

In light of our recent paper (Britten et al, 2016; LSSR) where it appears that hippocampal and PFC-dependent cognitive domains are not similarly impaired in individual rats, the Basal Forebrain, Infra-limbic Prefrontal cortex, and hippocampus have been recovered from each rat exposed to 5 cGy 600 MeV/n Fe and Si and subjected to proteomic analysis.

We have established that it is feasible to characterize the composition of the neuroproteome within defined (4 x 3 x 1 mm) areas of the brain from irradiated rats. Preliminary data suggest that there are marked differences in the neuroproteome in response to HZE exposure within each brain region, and that such changes may be very specific to the HZE ion.

Project Summary

We have demonstrated that low (5 cGy) doses of various HZE species results in significant impairment of ATSET performance. There appears to be quantitative and qualitative differences in the manner how Si, Ti, and Fe impair ATSET performance. Further batches of rats will be exposed to <5 cGy of these ions species and to 400 MeV/n 4He and 16O. Currently studies are underway to contrast the efficacy with which isofluences of the various HZE ions impair ATSET. Preliminary data suggest that there are marked differences in the neuroproteome in response to HZE exposure within each brain region, and that such changes may be very specific to the HZE ion.

Bibliography Type: Description: (Last Updated: 02/15/2022) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Britten RA, Miller V, Hadley M, Macadat E. "Executive function is significantly impaired following exposure to low (5 cGy) doses of HZE particles." Oral presentation at 2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016.

2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016. , Feb-2016

Abstracts for Journals and Proceedings Dutta S, Hadley M, Miller V, Macadat E, Britten R. "Changes in the hippocampal proteome associated with the induction of spatial memory impairment by mission-relevant HZE doses." Poster presentation at 2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016.

2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016. , Feb-2016

Abstracts for Journals and Proceedings Britten RA. "Effect of galactic cosmic radiation on the CNS." Oral presentation at 62nd Annual Meeting of the Radiation Research Society, Big Island, Hawaii, October 16-19, 2016.

RadRes16 Meeting proceedings. 62nd Annual Meeting of the Radiation Research Society, Big Island, Hawaii, October 16-19, 2016. , Oct-2016

Abstracts for Journals and Proceedings Peterman S, Parkash A, Dutta S, Britten RA. "Integrated workflows to perform large-scale, unbiased global protein profiling: an alternative way to find protein panels." Presented at the 62nd Annual Meeting of the Radiation Research Society, Big Island, Hawaii, October 16-19, 2016.

RadRes 16 Meeting Proceedings. 62nd Annual Meeting of the Radiation Research Society, Big Island, Hawaii, October 16-19, 2016. , Oct-2016

Articles in Peer-reviewed Journals Norbury JW, Schimmerling W, Slaba TC, Azzam E, Badavi FF, Baiocco G, Benton E, Bindi V, Blakely EA, Blattnig SR, Boothman DA, Borak TB, Britten RA, Curtis S, Dingfelder M, Durante M, Dynan W, Eisch AJ, Robin Elgart S, Goodhead DT, Guida PM, Heilbronn LH, Hellweg CE, Huff JL, Kronenberg A, La Tessa C, Lowenstein D, Miller J, Morita T, Narici L, Nelson GA, Norman RB, Ottolenghi A, Patel ZS, Reitz G, Rusek A, Schreurs A-S, Scott-Carnell LA, Semones E, Shay JW, Shurshakov VA, Sihver L, Simonsen LC, Story M, Turker MS, Uchihori Y, Williams J, Zeitlin CJ. "Galactic cosmic ray simulation at the NASA Space Radiation Laboratory." Life Sci Space Res. 2016 Feb;8:38-51. http://dx.doi.org/10.1016/j.lssr.2016.02.001 ; PubMed PMID: 26948012 , Feb-2016
Articles in Peer-reviewed Journals Parihar VK, Allen BD, Caressi C, Kwok S, Chu E, Tran KK, Chmielewski NN, Giedzinski E, Acharya MM, Britten RA, Baulch JE, Limoli CL. "Cosmic radiation exposure and persistent cognitive dysfunction." Sci Rep. 2016 Oct 10;6:34774. http://dx.doi.org/10.1038/srep34774 ; PubMed PMID: 27721383; PubMed Central PMCID: PMC5056393 , Oct-2016
Articles in Peer-reviewed Journals Britten RA, Miller VD, Hadley MM, Jewell JS, Macadat E. "Performance in hippocampus- and PFC- dependent cognitive domains are not concomitantly impaired in rats exposed to 20 cGy of 1 GeV/n 56Fe particles." Life Sci Space Res. 2016 Aug;10:17-22. http://dx.doi.org/10.1016/j.lssr.2016.06.005 , Aug-2016
Articles in Peer-reviewed Journals Wyrobek AJ, Britten RA. "Individual variations in dose response for spatial memory learning among outbred Wistar rats exposed from 5 to 20 cGy of Fe particles." Environ Mol Mutagen. 2016 Jun;57(5):331-40. http://dx.doi.org/10.1002/em.22018 ; PubMed PMID: 27237589 , Jun-2016
Articles in Peer-reviewed Journals Britten RA, Jewell JS, Miller VD, Davis LK, Hadley MM, Wyrobek AJ. "Impaired spatial memory performance in adult Wistar rats exposed to low (5-20 cGy) doses of 1 GeV/n Fe particles." Radiat Res. 2016 Mar;185(3):332-7. http://dx.doi.org/10.1667/RR14120.1 ; PubMed PMID: 26943453 , Mar-2016
Articles in Peer-reviewed Journals Hadley MM, Davis LK, Jewell JS, Miller VD, Britten RA. "Exposure to mission-relevant doses of 1 GeV/n (48)Ti particles impairs attentional set-shifting performance in retired breeder rats." Radiat Res. 2016 Jan;185(1):13-9. Epub 2015 Dec 31. http://dx.doi.org/10.1667/RR14086.1 ; PubMed PMID: 26720801 , Jan-2016
Project Title:  Changes in the Neuroproteome Associated with HZE-Induced Impairment of Cognition Reduce
Images: icon  Fiscal Year: FY 2016 
Division: Human Research 
Research Discipline/Element:
HRP HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Start Date: 02/27/2014  
End Date: 02/26/2018  
Task Last Updated: 12/29/2015 
Download report in PDF pdf
Principal Investigator/Affiliation:   Britten, Richard  Ph.D. / Eastern Virginia Medical School 
Address:  Radiation Oncology 
700 W Olney Rd 
Norfolk , VA 23507-1607 
Email: Brittera@evms.edu 
Phone: 757-446-5038  
Congressional District:
Web:  
Organization Type: NON-PROFIT 
Organization Name: Eastern Virginia Medical School 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Dutta, Sucharita  Eastern Virginia Medical School 
Semmes, Oliver  Eastern Virginia Medical School 
Lonart, Gyorgy  Eastern Virginia Medical School 
Project Information: Grant/Contract No. NNX14AE73G 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2013 Space Radiobiology NNJ13ZSA001N 
Grant/Contract No.: NNX14AE73G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Human Research Program Risks: (1) HFBP Bmed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders (IRP Rev J)
(2) Sensorimotor:Risk of Altered Sensorimotor/Vestibular Function Impacting Critical Mission Tasks (Revised as of IRP Rev M)
Human Research Program Gaps: (1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-103:What are the validated, efficacious treatments (individual or Team-based) and/or countermeasures to prevent adverse behavioral conditions, CNS/neurological, and/or psychiatric disorders caused by either single and/or integrated exposures to spaceflight hazards during exploration class missions? (IRP Rev L)
(3) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
(4) BMed-108:Given each crewmember will experience multiple spaceflight hazards simultaneously, we need to identify and characterize the potential additive, antagonistic, or synergistic impacts of multiple stressors (e.g., space radiation, altered gravity, isolation, altered immune, altered sleep) on crew health and/or CNS/ cognitive functioning to develop threshold limits and validate countermeasures for any identified adverse crew health and/or operationally-relevant performance outcomes (IRP Rev L)
(5) SM-104:Evaluate how weightlessness-induced changes in sensorimotor/vestibular function relate to and/or interact with changes in other brain functions (sleep, cognition, attention) (IRP Rev M)
Task Description: One of NASA's biggest concerns about the long-term health of astronauts who go on deep space missions is the impact that High Z, High Energy (HZE) particles have on brain function (neurocognition). Data from our laboratory and others suggests that there is significant impairment of certain neurocognitive tasks (spatial memory and Executive function-attentional set shifting) following exposure to low HZE doses. The goal of this application is to determine the Threshold dose for the induction of HZE-induced spatial memory impairments (HISMI) or Attentional Set Shifting Impairments (HIASSI) following exposure to 56Fe, 48Ti, and 28Si particles. The proposed studies will also identify the changes in the proteome of the brain (neuroproteome) of rats that differ in their susceptibility to HISMI and HIASSI, which will provide further insight into the factors that lead to HISMI/HIASSI and perhaps more importantly, that prevent its emergence. Our underlying hypothesis is that HISMI and HIASSI arise as the direct result of HZE-induced changes in the neuroproteome. We also hypothesize that exposure to HZE species that have different track structures will result in different mechanisms of HZE-induced cognitive impairment (HICI). Collectively, these studies will give some insight into the underlying cause for HISMI and HIASSI.

Our studies will thus address CNS Gaps 1, 2, and 6, and we shall specifically focus on the following aims:

Aim 1. Determine the Threshold dose for the induction of HISMI and HIASSI following exposure to 56Fe, 48Ti, and 28Si particles when delivered as a single dose.

Aim 2. Identify changes in the neuroproteome that are associated with susceptibility or resistance to developing HISMI and HIASSI following exposure to 56Fe particles.

Aim 3. Determine the mechanism of HISMI and HIASSI induced by HZE particles of differing LET.

In Aim 1, socially mature (~6 month old) male Wistar rats will be irradiated with 56Fe, 48Ti, and 28Si particles (with incident energies of 600 MeV/nucleon). Rats will receive whole body HZE irradiation (< 15 cGy), and HISMI and HIASSI will be assessed at 3 months post irradiation.

In Aim 2 and 3, the composition of the neuroproteome (hippocampus and selected regions of the prefrontal cortex) of irradiated rats that have “normal” cognitive performance or have developed HISMI or HIASSI will be established using an unbiased proteomic profiling approach. We shall use a label free differential protein profiling workflow on the Q-Exactive Orbitrap mass spectrometer.

These studies will give considerable insight into the underlying cause for HZE-induced neurocognitive failure. The proposed studies will continue to define the minimum dose of HZE particles that will induce HISMI and HIASSI. Moreover, our studies will provide considerable insight into the underlying mechanism of HICI, and will identify prognostic biomarkers that could be translated to human studies to monitor the emergence of HICI. These studies may also help to develop appropriate countermeasures and help identify sensitive individuals, so that NASA’s medical staff can implement appropriate countermeasures to protect these at risk individuals.

Research Impact/Earth Benefits: These studies will give considerable insight into the underlying cause for HZE-induced neurocognitive failure. The proposed studies will continue to define the minimum dose of HZE particles that will induce HISMI and HIASSI. Moreover, our studies will provide considerable insight into the underlying mechanism of HICI, and will identify prognostic biomarkers that could be translated to human studies to monitor the emergence of HICI. These studies may also help to develop appropriate countermeasures and help identify sensitive individuals, so that NASA’s medical staff can implement appropriate countermeasures to protect these at risk individuals.

Task Progress & Bibliography Information FY2016 
Task Progress: Project Objective

1. Identify the lowest HZE dose 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 HZE-exposed animals.

Project Approach

Adult (proven breeder) male rats are used in this study. These rats have a comparable chronological age to young astronauts, but are often overweight and “cage weary.” Thus the rats used in our study are placed on an exercise regimen (30 min treadmill sessions, 2-3 times a week) for the duration of the study. The rats are “vetted” for good attentional set shifting (ATSET) performance, and then exposed (single exposure) to <15 cGy of HZE ions (incident energy <600 MeV/n). ATSET performance is re-established at 3 months post exposure, using a reconfigured ATSET test that necessitates that the rats have to “relearn” the associative clues, which are non-olfactory dependent.

Regions of the cortex and basal forebrain (that regulated certain paradigms with the ATSET test) will be recovered and subjected to proteomic analysis to identify some of the processes that may be responsible for the HZE-induced impairment of ATSET.

Research Highlights

256 “vetted” rats have been irradiated at Brookhaven National Laboratory (BNL) with 5, 10, or 15 cGy of 600 MeV/n 56Fe (2 batches), 400 MeV/n 28Si (2 batches), or 1 GeV/n 48Ti (1 batch), and their ATSET performance assessed. ATSET performance was impaired at all doses studied. At 5 cGy, there are significant (>2 fold) increases in the percentage of rats that failed to successfully complete (on two occasions) one of the first 4 paradigms of the ATSET test. Twelve percent of Sham rats failed at least one stage of testing, whereas 25, 32, and 60% of rats irradiated with 5 cGy Ti, Fe, or Si ions failed at least one stage (on two occasions).

There appears to be some ion (perhaps LET) specific changes in the level and nature of cognitive impairment induced. Silicon (with the lowest LET) is the most potent at impairing the overall performance in the ATSET test, with 60% of rats failing a paradigm (on 2 separate occasions).

There are also marked differences in how the irradiated rats perform in the various paradigms. Silicon induced failures in Food Foraging (FF), Simple Discrimination (SD), and Compound Discrimination Reversal (CDR). Ti exposure induces significant changes in SD performance, while Fe induces changes in Compound Discrimination (CD) and CDR performance.

Potential implications for astronaut performance

The HZE-induced changes in ATSET performance could have some profound impacts on crew performance IF similar changes were induced in astronauts.

The failure to complete the FF paradigm appears to be attributable to an inability of the irradiated rats to maintain focus on that task. The irradiated rats started to dig for the food (suggesting that they encoded and retrieved the procedural memories of food retrieval necessary to perform ATSET), but stopped digging after 5-10 s. All the rats that failed the FF task in the present study showed no obvious signs of anhedonia (sucrose preference test, or general appearance and activity in the cage), and vigorously ate “rat chow” when returned to an unrestricted diet. Further experimentation is needed to determine if these rats truly have an impaired ability to maintain focus on task, but if this proves to be the case, HZE-exposed astronauts could have problems focusing on tasks/activities.

Impaired SD performance will result in a reduced ability to establish an attentional set (propensity) to the relevant dimension for the successful completion of a task, in this study identifying the associative clue for a food reward. CD is a reflection of the ability to maintain that attentional set, when there were distracting, irrelevant stimuli present. Astronauts will obviously not use attentional set shifting to find food rewards, but if astronauts were to experience HZE-induced SD impairments, this would result in a decreased ability to multi-task successfully. An HZE-induced impairment of CD performance, would result in a decreased ability to identify and focus on relevant aspects of the task being conducted. Such decrements would be undesirable in any work scenario.

These data suggest that the functionality of multiple brain regions may be impaired by these low HZE doses. SD is regulated by the mPFC (Bissonette et al., 2008); CD is probably regulated by perirhinal cortical region (Eacott et al., 2001; Norman et al., 2004; Lindquist et al., 2004; Feinberg et al., 2012), and requires optimal dopamine D2 receptor activation in pre-frontal cortex (Glickstein et al., 2005); and “reversal” tasks are regulated by the basal forebrain (Tait et al., 2008) and the orbital frontal cortex (McAlonan et al., 2003).

The Basal Forebrain, Infra-limbic Prefrontal cortex and hippocampus have been recovered from each irradiated rat and will be subjected to proteomic analysis in the near future. These studies will give considerable insight into the underlying cause for HZE-induced neurocognitive failure.

Project Summary

We have demonstrated that low (5 cGy) doses of various HZE species results in significant impairment of ATSET performance. There appears to be quantitative and qualitative differences in the manner how Si, Ti, and Fe impair ATSET performance. Further batches of rats will be exposed to <5 cGy of these ions species and to 400 MeV/n 16O. Currently studies are underway to contrast the efficacy with which isofluences of the various HZE ions impair ATSET.

References

Bissonette GB, Martins GJ, Franz TM, Harper ES, Schoenbaum G, Powell EM. Double dissociation of the effects of medial and orbital prefrontal cortical lesions on attentional and affective shifts in mice. J Neurosci 2008; 28:11124-30.

Eacott MJ, Machin PE, Gaffan EA. Elemental and configural visual discrimination learning following lesions to perirhinal cortex in the rat. Behav Brain Res 2001; 124:55–70.

Norman G, Eacott MJ. Impaired object recognition with increasing levels of feature ambiguity in rats with perirhinal cortex lesions. Behav Brain Res 2004; 148:79–91.

Lindquist DH, Jarrard LE, Brown TH. Perirhinal cortex supports delay fear conditioning to rat ultrasonic social signals. J Neurosci 2004; 24:3610–17.

Feinberg LM, Allen TA, Ly D, Fortin NJ. Recognition memory for social and non-social odors: differential effects of neurotoxic lesions to the hippocampus and perirhinal cortex. Neurobiol Learn Mem 2012; 97:7–16.

Glickstein SB, Desteno DA, Hof PR, Schmauss C. Mice lacking dopamine D2 and D3 receptors exhibit differential activation of prefrontal cortical neurons during tasks requiring attention. Cereb Cortex 2005; 15:1016-24.

McAlonan K, Brown VJ. Orbital prefrontal cortex mediates reversal learning and not attentional set shifting in the rat. Behav Brain Res 2003; 146:97-103.

Tait DS, Brown VJ. Lesions of the basal forebrain impair reversal learning but not shifting of attentional set in rats. Behav Brain Res 2008; 187:100-8.

Bibliography Type: Description: (Last Updated: 02/15/2022) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Britten RA. "Potential impact of space radiation on crew performance on deep space mission." NASA Blue Sky meeting: Biological Countermeasures (BCMs) Against Space Radiation Risks. Institute of Human and Machine Cognition, Pensacola, FL, August 18-19, 2015.

NASA Blue Sky meeting: Biological Countermeasures (BCMs) Against Space Radiation Risks. Institute of Human and Machine Cognition, Pensacola, FL, August 18-19, 2015. , Aug-2015

Abstracts for Journals and Proceedings Britten RA. "Impact of space radiation exposure on cognitive performance, neuronal physiology and psychology." Neurobehavioral Resilience during Prolonged Space Flight. National Space Biomedical Research Institute, Houston, TX, July 28-29, 2015.

Neurobehavioral Resilience during Prolonged Space Flight. National Space Biomedical Research Institute, Houston, TX, July 28-29, 2015. , Jul-2015

Abstracts for Journals and Proceedings Britten RA, Jewell J, Hadley M, Miller M, Macadat E. "Executive Function in Socially-Mature Rats Is Significantly Impaired by Low (<15 cGy) Doses of HZE Particles with LETs of 51-106 keV/um." Space Radiation and Heavy Ions in Therapy Symposium 2015, Osaka, Japan, May 22-24, 2015.

Space Radiation and Heavy Ions in Therapy Symposium 2015, Osaka, Japan, May 22-24, 2015. , May-2015

Abstracts for Journals and Proceedings Britten RA, Machida M, Wellman L, Sanford LD. "A pilot study on the impact that exposure to 20 cGy 1 GeV/nucleon 56Fe particles has on Delta and Theta wave activity and sleep homeostasis." 2015 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 13-15, 2015.

2015 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 13-15, 2015. , Jan-2015

Abstracts for Journals and Proceedings Hadley M, Jewell J, Macadat E, Miller V, Britten RA. "Executive function is significantly impaired following exposure to low (<20 cGy) doses of 1 GeV/n 48Ti particles." 2015 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 13-15, 2015.

2015 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 13-15, 2015. , Jan-2015

Abstracts for Journals and Proceedings Jewell J, Macadat E, Miller V, Hadley M, Dutta S, Britten RA. "Changes in the Hippocampal proteome associated with the induction of spatial memory impairment by mission relevant HZE doses." 2015 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 13-15, 2015.

2015 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 13-15, 2015. , Jan-2015

Abstracts for Journals and Proceedings Macadat E, Miller V, Jewell J, Hadley M, Britten RA. "Executive function is significantly impaired following exposure to mission relevant (10 cGy) doses of 600 MeV/u 56Fe particles." 2015 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 13-15, 2015.

2015 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 13-15, 2015. , Jan-2015

Abstracts for Journals and Proceedings Miller V, Jewell J, Hadley M, Macadat E, Britten RA. "Executive function is significantly impaired following exposure to low (15 cGy) doses of 600 MeV/u 28Si particles." 2015 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 13-15, 2015.

2015 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 13-15, 2015. , Jan-2015

Articles in Peer-reviewed Journals Hadley MM, Davis LK, Jewell JS, Miller VD, Britten RA. "Exposure to mission relevant doses of 1 GeV/n 48Ti particles impairs attentional set-shifting performance in retired breeder rats." Radiation Research. In press, January 2016. Online ahead of print: http://dx.doi.org/10.1667/RR14086.1 , Jan-2016
Project Title:  Changes in the Neuroproteome Associated with HZE-Induced Impairment of Cognition Reduce
Images: icon  Fiscal Year: FY 2015 
Division: Human Research 
Research Discipline/Element:
HRP HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Start Date: 02/27/2014  
End Date: 02/26/2018  
Task Last Updated: 01/07/2015 
Download report in PDF pdf
Principal Investigator/Affiliation:   Britten, Richard  Ph.D. / Eastern Virginia Medical School 
Address:  Radiation Oncology 
700 W Olney Rd 
Norfolk , VA 23507-1607 
Email: Brittera@evms.edu 
Phone: 757-446-5038  
Congressional District:
Web:  
Organization Type: NON-PROFIT 
Organization Name: Eastern Virginia Medical School 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Dutta, Sucharita  Eastern Virginia Medical School 
Semmes, Oliver  Eastern Virginia Medical School 
Project Information: Grant/Contract No. NNX14AE73G 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2013 Space Radiobiology NNJ13ZSA001N 
Grant/Contract No.: NNX14AE73G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Human Research Program Risks: (1) HFBP Bmed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders (IRP Rev J)
(2) Sensorimotor:Risk of Altered Sensorimotor/Vestibular Function Impacting Critical Mission Tasks (Revised as of IRP Rev M)
Human Research Program Gaps: (1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-103:What are the validated, efficacious treatments (individual or Team-based) and/or countermeasures to prevent adverse behavioral conditions, CNS/neurological, and/or psychiatric disorders caused by either single and/or integrated exposures to spaceflight hazards during exploration class missions? (IRP Rev L)
(3) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
(4) BMed-108:Given each crewmember will experience multiple spaceflight hazards simultaneously, we need to identify and characterize the potential additive, antagonistic, or synergistic impacts of multiple stressors (e.g., space radiation, altered gravity, isolation, altered immune, altered sleep) on crew health and/or CNS/ cognitive functioning to develop threshold limits and validate countermeasures for any identified adverse crew health and/or operationally-relevant performance outcomes (IRP Rev L)
(5) SM-104:Evaluate how weightlessness-induced changes in sensorimotor/vestibular function relate to and/or interact with changes in other brain functions (sleep, cognition, attention) (IRP Rev M)
Task Description: One of NASA's biggest concerns about the long-term health of astronauts who go on deep space missions is the impact that High Z, High Energy (HZE) particles have on brain function (neurocognition). Data from our laboratory and others suggests that there is significant impairment of certain neurocognitive tasks (spatial memory and Executive function-attentional set shifting) following exposure to low HZE doses. The goal of this application is to determine the Threshold dose for the induction of HZE-induced spatial memory impairments (HISMI) or Attentional Set Shifting Impairments (HIASSI) following exposure to 56Fe, 48Ti, and 28Si particles. The proposed studies will also identify the changes in the proteome of the brain (neuroproteome) of rats that differ in their susceptibility to HISMI and HIASSI, which will provide further insight into the factors that lead to HISMI/HIASSI and perhaps more importantly, that prevent its emergence. Our underlying hypothesis is that HISMI and HIASSI arise as the direct result of HZE-induced changes in the neuroproteome. We also hypothesize that exposure to HZE species that have different track structures will result in different mechanisms of HZE-induced cognitive impairment (HICI). Collectively, these studies will give some insight into the underlying cause for HISMI and HIASSI.

Our studies will thus address CNS Gaps 1, 2, and 6, and we shall specifically focus on the following aims:

Aim 1. Determine the Threshold dose for the induction of HISMI and HIASSI following exposure to 56Fe, 48Ti, and 28Si particles when delivered as a single dose.

Aim 2. Determine the Threshold dose for the induction of HISMI and HIASSI following exposure to 56Fe, 48Ti, and 28Si particles when delivered in three fractions over a 5-day period.

Aim 3. Identify changes in the neuroproteome that are associated with susceptibility or resistance to developing HISMI and HIASSI following exposure to 56Fe particles.

Aim 4. Determine the mechanism of HISMI and HIASSI induced by HZE particles of differing LET.

In Aim 1, socially mature (~6 month old) male Wistar rats will be irradiated with 56Fe, 48Ti, and 28Si particles (with incident energies of 600 and 1000 MeV/nucleon). Rats will receive whole body HZE irradiation (2.5, 5, 10, 15, and 20 cGy), and HISMI and HIASSI will be assessed at 3 months post irradiation.

In Aim 2, 6-month old male Wistar rats will be exposed to the 56Fe, 48Ti, and 28Si particle beams using a 5 day, 3 x 5 cGy fraction irradiation scheme with a 48 h inter-fraction time. HISMI and HIASSI will be assessed at 3 months post irradiation and the severity of HISMI and HIASSI compared to that induced when 15 cGy was delivered as a single dose. These studies can be iteratively modified (change in fraction size, number, and inter-fraction time) if warranted so that modelers can extrapolate our findings to a more realistic HZE exposure pattern.

In Aims 3 and 4, the composition of the neuroproteome (hippocampus and selected regions of the prefrontal cortex) of irradiated rats that have “normal” cognitive performance or have developed HISMI or HIASSI will be established using an unbiased proteomic profiling approach. We shall use a label free differential protein profiling workflow on the Q-Exactive Orbitrap mass spectrometer.

These studies will give considerable insight into the underlying cause for HZE-induced neurocognitive failure. The proposed studies will continue to define the minimum dose of HZE particles that will induce HISMI and HIASSI. Moreover, our studies will provide considerable insight into the underlying mechanism of HICI, and will identify prognostic biomarkers that could be translated to human studies to monitor the emergence of HICI. These studies may also help to develop appropriate countermeasures and help identify sensitive individuals, so that NASA’s medical staff can implement appropriate countermeasures to protect these at risk individuals.

Research Impact/Earth Benefits: 0

Task Progress & Bibliography Information FY2015 
Task Progress: During the first year of this study we have pre-screened 184 rats for their ability to complete the first 4 paradigms of the attentional set shifting test (up to Intra-dimensional shifting).

Of the first batch of 79 rats, 49 (62%) rats were able to complete the IDS paradigm. These were shipped to BNL for irradiation with 5, 10, and 15 cGy of 1 GeV/n 48Ti or 600 MeV/n 56Fe ions during NSRL14B. Some rats did not survive transit and the remaining rats were exposed to only 48Ti ions. These irradiated rats have now been re-evaluated for their post radiation exposure ability to perform Attentional Set Shifting (up to and including Extra-dimensional Shifting-EDS).

1. The rats were retested using the exact same protocol as used in the prescreening process, i.e. the same associative clues for the food reward were used. It became apparent that the rats remembered the food reward clue (as evidenced by the fact that they did not even investigate the other bowl) from the prescreening stages.

2. The rats were subsequently retested for ATSET performance but with the food reward associative clue being altered from an olfactory one (scent) to a tactile one (digging medium) in the SD, CD, CDR. IDS, and IDR stages (with the opposite changes being implanted in the EDS and EDR stages.

3. An analysis of this second round of data revealed that there was no difference between the ability of the irradiated rats to complete the Attentional Set Shifting task, but that rats exposed to 15 cGy 1 GeV/n Titanium ions took twice as many attempts to complete the EDS paradigm than did the sham-irradiated rats (P=0.041, N=6).

A second batch of 105 rats have been pre-screened for their ability to complete the first 4 paradigms of the attentional set shifting test (up to Intra-dimensional shifting); 70 (66.66%) were able to complete the IDS paradigm. These were shipped to BNL for irradiation with 5, 10, and 15 cGy of 600 MeV/n 28Si or 600 MeV/n 56Fe ions during NSRL14C. These rats are scheduled to be re-evaluated for their ATSET performance at the start of Feb 2015, in accordance with the procedures outlined in Item # 2 above.

Bibliography Type: Description: (Last Updated: 02/15/2022) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Britten RA. "Interrogating the neuroproteome for clues to the mechanism of HZE-induced neurocognitive impairment." 60th Annual Meeting of the Radiation Research Society, Las Vegas, Nevada, September 21-24, 2014.

60th Annual Meeting of the Radiation Research Society, Las Vegas, Nevada, September 21-24, 2014. , Sep-2014

Abstracts for Journals and Proceedings Britten RA, Davis L, Jewell J, Miller V, Lonart G. "Executive function in socially - mature rats is significantly impaired by low (<20 cGy) doses of HZE particles with LETs of 51-180 keV/um." CENTRAL NERVOUS SYSTEM RISKS. 2014 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 12-13, 2014.

2014 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 12-13, 2014. http://www.hou.usra.edu/meetings/hrp2014/pdf/3033.pdf , Feb-2014

Articles in Peer-reviewed Journals Britten RA, Davis LK, Jewell JS, Miller VD, Hadley MM, Sanford LD, Machida M, Lonart G. "Exposure to mission relevant doses of 1 GeV/nucleon 56Fe particles leads to impairment of attentional set-shifting performance in socially mature rats." Radiat Res. 2014 Sep;182(3):292-8. Epub 2014 Jul 16. http://dx.doi.org/10.1667/RR3766.1 ; PubMed PMID: 25029107; PubMed Central PMCID: PMC4154313 , Sep-2014
Project Title:  Changes in the Neuroproteome Associated with HZE-Induced Impairment of Cognition Reduce
Images: icon  Fiscal Year: FY 2014 
Division: Human Research 
Research Discipline/Element:
HRP HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Start Date: 02/27/2014  
End Date: 02/26/2018  
Task Last Updated: 03/26/2014 
Download report in PDF pdf
Principal Investigator/Affiliation:   Britten, Richard  Ph.D. / Eastern Virginia Medical School 
Address:  Radiation Oncology 
700 W Olney Rd 
Norfolk , VA 23507-1607 
Email: Brittera@evms.edu 
Phone: 757-446-5038  
Congressional District:
Web:  
Organization Type: NON-PROFIT 
Organization Name: Eastern Virginia Medical School 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Dutta, Sucharita  Eastern Virginia Medical School 
Semmes, Oliver  Eastern Virginia Medical School 
Project Information: Grant/Contract No. NNX14AE73G 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2013 Space Radiobiology NNJ13ZSA001N 
Grant/Contract No.: NNX14AE73G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:  
No. of PhD Candidates:  
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Human Research Program Risks: (1) HFBP Bmed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders (IRP Rev J)
(2) Sensorimotor:Risk of Altered Sensorimotor/Vestibular Function Impacting Critical Mission Tasks (Revised as of IRP Rev M)
Human Research Program Gaps: (1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-103:What are the validated, efficacious treatments (individual or Team-based) and/or countermeasures to prevent adverse behavioral conditions, CNS/neurological, and/or psychiatric disorders caused by either single and/or integrated exposures to spaceflight hazards during exploration class missions? (IRP Rev L)
(3) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
(4) BMed-108:Given each crewmember will experience multiple spaceflight hazards simultaneously, we need to identify and characterize the potential additive, antagonistic, or synergistic impacts of multiple stressors (e.g., space radiation, altered gravity, isolation, altered immune, altered sleep) on crew health and/or CNS/ cognitive functioning to develop threshold limits and validate countermeasures for any identified adverse crew health and/or operationally-relevant performance outcomes (IRP Rev L)
(5) SM-104:Evaluate how weightlessness-induced changes in sensorimotor/vestibular function relate to and/or interact with changes in other brain functions (sleep, cognition, attention) (IRP Rev M)
Task Description: One of NASA's biggest concerns about the long-term health of astronauts who go on deep space missions is the impact that High Z, High Energy (HZE) particles have on brain function (neurocognition). Data from our laboratory and others suggests that there is significant impairment of certain neurocognitive tasks (spatial memory and Executive function-attentional set shifting) following exposure to low HZE doses. The goal of this application is to determine the Threshold dose for the induction of HZE-induced spatial memory impairments (HISMI) or Attentional Set Shifting Impairments (HIASSI) following exposure to 56Fe, 48Ti, and 28Si particles. The proposed studies will also identify the changes in the proteome of the brain (neuroproteome) of rats that differ in their susceptibility to HISMI and HIASSI, which will provide further insight into the factors that lead to HISMI/HIASSI and perhaps more importantly, that prevent its emergence. Our underlying hypothesis is that HISMI and HIASSI arise as the direct result of HZE-induced changes in the neuroproteome. We also hypothesize that exposure to HZE species that have different track structures will result in different mechanisms of HZE-induced cognitive impairment (HICI). Collectively, these studies will give some insight into the underlying cause for HISMI and HIASSI.

Our studies will thus address CNS Gaps 1, 2, and 6, and we shall specifically focus on the following aims:

Aim 1. Determine the Threshold dose for the induction of HISMI and HIASSI following exposure to 56Fe, 48Ti, and 28Si particles when delivered as a single dose.

Aim 2. Determine the Threshold dose for the induction of HISMI and HIASSI following exposure to 56Fe, 48Ti, and 28Si particles when delivered in three fractions over a 5-day period.

Aim 3. Identify changes in the neuroproteome that are associated with susceptibility or resistance to developing HISMI and HIASSI following exposure to 56Fe particles.

Aim 4. Determine the mechanism of HISMI and HIASSI induced by HZE particles of differing LET.

In Aim 1, socially mature (~6 month old) male Wistar rats will be irradiated with 56Fe, 48Ti, and 28Si particles (with incident energies of 600 and 1000 MeV/nucleon). Rats will receive whole body HZE irradiation (2.5, 5, 10, 15, and 20 cGy), and HISMI and HIASSI will be assessed at 3 months post irradiation.

In Aim 2, 6-month old male Wistar rats will be exposed to the 56Fe, 48Ti, and 28Si particle beams using a 5 day, 3 x 5 cGy fraction irradiation scheme with a 48 h. inter-fraction time. HISMI and HIASSI will be assessed at 3 months post irradiation and the severity of HISMI and HIASSI compared to that induced when 15 cGy was delivered as a single dose. These studies can be iteratively modified (change in fraction size, number, and inter-fraction time) if warranted so that modelers can extrapolate our findings to a more realistic HZE exposure pattern.

In Aims 3 and 4, the composition of the neuroproteome (hippocampus and selected regions of the prefrontal cortex) of irradiated rats that have “normal” cognitive performance or have developed HISMI or HIASSI will be established using an unbiased proteomic profiling approach. We shall use a label free differential protein profiling workflow on the Q-Exactive Orbitrap mass spectrometer.

These studies will give considerable insight into the underlying cause for HZE-induced neurocognitive failure. The proposed studies will continue to define the minimum dose of HZE particles that will induce HISMI and HIASSI. Moreover, our studies will provide considerable insight into the underlying mechanism of HICI, and will identify prognostic biomarkers that could be translated to human studies to monitor the emergence of HICI. These studies may also help to develop appropriate countermeasures and help identify sensitive individuals, so that NASA’s medical staff can implement appropriate countermeasures to protect these at risk individuals.

Research Impact/Earth Benefits: 0

Task Progress & Bibliography Information FY2014 
Task Progress: New project for FY2014.

Bibliography Type: Description: (Last Updated: 02/15/2022) 

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 None in FY 2014