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Fiscal Year: FY 2015  Task Last Updated:  02/20/2015 
PI Name: Davis, Catherine M. Ph.D. 
Project Title: Mitigating Neurobehavioral Vulnerabilities to Space Radiation (Postdoctoral Fellowship) 
   
Division Name: Human Research 
Program/Discipline--
Element/Subdiscipline:
NSBRI--Neurobehavioral and Psychosocial Factors Team 
 
Joint Agency Name:   TechPort:  No 
Human Research Program Elements: (1) BHP:Behavioral Health & Performance
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)
Space Biology Element: None
Space Biology Cross-Element Discipline: None
Space Biology Special Category: None
PI Email: cdavis91@jhmi.edu  Fax:  410-550-2780 
PI Organization Type: UNIVERSITY  Phone: 410-550-2775  
Organization Name: Johns Hopkins Medical School 
PI Address 1: Bayview Campus 
PI Address 2: Behavioral Biology Research Center, Suite 3000 
PI Web Page:  
City: Baltimore  State: MD 
Zip Code: 21224-6823  Congressional District: 
Comments:  
Project Type: GROUND  Solicitation:  2011 NSBRI-RFA-11-01 Postdoctoral Fellowships 
Start Date: 11/01/2011  End Date:  10/31/2014 
No. of Post Docs: No. of PhD Degrees: 
No. of PhD Candidates: No. of Master' Degrees: 
No. of Master's Candidates: No. of Bachelor's Degrees: 
No. of Bachelor's Candidates: Monitoring Center:  NSBRI 
Contact Monitor:   Contact Phone:   
Contact Email:  
Flight Program:  
Flight Assignment: NOTE: New end date per NSBRI December 2013 report (Ed., 12/24/13)

 

Key Personnel Changes/Previous PI:  
COI Name (Institution): Hienz, Robert  Ph.D. ( MENTOR/ Johns Hopkins University ) 
Grant/Contract No.: NCC 9-58-PF02602 
Performance Goal No.:  
Performance Goal Text:

 

Task Description: POSTDOCTORAL FELLOWSHIP

Original Aims/Objectives

Aim 1: To determine the degree to which radiation-induced deficits in neurobehavioral function differ as a function of basal dopaminergic tone.

Aim 2: To determine the radioprotective effectiveness of dietary flaxseed (FS) to mitigate the deleterious effects of low-dose proton radiation on neurobehavioral function.

Aim 3: To determine DAergic and inflammatory protein levels in radiation-induced, neurobehaviorally-impaired Fischer and Lewis rats and in radioprotectant-treated (FS) rats.

Aim 4: To assess functional changes in dopaminergic neurotransmission following head-only proton radiation using well-characterized dopamine receptor-mediated behaviors (i.e., DA agonist-induced yawning and hypothermia).

To assess the likelihood of space radiation producing changes in the central nervous system (CNS), neurobehavioral functions are being measured in rodents via an animal test analogous to 'vigilance' tests in humans. Cognitive neurobehavioral functions relevant to astronaut mission performance effectiveness are assessed with a rodent analog of the Psychomotor Vigilance Test (PVT) currently used in space analog environments and by astronauts aboard the International Space Station (ISS). Neurobehavioral functions examined include assessments of general motor function and speed, vigilance, memory, inhibitory control ('impulsivity'), timing, and motivation. Groups of PVT-trained animals with inherent differences in dopamine system function were exposed to radiation and then re-tested for up to 5 months post-exposure. In an additional study, separate groups of animals were given an experimental diet supplemented with flaxseed and underwent the same behavioral testing using the rPVT. Likely mechanisms of damage to the CNS following radiation exposure and flaxseed treatment are being examined using Western blotting of proteins relevant to neurotransmitter function and inflammation.

Key Findings

• Exposure to protons, 56Fe, or 28Si ions produces highly specific effects on vigilance that include a phenotypic individual differences effect in that only a subset of irradiated animals show neurobehavioral deficits (i.e., are radiation sensitive ).

• Deficits in rPVT performance are associated with changes in several proteins important for dopaminergic neurotransmission, such as tyrosine hydroxylase and the dopamine transporter, in the frontal and parietal cortices, two brain regions thought to regulate PVT performance in humans.

• Radiation-insensitive animals appear to have increased density and/or sensitivity of D3 receptors, while radiation-sensitive rats appear to have a decrease in these same receptors or possibly an increase in D2 receptor sensitivity or levels.

• d-Amphetamine dose dependently improves rPVT performance in rats displaying proton-induced deficits (i.e., radiation sensitive rats), while these same doses have no impact on sham control performance levels.

Impact

The key findings during this funding period further support the hypothesis that the dopamine system is sensitive to the effects of radiation exposure and is an important system underlying the behavioral deficits in radiation-sensitive rats.

Proposed research for the coming year

Behavioral pharmacology studies assessing the effects dopamine receptor agonists in rats pre- and post-exposure will be conducted. In addition, assessments of spontaneous locomotor activity and core body temperature in rPVT-trained rats will be recorded pre- and post-radiation to determine if any behavioral markers related to fatigue and/or inflammation are associated with radiation-induced deficits.

 

Rationale for HRP Directed Research:

 

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. Moreover, 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: Radiation-induced alterations in tyrosine hydroxylase in the frontal and parietal cortices, in addition to changes in the levels of the cytokine vascular endothelial growth factor (VEGF) in the frontal cortex are associated with behavioral deficits in the rPVT and could be involved in the underlying mechanisms of radiation-induced cognitive deficits. Decreases in VEGF are associated with deficits in the rPVT, whereas increases in VEGF are associated with a lack of radiation-induced deficits, when assessed 9-10 months post-radiation, and could be associated with long-term cognitive outcomes following radiation exposure. Dopamine D2 receptor-mediated hypothermia are similar in rats following radiation exposure; however, attenuation of this response via a relatively specific D2 receptor antagonist differs between radiation-sensitive and -insensitive rats, which suggests brain-region specific differences in dopamine D2 receptors or a radiation-induced change in D2 hypersensitivity. Dopamine D3 receptor-mediated yawning behavior is increased in 100 cGy-exposed radiation-sensitive rats, a finding that suggests an increase in function and/or density of D3 receptors in these rats. 100 cGy-exposed radiation-sensitive rats display minimal increases in yawning behavior and no attenuation of its inhibition by D2 antagonism, which suggests an increase in D2 receptor density in these animals. This finding supports the increased D2 receptor levels in 100 cGy-exposed radiation-sensitive rats we previously reported. d-Amphetamine appears to dose-dependently attenuate radiation-induced rPVT deficits in proton-exposed radiation-sensitive rats. Following amphetamine administration, radiation-sensitive rats display increased accuracy and decreased reaction times that approach sham-irradiated control performance levels.

 

Bibliography Type: Description: (Last Updated: 04/11/2019) Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Davis CM, Hienz RD "The effects of radiation on schedule-controlled responding and quinpirole-induced yawning" Experimental Biology 2014, San Diego, CA, April 26-30, 2014.

FASEB Journal. 2014 April;28(1 Suppl):839.6. See also http://www.fasebj.org/content/28/1_Supplement.toc for searching. , Apr-2014

Articles in Peer-reviewed Journals Davis CM, DeCicco-Skinner KL, Roma PG, Hienz RD. "Individual differences in attentional deficits and dopaminergic protein levels following exposure to proton radiation." Radiation Research. 2014 Mar;181(3):258-71. http://dx.doi.org/10.1667/RR13359.1 ; PMID: 24611657 , Mar-2014
Articles in Peer-reviewed Journals Davis CM, Roma PG, Armour E, Gooden VL, Brady JV, Weed MR, Hienz RD. "Effects of X-ray radiation on complex visual discrimination learning and social recognition memory in rats." PLoS One. 2014 Aug 6;9(8):e104393. eCollection 2014. http://dx.doi.org/10.1371/journal.pone.0104393 ; PubMed PMID: 25099152; PubMed Central PMCID: PMC4123910 , Aug-2014
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. https://doi.org/10.1016/j.jneumeth.2015.11.014 ; PubMed PMID: 26639896 (Reported originally in Feb. 2015 as 'Submitted in August 2014.') , Feb-2016
Awards Davis CM. "1st Place, Best Abstract Poster Competition, Behavioral Pharmacology Division of American Society for Pharmacology and Experimental Therapeutics (ASPET) meeting, April 2014." Apr-2014
Significant Media Coverage Desmon S. "Some Astronauts at Risk for Cognitive Impairment, Animal Studies Suggest. Press release describing our findings in our Radiation Research paper (Radiat Res. 2014 Mar;181(3):258-71. PMID: 24611657 )." Johns Hopkins Medicine Eureka Alert: http://www.eurekalert.org/pub_releases/2014-04/jhm-saa042314.php ; accessed 2/20/15., Apr-2014
Significant Media Coverage Lafrance A. "How Going to Space Can Mess with the Astronaut Brain. Article describing our findings in our Radiation Research paper (Radiat Res. 2014 Mar;181(3):258-71. PMID: 24611657 )." The Atlantic, April 23, 2014. http://www.theatlantic.com/technology/archive/2014/04/how-going-to-space-can-mess-with-the-astronaut-brain/361106/ ; accessed 2/20/15., Apr-2014
Download in PDF pdf     
Fiscal Year: FY 2014  Task Last Updated:  12/24/2013 
PI Name: Davis, Catherine M. Ph.D. 
Project Title: Mitigating Neurobehavioral Vulnerabilities to Space Radiation (Postdoctoral Fellowship) 
   
Division Name: Human Research 
Program/Discipline--
Element/Subdiscipline:
NSBRI--Neurobehavioral and Psychosocial Factors Team 
 
Joint Agency Name:   TechPort:  No 
Human Research Program Elements: (1) BHP:Behavioral Health & Performance
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)
Space Biology Element: None
Space Biology Cross-Element Discipline: None
Space Biology Special Category: None
PI Email: cdavis91@jhmi.edu  Fax:  410-550-2780 
PI Organization Type: UNIVERSITY  Phone: 410-550-2775  
Organization Name: Johns Hopkins Medical School 
PI Address 1: Bayview Campus 
PI Address 2: Behavioral Biology Research Center, Suite 3000 
PI Web Page:  
City: Baltimore  State: MD 
Zip Code: 21224-6823  Congressional District: 
Comments:  
Project Type: GROUND  Solicitation:  2011 NSBRI-RFA-11-01 Postdoctoral Fellowships 
Start Date: 11/01/2011  End Date:  10/31/2014 
No. of Post Docs: No. of PhD Degrees: 
No. of PhD Candidates: No. of Master' Degrees: 
No. of Master's Candidates: No. of Bachelor's Degrees: 
No. of Bachelor's Candidates: Monitoring Center:  NSBRI 
Contact Monitor:   Contact Phone:   
Contact Email:  
Flight Program:  
Flight Assignment: NOTE: New end date per NSBRI December 2013 report (Ed., 12/24/13)

 

Key Personnel Changes/Previous PI:  
COI Name (Institution): Hienz, Robert   ( MENTOR/ Johns Hopkins University ) 
Grant/Contract No.: NCC 9-58-PF02602 
Performance Goal No.:  
Performance Goal Text:

 

Task Description: POSTDOCTORAL FELLOWSHIP

Original Aims/Objectives Aim 1: To determine the degree to which radiation-induced deficits in neurobehavioral function differ as a function of basal dopaminergic tone. Aim 2: To determine the radioprotective effectiveness of dietary flaxseed (FS) to mitigate the deleterious effects of low-dose proton radiation on neurobehavioral function. Aim 3: To determine DAergic and inflammatory protein levels in radiation-induced, neurobehaviorally-impaired Fischer and Lewis rats and in radioprotectant-treated (FS) rats. To assess the likelihood of space radiation producing changes in the CNS, neurobehavioral functions are being measured in rodents via an animal test analogous to 'vigilance' tests in humans. Cognitive neurobehavioral functions relevant to astronaut mission performance effectiveness are assessed with a rodent analog of the Psychomotor Vigilance Test (PVT) currently used in space analog environments and by astronauts aboard ISS. Neurobehavioral functions examined include assessments of general motor function and speed, vigilance, memory, inhibitory control ('impulsivity'), timing, and motivation. Groups of PVT-trained animals with inherent differences in dopamine system function were exposed to radiation and then re-tested for up to 5 months post-exposure. In an additional study, separate groups of animals were given an experimental diet supplemented with flaxseed and underwent the same behavioral testing using the rPVT. Likely mechanisms of damage to the CNS following radiation exposure and flaxseed treatment are being examined using Western blotting of proteins relevant to neurotransmitter function and inflammation.

Key Findings

• Radiation-induced changes in rPVT performance in the Fischer 344 and Lewis rat strains was accompanied by differential cytokine expression in the frontal cortex. Interestingly, two of the cytokines elevated in the Lewis rats, the strain that did not display any radiation-induced rPVT deficits, are cytokines reported to decrease cognitive impairments in animal models of Alzheimer's disease and ischemic injury, suggesting CNTF and GM-CSF as possible future candidates for treatments of radiation-induced cognitive deficits.

• Radiation-induced changes in rPVT performance were evident in rats supplemented with a 10% flaxseed diet. However, these rats recovered from the radiation-induced rPVT deficits by the end of post-radiation testing period, whereas irradiated rats receiving a control diet had rPVT deficits that remained throughout the post-radiation test period.

• Quinpirole, a D2/3 receptor agonist, and amisuplride, a D2 receptor antagonist, had differing effects on behavioral performances of rats exposed to 56Fe that were related to their performances on the rPVT following exposure. Rats displaying no rPVT deficits following exposure were more sensitive to the behavior-decreasing effects of quinpirole; rats displaying rPVT deficits were more sensitive to the behavior-increasing effects of amisulpride. These data demonstrate the importance of the dopamine system in individual behavioral differences following irradiation.

Impact

The key findings during this funding period support the stated hypothesis that differences in brain-region specific cytokine differences would be related to the degree of deficit on the rPVT following radiation exposure. Further, a flaxseed-containing diet appears to aid in recovery of behavioral performance following proton exposure.

Proposed research for the coming year

Western blot analyses will be completed on the brain tissue from rats in the flaxseed study. Relevant brain regions will be excised and subjected to Western blot analysis and mRNA detection. Proteins of interest include the dopamine D2 receptor, the dopamine transporter, cell survival proteins, and cytokines (e.g., CNTF, GM-CSF). Additional behavioral pharmacology studies assessing the effects dopamine receptor agonists in rats pre- and post-exposure will also be conducted.

 

Rationale for HRP Directed Research:

 

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. Moreover, 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: Radiation-induced changes in rPVT performance in the Fischer 344 and Lewis rat strains was accompanied by differential cytokine expression in the frontal cortex. Interestingly, two of the cytokines elevated in the Lewis rats, the strain that did not display any radiation-induced rPVT deficits, are cytokines reported to decrease cognitive impairments in animal models of Alzheimer's disease and ischemic injury. Given these results, CNTF and GM-CSF could be possible candidates for treatments for radiation-induced cognitive deficits in future studies. Radiation-induced changes in rPVT performance were evident in rats supplemented with a 10% flaxseed diet. However, these rats recovered from the radiation-induced rPVT deficits by the end of post-radiation testing period, whereas irradiated rats receiving a control diet had rPVT deficits that remained throughout the post-radiation test period. Quinpirole, a D2/3 receptor agonist, and amisuplride, a D2 receptor antagonist, had differing effects on behavioral performances of rats exposed to 56Fe that were related to their performances on the rPVT following exposure. Rats displaying no rPVT deficits following exposure were more sensitive to the behavior-decreasing effects of quinpirole; rats displaying rPVT deficits were more sensitive to the behavior-increasing effects of amisulpride. These data demonstrate the importance of the dopamine system in individual behavioral differences following irradiation.

 

Bibliography Type: Description: (Last Updated: 04/11/2019) Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Davis CM, Hienz RD. "Assessing neurobehavioral function with the rat psychomotor vigilance task." Experimental Biology 2012, San Diego, CA, April 21-25, 2012.

FASEB Journal 2012 Apr;26(Meeting Abstract Supplement):1042.2. Search: http://www.fasebj.org/content/vol26/1_MeetingAbstracts , Apr-2012

Abstracts for Journals and Proceedings Davis CM, Hienz RD. "Behavioral effects of quinpirole on schedule-controlled responding in radiation sensitive and insensitive rats." Experimental Biology 2013 meeting, Boston, MA, April 20-24, 2013.

FASEB J. 2013 Apr;27(Meeting Abstract Supplement):1098.15. See also http://www.fasebj.org/content/vol27/1_MeetingAbstracts for searching. , Apr-2013

Articles in Peer-reviewed Journals Davis CM, DeCicco-Skinner KL, Roma PG, Hienz RD. "Individual differences in attentional deficits and dopaminergic protein levels following exposure to proton radiation." Radiation Research. Resubmitted August 30th, 2013. Currently under review as of December 2013. , Dec-2013
Articles in Peer-reviewed Journals Davis CM, Roma PG, Hienz RD. "A rodent model of the human psychomotor vigilance test: Performance comparisons." Behavioral Brain Research. Submitted in January 2012. Currently under revision as of October 2012. (Ed. note 12/2013: No update since then) , Oct-2012
Awards Davis CM. "1st Place Postdoctoral Poster Contest HRP Investigators' Meeting, February 2013." Feb-2013
Awards Davis CM. "American Society for Pharmacology and Experimental Therapeutics (ASPET) Washington Policy Fellow, November 2012." Nov-2012
Awards Davis CM. "American Society for Pharmacology and Experimental Therapeutics (ASPET) Young Investigator Travel Award, April 2013." Apr-2013
Books/Book Chapters Davis CM. "Chapter 28–Animal Models of Drug Abuse: Place and Taste Conditioning." in "Animal Models for the Study of Human Disease." Ed. P.M. Conn. London ; Waltham, MA : Elsevier, 2013. p. 681-707. http://dx.doi.org/10.1016/B978-0-12-415894-8.00028-2 , Aug-2013
Download in PDF pdf     
Fiscal Year: FY 2013  Task Last Updated:  12/19/2012 
PI Name: Davis, Catherine M. Ph.D. 
Project Title: Mitigating Neurobehavioral Vulnerabilities to Space Radiation (Postdoctoral Fellowship) 
   
Division Name: Human Research 
Program/Discipline--
Element/Subdiscipline:
NSBRI--Neurobehavioral and Psychosocial Factors Team 
 
Joint Agency Name:   TechPort:  No 
Human Research Program Elements: (1) BHP:Behavioral Health & Performance
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)
Space Biology Element: None
Space Biology Cross-Element Discipline: None
Space Biology Special Category: None
PI Email: cdavis91@jhmi.edu  Fax:  410-550-2780 
PI Organization Type: UNIVERSITY  Phone: 410-550-2775  
Organization Name: Johns Hopkins Medical School 
PI Address 1: Bayview Campus 
PI Address 2: Behavioral Biology Research Center, Suite 3000 
PI Web Page:  
City: Baltimore  State: MD 
Zip Code: 21224-6823  Congressional District: 
Comments:  
Project Type: GROUND  Solicitation:  2011 NSBRI-RFA-11-01 Postdoctoral Fellowships 
Start Date: 11/01/2011  End Date:  10/31/2013 
No. of Post Docs: No. of PhD Degrees: 
No. of PhD Candidates: No. of Master' Degrees: 
No. of Master's Candidates: No. of Bachelor's Degrees: 
No. of Bachelor's Candidates: Monitoring Center:  NSBRI 
Contact Monitor:   Contact Phone:   
Contact Email:  
Flight Program:  
Flight Assignment:

 

Key Personnel Changes/Previous PI:  
COI Name (Institution): Hienz, Robert   ( MENTOR/ Johns Hopkins University ) 
Grant/Contract No.: NCC 9-58-PF02602 
Performance Goal No.:  
Performance Goal Text:

 

Task Description: POSTDOCTORAL FELLOWSHIP

(1) Original Aims Aim 1: To determine the degree to which radiation-induced deficits in neurobehavioral function differ as a function of basal dopaminergic tone. Aim 2: To determine the radioprotective effectiveness of dietary flaxseed (FS) to mitigate the deleterious effects of low-dose proton radiation on neurobehavioral function. Aim 3: To determine DAergic and inflammatory protein levels in radiation-induced, neurobehaviorally-impaired rats and in radioprotectant-treated rats. To assess the likelihood of space radiation producing long-term functional changes in the CNS, neurobehavioral functions are being measured in rodents via an animal test analogous to 'vigilance' tests in humans. Cognitive neurobehavioral functions relevant to astronaut mission performance effectiveness are assessed with a rodent analog of the Psychomotor Vigilance Test (PVT) currently used in space analog environments and by astronauts aboard ISS. Neurobehavioral functions examined include assessments of general motor function and speed, vigilance, memory, inhibitory control ('impulsivity'), timing, motivation, and basic sensory function. Groups of animals with inherent differences in dopamine system function were trained on the rodent version of the PVT, following which they were exposed to radiation and then re-tested periodically for up to 5 months post-exposure to assess potential performance deficits. In an upcoming study, separate groups of animals will be given an experimental diet supplemented with flaxseed and will undergo the same behavioral testing using the rPVT. Likely mechanisms of damage to the CNS following radiation exposure and flaxseed treatment are being examined using Western blotting of proteins relevant to neurotransmitter function and inflammation.

(2) Key Findings

• Discovery that the initial inflammatory response in the brain is elevated in the forebrain, cerebellum, and whole brain tissue following proton exposure immediately following and up to 14 days post-exposure. This inflammatory response continues for a significant amount of time following irradiation and that could possibly lead to cellular changes and negatively impact neurobehavioral function, and suggests that the immediate inflammatory response and likely subsequent glial cell death and extended brain inflammation could underlie such neurobehavioral changes following proton exposure and impact an individual's sensitivity to proton radiation.

• Data showing that radiation-induced deficits in neurobehavioral function differ as a function of basal dopaminergic tone when examined in inbred strains of rats with inherent differences in dopamine (DA) function, and indicating a likely involvement of the dopaminergic system in determining an individual's susceptibility to radiation-induced neurobehavioral damage to the CNS.

(3) Impact of key findings. The key findings during this funding period support the stated hypothesis that basal differences in dopaminergic tone would influence the extent of neurobehavioral deficits following irradiation.

(4) Proposed research plan for the coming year. Western blot analyses will be completed on the brain tissue from the Fischer 344 and Lewis rats from the previous funding year. More specifically, brain regions implicated in attentional performance will be subjected to Western blot analysis and mRNA detection. Proteins of interest include, but are not limited to, the dopamine D2 receptor, the dopamine transporter, cell survival proteins, and inflammatory cytokines. In addition, separate groups of rats will be maintained on a diet containing 10% flax seed or a control diet, trained on the rPVT, and exposed to proton radiation. Follow-up behavioral testing will occur for at least 5 months after irradiation to determine if dietary flax seed mitigates the neurobehavioral deficits following proton exposure. Once the behavioral testing period has ended, brain tissue will be removed and analyzed as described above.

 

Rationale for HRP Directed Research:

 

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. Moreover, 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: Highlights for this first year include:

• Findings of radiation-sensitive animals showing significantly higher levels of dopamine D2 receptors as well as dopamine transporter (DAT) in the brain, with non-sensitive-but-exposed rats as well as control rats showing no such changes in DA protein levels, suggesting that DA level differences may play an important role in how an organism responds to radiation neurobehaviorally, and may have important implications for possible screening of radiation sensitivity and future development of radioprotectants.

• Discovery that the initial inflammatory response in the brain is elevated in the forebrain, cerebellum, and whole brain tissue following proton exposure immediately following and up to 14 days post-exposure. This inflammatory response continues for a significant amount of time following irradiation and that could possibly lead to cellular changes and negatively impact neurobehavioral function, and suggests that the immediate inflammatory response and likely subsequent glial cell death and extended brain inflammation could underlie such neurobehavioral changes following proton exposure and impact an individual's sensitivity to proton radiation.

• Data showing that radiation-induced deficits in neurobehavioral function differ as a function of basal dopaminergic function when examined in Inbred strains of rats with inherent differences in dopamine (DA) function, and indicating a likely involvement of the dopaminergic system in determining an individual's susceptibility to radiation-induced neurobehavioral damage to the CNS.

 

Bibliography Type: Description: (Last Updated: 04/11/2019) Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Davis CM, Guida PM, Hienz RD. "Individual Differences in Neurobehavioral Deficits Following Proton Irradiation are Related to Basal Dopamine Function." 23rd Annual NASA Space Radiation Investigators' Workshop, Durham, NC, July 8-11, 2012.

23rd Annual NASA Space Radiation Investigators' Workshop, Durham, NC, July 8-11, 2012. , Jul-2012

Awards Davis CM. "2nd Place, Best Abstract Competition (Postdoc), Behavioral Pharmacology Division of the American Society for Pharmacology and Experimental Therapeutics (ASPET), April 2012." Apr-2012
Awards Davis CM. "3rd Place, Postdoctoral Fellow Poster Contest, for 'Individual Differences in Neurobehavioral Deficits Following Proton Irradiation are Related to Basal Dopamine Function," 23rd Annual NASA Space Radiation Investigators' Workshop, July 2012." Jul-2012
Awards Davis CM. "ASPET Young Scientist Travel Award to attend Annual Experimental Biology Meeting in San Diego, CA, April 2012." Apr-2012
Awards Davis CM. "Honorable Mention, Postdoctoral Fellow Poster Contest for 'Neurobehavioral Effects of Space Radiation on Psychomotor Vigilance,' 22nd Annual NASA Space Radiation Investigators' Workshop, September 2011." Sep-2011
Awards Davis CM. "Student (competitive enrollment), NASA Space Radiation Summer School at Brookhaven National Laboratory, May 2012." May-2012
Books/Book Chapters Davis CM. "Animal Models of Drug Abuse: Place and Taste Conditioning." in "Animal Models for the Study of Human Disease." Ed. P.M. Conn. New York : Elsevier, in press as of December 2012., Dec-2012
Download in PDF pdf     
Fiscal Year: FY 2012  Task Last Updated:  10/26/2011 
PI Name: Davis, Catherine M. Ph.D. 
Project Title: Mitigating Neurobehavioral Vulnerabilities to Space Radiation (Postdoctoral Fellowship) 
   
Division Name: Human Research 
Program/Discipline--
Element/Subdiscipline:
NSBRI--Neurobehavioral and Psychosocial Factors Team 
 
Joint Agency Name:   TechPort:  No 
Human Research Program Elements: (1) BHP:Behavioral Health & Performance
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)
Space Biology Element: None
Space Biology Cross-Element Discipline: None
Space Biology Special Category: None
PI Email: cdavis91@jhmi.edu  Fax:  410-550-2780 
PI Organization Type: UNIVERSITY  Phone: 410-550-2775  
Organization Name: Johns Hopkins Medical School 
PI Address 1: Bayview Campus 
PI Address 2: Behavioral Biology Research Center, Suite 3000 
PI Web Page:  
City: Baltimore  State: MD 
Zip Code: 21224-6823  Congressional District: 
Comments:  
Project Type: GROUND  Solicitation:  2011 NSBRI-RFA-11-01 Postdoctoral Fellowships 
Start Date: 11/01/2011  End Date:  10/31/2013 
No. of Post Docs:   No. of PhD Degrees:   
No. of PhD Candidates:   No. of Master' Degrees:   
No. of Master's Candidates:   No. of Bachelor's Degrees:   
No. of Bachelor's Candidates:   Monitoring Center:  NSBRI 
Contact Monitor:   Contact Phone:   
Contact Email:  
Flight Program:  
Flight Assignment:

 

Key Personnel Changes/Previous PI:  
COI Name (Institution): Hienz, Robert   ( MENTOR/ Johns Hopkins University ) 
Grant/Contract No.: NCC 9-58-PF02602 
Performance Goal No.:  
Performance Goal Text:

 

Task Description: POSTDOCTORAL FELLOWSHIP

Assessing the biological consequences of living in the space radiation environment represents one of the highest priority areas of NASA research. Of critical importance is the need for an assessment of the vulnerabilities of the central nervous system (CNS) leading to functional neurobehavioral changes during long-term space missions, and the development of effective countermeasures to such risks.

The present proposal addresses this need via the application of an animal model to determine:

1) The long-term effects of radiation exposure on cognitive neurobehavioral function and the dopamine neurotransmitter system; and

2) The effectiveness of flaxseed dietary supplementation to mitigate the neurobehavioral and neurochemical effects of radiation exposure.

To assess the likelihood of space radiation producing long-term functional changes in the CNS, neurobehavioral functions will be measured in rodents via an animal test analogous to 'vigilance' tests in humans. Cognitive neurobehavioral functions relevant to astronaut mission performance effectiveness will be assessed with a rodent analog of the Psychomotor Vigilance Test (PVT) currently used in space analog environments and by astronauts aboard the International Space Station.

Neurobehavioral functions to be examined include assessments of general motor function and speed, vigilance, memory, inhibitory control ('impulsivity'), timing, motivation and basic sensory function. Groups of animals with inherent differences in dopamine system function will be trained on the rodent version of the PVT, following which they will be exposed to radiation and then re-tested periodically for up to five months post-exposure to assess potential performance deficits. Separate groups of animals will be given an experimental diet supplemented with flaxseed and will undergo the same behavioral testing using the rPVT. Likely mechanisms of damage to the CNS following radiation exposure and flaxseed treatment will be examined using Western blotting of proteins relevant to neurotransmitter function and inflammation.

 

Rationale for HRP Directed Research:

 

Research Impact/Earth Benefits: 0

 

Task Progress: New project for FY2012.

 

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