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Project Title:  Countermeasures for Neurobehavioral Vulnerabilities to Space Radiation Reduce
Fiscal Year: FY 2017 
Division: Human Research 
Research Discipline/Element:
HRP HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Start Date: 06/01/2015  
End Date: 05/31/2017  
Task Last Updated: 02/05/2018 
Download report in PDF pdf
Principal Investigator/Affiliation:   Hienz, Robert D. Ph.D. / The Johns Hopkins University School of Medicine 
Address:  Department of Psychiatry & Behavioral Sciences 
5510 Nathan Shock Drive 
Baltimore , MD 21224-6823 
Email: bhienz@jhmi.edu 
Phone: 410-550-2788  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: The Johns Hopkins University School of Medicine 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Davis, Catherine  Ph.D. Johns Hopkins Medical School 
Roma, Peter  Ph.D. Institutes for Behavior Resources, Inc. 
Project Information: Grant/Contract No. NCC 9-58-NBPF04201 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2013 HERO NNJ13ZSA002N-Crew Health (FLAGSHIP & NSBRI) 
Grant/Contract No.: NCC 9-58-NBPF04201 
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) Bmed:Risk of Adverse Behavioral Conditions and Psychiatric Disorders
Human Research Program Gaps: (1) BMed01:We need to identify and validate countermeasures that promote individual behavioral health and performance during exploration class missions (IRP Rev F)
Flight Assignment/Project Notes: NOTE: Element change to Human Factors & Behavioral Performance; previously Behavioral Health & Performance (Ed., 1/18/17)

NOTE: Change in period of performance per NSBRI (formerly 7/1/15-6/30/17)--Ed., 7/7/15

Task Description: This research determined the effectiveness of biomedical countermeasures to mitigate the effects of space radiation on central nervous system (CNS) function. Using an animal analog of the human Psychomotor Vigilance Test (PVT) that is used for human risk assessment, the studies assessed the effectiveness of a number of Food and Drug Administration (FDA)-approved compounds to lessen the deleterious effects of radiation exposure on CNS function (sustained attention) in rats. Rats were trained in a rodent version of the human PVT, exposed to proton irradiation at NASA's Space Radiation Laboratory at Brookhaven National Laboratory, and returned to Johns Hopkins for post-exposure testing to 1) identify long-term neurobehavioral deficits, and 2) assess the effectiveness of pharmacologic compounds to mitigate the deficits. Mechanisms of action were evaluated by employing different types of potential mitigating compounds (i.e., given after radiation exposure), such as those that directly alter dopaminergic (DA) signaling by binding to the DA transporter protein (DAT; e.g., methylphenidate), those that directly alter DA signaling by binding to receptors from the D2 receptor family (e.g., aripiprazole), and those that indirectly alter DA and other monoamine levels (e.g., NE reuptake inhibition, atomoxetine). Two FDA-approved compounds – the putative DNA repair targeting drug cholorquine (CLQ), and the hemopoietic growth factor erythropoietin (EPO) – were also assessed for their potential radioprotective effects (i.e., given prior to radiation exposure) and their alternative mechanisms of action.

Key Findings from this 2-year project include:

Psychostimulants as potential countermeasures for proton-induced deficits in neurobehavioral function

• The psychostimulant d-amphetamine (DA releaser, indirect DA agonist) produced dose-dependent recovery of both accuracy and reaction time in radiation-sensitive animals, but produced performance decrements in radiation-insensitive animals.

• The DA/NE reuptake inhibitor methylphenidate also produced dose-dependent recovery of performance in radiation-sensitive animals, but did not impair performances in radiation-insensitive animals.

• The NE reuptake inhibitor atomoxetine showed no differential effects on rPVT performance in radiation-sensitive or radiation-insensitive rats.

• SCH 39166, a D1 receptor antagonist, blocked amphetamine's effects on percent correct responding, indicating that D1 receptors are responsible for amphetamine-induced changes in rPVT performance.

• L-741,626, a D2 receptor antagonist, did not block amphetamine's effects, indicating that D2 receptors are not involved in the amphetamine-induced changes in rPVT performance.

• Both pramipexole (a D3 agonist) and aripiprazole (a partial D2 agonist) produced dose-dependent recovery of radiation-induced slowing of reaction times, suggesting that altered dopamine D2-like receptor signaling is involved in these deficits. Further, the improvements following aripiprazole suggest that DA tone could differ in various brain regions, with this partial agonist acting like an antagonist in areas of high DA tone and acting like an agonist in areas of low DA tone.

• The data provide evidence of the specific involvement of both D1-like and D2-like dopamine receptor systems in radiation-induced neurobehavioral deficits. Studies of potential radiation-protective compounds

• EPO – a compound involved in the brain's response to various insults, including radiation – did not improve the radiation-induced deficits in performance in radiation-sensitive rats at any doses tested.

• CLQ – a drug that improves clinical outcomes following whole-brain radiotherapy – also did not lessen radiation-induced deficits in rPVT performance; fine-grain analyses of these data are still ongoing.

Changes in Dopaminergic Modulation following Radiation

• Differences in dopamine-agonist induced yawning and its antagonism by a dopamine D2 receptor antagonist (L-741,626) were found between radiation-sensitive and radiation-insensitive rats. Greater levels of yawning were found in radiation insensitive rats, whereas radiation sensitive rats displayed reduced levels of induced yawning. ED50 values (the dose effective in 50% of subjects) also significantly differed between the radiation sensitive and insensitive rats. Thus D2 dopamine receptors are altered in radiation sensitive rats, and D3 receptors may be altered in radiation insensitive rats.

Predicting an individual's sensitivity via analyses of pre-exposure rPVT performances

• Prior to irradiation, rats that were to subsequently show sensitivity to radiation were found to be more prone to exhibit higher levels of premature responding and lower levels of lapses in attention, thus suggesting a potential method for predicting pre-exposure individual sensitivity to radiation (see Main Findings in Task Progress section).

Two new publications during this reporting period:

• The rodent psychomotor vigilance test (rPVT): A method for assessing neurobehavioral performance in rats and mice is both a publication and a video demonstrating the procedure and documenting that rats show a high degree of similarity to human PVT performances, including similarities in lapses in attention, reaction times, decrements across a session (i.e., human time-on-task effects), and the human response-stimulus interval (RSI) effect.

• Whole-Body Oxygen Ion Exposure-Induced Impairments in Social Odor Recognition Memory in Rats are Dose and Time Dependent demonstrated that at 1 month post-exposure, irradiated rats display a memory deficit for recall of a conspecific odor experienced 24 hours prior. At 6 months post-exposure, 25 cGy-exposed rats show persistent deficits in 24-hr recognition memory, while the 5 cGy-exposed rats show recovery of recognition memory, demonstrating that space-relevant 16O ion exposure has deleterious effects on the central nervous system related to exposure dose and time post-exposure.

Research Impact/Earth Benefits: The critically needed research on the effects of ionizing radiation on cognitive/behavioral functions will provide the basis for extrapolating the effects of the space radiation environment on human cognitive function and performance. Earth-based applications of this research will extend to comparing the effects of other types of radiation exposures (e.g., from the workplace, medical environment, home) on neurobehavioral functions. Knowledge of those neurobehavioral functions and related brain areas affected by acute exposure to space radiation is extremely important in not only the development of a biobehavioral risk assessment model of radiation-induced deficits that could compromise operational performance during long-duration space exploration missions, but also in the development of mitigation strategies, countermeasures, as well as appropriate self-administered tests that astronauts can use to gauge their performance readiness for critical tasks. In addition, the development of a comprehensive and experimentally flexible animal model of neurobehavioral performance provides a useful tool for preclinical research and development in other domains such as sleep/chronobiology, neuropsychiatric disorders, aging, and cognitive enhancement. Moreover, the human Psychomotor Vigilance Test (PVT) is a standardized and widely validated objective measure of neurobehavioral status not only employed by NASA, but also utilized in a variety of settings such as clinical neuropsychiatric assessment, military, shiftwork, and aviation. As such, the present rodent analog of the PVT provides a direct translational link to performance capacity on Earth. Once validated, the rPVT model developed here may be used as a basic and translational research tool to predict performance deficits induced by radiation or other CNS insults while providing an innovative experimental platform for exploring the bases of individual vulnerability to performance impairments and evaluating potential prophylactics, countermeasures, and treatments.

Task Progress & Bibliography Information FY2017 
Task Progress: During this year 220 male Long-Evans rats were used. In April 2016, N=60 rats were trained in the rPVT and exposed to protons (100 & 25 cGy, 150 MeV/n), and subsequently tested with DA compounds (atomoxetine, memantine, pramipexole, aripiprazole). June 2016, N=80 rats were trained in the rPVT and exposed to protons (100 cGy, 150 MeV/n). Prior to exposure, subgroups were treated with 5,000, 3,000, 1,000, and 0 U/kg EPO. In October 2016, N=80 rats were trained in the rPVT and exposed to protons (100 cGy @ 150 MeV/n). Prior to exposure, subgroups were treated with 7.0, 3.5, 1.0, and 0 mg/kg chloroquine.

Specific findings from the past year include:

Psychostimulants as potential countermeasures for proton-induced deficits in neurobehavioral function

• Both pramipexole (a D3 agonist) and aripiprazole (a partial D2 agonist) produced dose-dependent recovery of radiation-induced slowing of reaction times in the rPVT procedure, thus suggesting that altered dopamine D2-like receptor signaling is involved in radiation-induced deficits. Further, the improvements following aripiprazole suggest that dopaminergic tone could differ in various brain regions, with this partial agonist acting like an antagonist in areas of high dopaminergic tone and acting like an agonist in areas of low dopaminergic tone. The data provide evidence of the specific involvement of the DA system in radiation-induced neurobehavioral deficits.

Studies of potential radiation-protective compounds

• EPO – a compound involved in the brain's response to various insults, including radiation – did not improve the radiation-induced deficits in performance in radiation-sensitive rats at any doses tested.

• CLQ – a drug that improves clinical outcomes following whole-brain radiotherapy – also did not lessen radiation-induced deficits in rPVT performance; fine-grain analyses of these data are still ongoing.

• Both EPO and CLQ rats were tested for intact 24-hr recognition memory using the social odor recognition memory test at 6-months post-radiation. Preliminary analyses of the EPO data suggest no benefit of EPO treatment proton-induced deficits in recognition memory. Analysis of the CLQ data is ongoing.

Predicting an individual's sensitivity via analyses of pre-exposure rPVT performances

• A database was developed for over 400 rats subsequently exposed to proton radiation by rating each animal's rPVT performance efficiency relative to all other animals. Efficiency ratings for rats later categorized as radiation-sensitive were compared to those later categorized as radiation-insensitive. Rats that subsequently showed radiation sensitivity were more prone to exhibit high levels of premature responding and low levels of lapses in attention. Further analyses are underway to accurately pinpoint the differences in pre-exposure performances that may predict future sensitivity to radiation exposure, and whether these differences may be related to DA system tone.

Bibliography Type: Description: (Last Updated: 01/12/2021) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Davis CM, Roma PG, Hienz RD. "The Rodent Psychomotor Vigilance Test (rPVT): A method for assessing neurobehavioral performance in rats and mice." J Vis Exp. 2016 Dec 29;(118). https://doi.org/10.3791/54629 ; PubMed PMID: 28060276 , Dec-2016
Articles in Peer-reviewed Journals Mange A, Cao Y, Zhang S, Hienz RD, Davis CM. "Whole-body oxygen (16O) ion-exposure-induced impairments in social odor recognition memory in rats are dose and time dependent." Radiat Res. 2018 Mar;189(3):292-9. Epub 2018 Jan 13. https://doi.org/10.1667/RR14849.1 ; PubMed PMID: 29332539 , Mar-2018
Articles in Peer-reviewed Journals Johnson D, Lawrence SE, Livingston EW, Hienz RD, Davis CM, Lau AG. "Modeling space radiation induced bone changes in rat femurs through finite element analysis." Conf Proc IEEE Eng Med Biol Soc. 2018 Jul;2018:1763-6. https://doi.org/10.1109/EMBC.2018.8512620 ; PubMed PMID: 30440736 , Jul-2018
Awards Davis C. "Johns Hopkins Venture Discovery Award, January 2017." Jan-2017
Awards Hienz R, Davis C. "Seed grant from the new Space@Hopkins Institute, July 2016." Jul-2016
Project Title:  Countermeasures for Neurobehavioral Vulnerabilities to Space Radiation Reduce
Fiscal Year: FY 2016 
Division: Human Research 
Research Discipline/Element:
HRP HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Start Date: 06/01/2015  
End Date: 05/31/2017  
Task Last Updated: 06/10/2016 
Download report in PDF pdf
Principal Investigator/Affiliation:   Hienz, Robert D. Ph.D. / The Johns Hopkins University School of Medicine 
Address:  Department of Psychiatry & Behavioral Sciences 
5510 Nathan Shock Drive 
Baltimore , MD 21224-6823 
Email: bhienz@jhmi.edu 
Phone: 410-550-2788  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: The Johns Hopkins University School of Medicine 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Davis, Catherine  Ph.D. Johns Hopkins Medical School 
Roma, Peter  Ph.D. Institutes for Behavior Resources, Inc. 
Project Information: Grant/Contract No. NCC 9-58-NBPF04201 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2013 HERO NNJ13ZSA002N-Crew Health (FLAGSHIP & NSBRI) 
Grant/Contract No.: NCC 9-58-NBPF04201 
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) Bmed:Risk of Adverse Behavioral Conditions and Psychiatric Disorders
Human Research Program Gaps: (1) BMed01:We need to identify and validate countermeasures that promote individual behavioral health and performance during exploration class missions (IRP Rev F)
Flight Assignment/Project Notes: NOTE: Element change to Human Factors & Behavioral Performance; previously Behavioral Health & Performance (Ed., 1/18/17)

NOTE: Change in period of performance per NSBRI (formerly 7/1/15-6/30/17)--Ed., 7/7/15

Task Description: As spelled out in NASA's Integrated Research Plan, it is essential that methods are developed to detect behavioral changes induced by radiation exposures and that potential countermeasures are developed for mitigating radiation damage. To this end, this research focuses on determining the effectiveness of biomedical countermeasures for mitigating the effects of space radiation on human central nervous system (CNS) function. Specifically, the studies assess the effectiveness of a number of Food and Drug Administration (FDA)-approved compounds to lessen the deleterious effects of radiation exposure on CNS function (sustained attention). This work provides data in an animal analog of the human Psychomotor Vigilance Test (PVT) that is used for human risk assessments. Rats are trained in a rodent version of the human PVT, exposed to proton irradiation at NASA's Space Radiation Laboratory at Brookhaven National Laboratory, and then returned to Johns Hopkins for extended post-exposure testing to identify long-term neurobehavioral deficits and assess the effectiveness of pharmacologic compounds to mitigate the deficits. Mechanisms of action are evaluated by employing different types of potential mitigating compounds (i.e., when administered after radiation exposure), including those that directly alter dopaminergic (DA) signaling by binding to the DA transporter protein (DAT; e.g., methylphenidate), compounds that directly alter DA signaling by binding to receptors from the D2 receptor family (e.g., aripiprazole), and compounds that otherwise indirectly alter DA levels (e.g., NE reuptake inhibition, atomoxetine). Two additional FDA-approved compounds – the putative DNA repair targeting drug cholorquine, and the hemopoietic growth factor erythropoietin (EPO)– will also be assessed for their potential radioprotective effects (i.e., when administered prior to radiation exposure) as well as their alternative mechanisms of action.

Key Findings from the past year include: Psychostimulants as potential countermeasures for proton-induced deficits in neurobehavioral function

• The psychostimulant d-amphetamine (DA releaser, indirect DA agonist) produced dose-dependent recovery of both accuracy and reaction time speed in radiation-sensitive animals; in radiation-insensitive animals, d-amphetamine produced decrements in performances.

• The DA/NE reuptake inhibitor methylphenidate also produced dose-dependent recovery of performance in radiation-sensitive animals, but had no effect in radiation-insensitive animals (i.e., unlike d-amphetamine, it did not impair performances in this latter group).

• The NE reuptake inhibitor atomoxetine showed no differential effects on rPVT performance in radiation-sensitive or radiation-insensitive rats.

• SCH 39166, a D1 receptor antagonist, blocked amphetamine's effects on percent correct responding, indicating that D1 receptors are responsible for amphetamine-induced changes in rPVT performance.

• L-741,626, a D2 receptor antagonist, did not block amphetamine's effects, indicating that D2 receptors are not involved in the amphetamine-induced changes in rPVT performance. The data provide evidence of the specific involvement of the DA system in radiation-induced neurobehavioral deficits.

Changes in Dopaminergic Modulation following Radiation

• Drug-induced yawning is a sensitive metric for determining subtle changes in the DA system. DA D2/D3 receptor agonists produce a predictable pattern of drug-induced yawning in which yawning frequency first increases as the drug dose is increased, and then decreases at successively higher doses. The rising/falling pattern results from reflex activation by D3 receptors on the ascending limb, and by inhibition by D2 receptors on the descending limb.

• Differences in dopamine-agonist induced yawning and its antagonism by a dopamine D2 receptor antagonist (L-741,626) were found between radiation-sensitive and radiation-insensitive rats. Greater levels of yawning were found in radiation insensitive rats, whereas radiation sensitive rats displayed reduced levels of induced yawning. ED50 values (the dose effective in 50% of subjects) also significantly differed between the radiation sensitive and insensitive rats. Thus D2 dopamine receptors are altered in radiation sensitive rats, and D3 receptors may be altered in radiation insensitive rats.

Two new publications during this reporting period:

• "Deficits in Sustained Attention and Changes in Dopaminergic Protein Levels following Exposure to Proton Radiation Are Related to Basal Dopaminergic Function" describes the effects of proton irradiation in inbred adult male Fischer 344 and Lewis rats performing the rPVT. These strains were used to determine if genetic differences in dopaminergic function would impact radiation-induced deficits in sustained attention. Proton irradiation disrupted rPVT performance in a strain-specific manner, with Fischer 344 rats displaying deficits in sustained attention while Lewis rats did not, indicating that basal dopaminergic function impacts the severity of radiation-induced deficits in sustained attention.

• "A rodent model of the human psychomotor vigilance test: Performance comparisons" describes the design and empirical validation of the rPVT, and demonstrates that 1) rats and humans show similar performances on several PVT behavioral measures, 2) the rPVT is an effective task for preclinical studies assessing attention, and 3) the rPVT is extremely sensitive to radiation-induced deficits.

Plans for the Coming Year: Sixty animals were irradiated in April of 2016, and will receive administrations of 5 compounds to assess their potential radiation-mitigating effects on neurocognitive function (modafinil, reboxetine, aripiprazole, pramipexole, memantine). Two additional groups of 80 rats each will be exposed in June and November of 2016 to assess the effects of human EPO and chloroquine, respectively, in preventing radiation-induced deficits in neurocognitive function.

Research Impact/Earth Benefits: The critically needed research on the effects of ionizing radiation on cognitive/behavioral functions will provide the basis for extrapolating the effects of the space radiation environment on human cognitive function and performance. Earth-based applications of this research will extend to comparing the effects of other types of radiation exposures (e.g., from the workplace, medical environment, home) on neurobehavioral functions. Knowledge of those neurobehavioral functions and related brain areas affected by acute exposure to space radiation is extremely important in not only the development of a biobehavioral risk assessment model of radiation-induced deficits that could compromise operational performance during long-duration space exploration missions, but also in the development of mitigation strategies, countermeasures, as well as appropriate self-administered tests that astronauts can use to gauge their performance readiness for critical tasks. In addition, the development of a comprehensive and experimentally flexible animal model of neurobehavioral performance provides a useful tool for preclinical research and development in other domains such as sleep/chronobiology, neuropsychiatric disorders, aging, and cognitive enhancement. Moreover, the human Psychomotor Vigilance Test (PVT) is a standardized and widely validated objective measure of neurobehavioral status not only employed by NASA, but also utilized in a variety of settings such as clinical neuropsychiatric assessment, military, shiftwork, and aviation. As such, the present rodent analog of the PVT provides a direct translational link to performance capacity on Earth. Once validated, the rPVT model developed here may be used as a basic and translational research tool to predict performance deficits induced by radiation or other CNS insults while providing an innovative experimental platform for exploring the bases of individual vulnerability to performance impairments and evaluating potential prophylactics, countermeasures, and treatments.

Task Progress & Bibliography Information FY2016 
Task Progress: During this funding year 60 male Long-Evans rats were used in the studies. The new rats were trained in the rPVT and exposed to protons (10, 100 cGy at 150 MeV/n) in April of 2016. They will subsequently be tested with multiple DA compounds to determine the susceptibility of individual rats to DA agonists and antagonists prior to and following irradiation.

Specific findings from this year include:

Psychostimulants as potential countermeasures for proton-induced deficits in neurobehavioral function:

• The psychostimulant d-amphetamine (DA releaser, indirect DA agonist) produced dose-dependent recovery of both accuracy and reaction time speed in radiation-sensitive animals; in radiation-insensitive animals, d-amphetamine produced decrements in performances.

• The DA/NE reuptake inhibitor methylphenidate also produced dose-dependent recovery of performance in radiation-sensitive animals, but had no effect in radiation-insensitive animals (i.e., unlike d-amphetamine, it did not impair performances in this latter group).

• The NE reuptake inhibitor atomoxetine showed no differential effects on rPVT performance in radiation-sensitive or radiation-insensitive rats.

• SCH 39166, a D1 receptor antagonist, blocked amphetamine's effects on percent correct responding, indicating that D1 receptors are responsible for amphetamine-induced changes in rPVT performance.

• L-741,626, a D2 receptor antagonist, did not block amphetamine's effects, indicating that D2 receptors are not involved in the amphetamine-induced changes in rPVT performance. The data provide evidence of the specific involvement of the DA system in radiation-induced neurobehavioral deficits.

Changes in Dopaminergic Modulation following Radiation:

• Drug-induced yawning is a sensitive metric for determining subtle changes in the DA system. DA D2/D3 receptor agonists produce a predictable pattern of drug-induced yawning in which yawning frequency first increases as the drug dose is increased, and then decreases at successively higher doses. The rising/falling pattern results from reflex activation by D3 receptors on the ascending limb, and by inhibition by D2 receptors on the descending limb.

• Differences in dopamine-agonist induced yawning and its antagonism by a dopamine D2 receptor antagonist (L-741,626) were found between radiation-sensitive and radiation-insensitive rats. Greater levels of yawning were found in radiation insensitive rats, whereas radiation sensitive rats displayed reduced levels of induced yawning. ED50 values (the dose effective in 50% of subjects) also differed significantly between the radiation sensitive and insensitive rats. Thus D2 dopamine receptors are altered in radiation sensitive rats, and D3 receptors may be altered in radiation insensitive rats.

Bibliography Type: Description: (Last Updated: 01/12/2021) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Davis CM, DeCicco-Skinner KL, Hienz RD. "Deficits in sustained attention and changes in dopaminergic protein levels following exposure to proton radiation are related to basal dopaminergic function." PLoS One. 2015 Dec 10;10(12):e0144556. eCollection 2015. http://dx.doi.org/10.1371/journal.pone.0144556 ; PubMed PMID: 26658810; PubMed Central PMCID: PMC4684339 , Dec-2015
Articles in Peer-reviewed Journals Davis CM, Roma PG, Hienz RD. "A rodent model of the human psychomotor vigilance test: Performance comparisons." Journal of Neuroscience Methods. 2016 Feb 1;259:57-71. Epub 2015 Nov 27. http://dx.doi.org/10.1016/j.jneumeth.2015.11.014 ; PubMed PMID: 26639896 , Feb-2016
Awards King S. (Scott King) "Summer Intern Fellowship awarded by the American Society of Pharmacology and Experimental Therapeutics (mentored by Dr. Davis), April 2016." Apr-2016
Project Title:  Countermeasures for Neurobehavioral Vulnerabilities to Space Radiation Reduce
Fiscal Year: FY 2015 
Division: Human Research 
Research Discipline/Element:
HRP HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Start Date: 06/01/2015  
End Date: 05/31/2017  
Task Last Updated: 06/19/2015 
Download report in PDF pdf
Principal Investigator/Affiliation:   Hienz, Robert D. Ph.D. / The Johns Hopkins University School of Medicine 
Address:  Department of Psychiatry & Behavioral Sciences 
5510 Nathan Shock Drive 
Baltimore , MD 21224-6823 
Email: bhienz@jhmi.edu 
Phone: 410-550-2788  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: The Johns Hopkins University School of Medicine 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Davis, Catherine  Ph.D. Johns Hopkins University 
Roma, Peter  Ph.D. Institutes For Behavior Resources, Inc. 
Project Information: Grant/Contract No. NCC 9-58-NBPF04201 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2013 HERO NNJ13ZSA002N-Crew Health (FLAGSHIP & NSBRI) 
Grant/Contract No.: NCC 9-58-NBPF04201 
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) Bmed:Risk of Adverse Behavioral Conditions and Psychiatric Disorders
Human Research Program Gaps: (1) BMed01:We need to identify and validate countermeasures that promote individual behavioral health and performance during exploration class missions (IRP Rev F)
Flight Assignment/Project Notes: NOTE: Change in period of performance per NSBRI (formerly 7/1/15-6/30/17)--Ed., 7/7/15

Task Description: Risk assessment of the biological consequences of living in the space radiation environment represents one of the highest priority areas of NASA radiation research. Our astronauts will be spending more time in space and ultimately will venture to the Moon, Mars, and other destinations outside of the protection of Earth’s magnetosphere. As spelled out in NASA’s Integrated Research Plan, it is essential that methods are developed to detect behavioral changes induced by radiation exposures and that potential strategies and countermeasures are developed for ameliorating radiation damage, with the long term goal being the prevention of those sequelae that impact on astronaut health and mission success. To this end, the proposed research will focus on determining the effectiveness of biomedical countermeasures for mitigating the effects of space radiation on human CNS function. The proposed studies will assess the effectiveness of a number of pharmacologic compounds in ameliorating the deleterious effects of radiation exposure on neurobehavioral function. This work will provide animal performance data obtained with an animal analog of the human Psychomotor Vigilance Test (PVT) that is currently employed for human risk assessments via quantification of sustained attention (e.g., ‘vigilance’ or ‘readiness to perform’ tasks). The proposed research will thus use an animal model that employs neurobehavioral tests identical or homologous to those currently in use in human models of risk assessment.

Within this framework, the first aim of this research will be to assess the degree to which likely biomedical countermeasures can mitigate the known effects of space radiation on cognitive neurobehavioral functions relevant to astronaut mission performance. Rodents will be trained in tests analogous to human neurobehavioral tests (e.g., a rodent version of the human PVT). Performance measures will include assessments of general motor function and speed, inhibitory control (“impulsivity”), attention, motivation, and basic sensory function. Separate groups of rats will be trained until stable performances are obtained, following which they will be transferred to NASA’s Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory (BNL) for radiation exposure to protons (25 and 100 cGy, 150 MeV/n) encountered in the space radiation environment, and then returned to Johns Hopkins for extended post-exposure testing to 1) identify neurobehavioral performance deficits over durations similar to a long-term exploratory mission, and 2) assess the effectiveness of a number of pharmacologic compounds to mitigate the deficits.

The second aim will be to assess the mechanisms of action of effective radioprotective countermeasures on the CNS by employing different types of potential mitigating and protective compounds. These will include compounds that directly alter dopaminergic (DA) signaling by binding to the dopamine transporter protein (DAT; e.g., amphetamine), compounds that directly alter dopaminergic signaling by binding to one or more receptors from the D2 receptor family (e.g., aripiprazole), and compounds that indirectly alter dopamine levels through another mechanism (e.g., norepinephrine reuptake inhibition, atomoxetine). Two FDA-approved radioprotective compounds that have mechanisms of action not specifically DA-related will also be employed (the putative DNA repair targeting drug cholorquine, and the hemopoietic growth factor erythropoietin) to provide assessments of alternative mechanisms of action.

Research Impact/Earth Benefits:

Task Progress & Bibliography Information FY2015 
Task Progress: New project for FY2015.

Bibliography Type: Description: (Last Updated: 01/12/2021) 

Show Cumulative Bibliography Listing
 
 None in FY 2015