| 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 research addresses this need via the application of an innovative animal model to determine 1) the short- and long-term effects of radiation exposure on cognitive neurobehavioral function; and 2) the likely mechanisms of damage to the CNS following radiation exposure.
Cognitive neurobehavioral functions relevant to astronaut mission performance effectiveness are being assessed with a rodent analog of the human Psychomotor Vigilance Test (PVT) currently used in space analog environments and by astronauts aboard ISS, which includes assessments of general motor function and speed, vigilance, inhibitory control ('impulsivity'), timing, motivation, and basic sensory function. Animals trained on the rodent version of the PVT (the rPVT) are subsequently exposed to protons and high-energy particle radiation and then tested for up to 12 months post-exposure to assess potential short- and long-term performance deficits. Likely mechanisms of damage to the CNS following radiation exposure are examined via pre-radiation behavioral pharmacology studies as well as post-radiation behavioral pharmacology studies and neurochemical assessments of CNS proteins relevant to neurotransmitter function and inflammation.
Key aims of the study are to determine 1) whether pre-existing individual differences in neurotransmitter function may be predictive of the observed differential neurobehavioral susceptibility of individuals following proton radiation; 2) whether the observed neurotransmitter changes are restricted to specific brain regions; and 3) whether differential neurobehavioral susceptibility occurs following exposure to other ion species.
Key Findings: Results from the project have demonstrated that head-only exposure to space radiation (protons, 56Fe, 28Si) significantly impairs neurobehavioral function (e.g., decrease accuracy, increase impulsivity, increase lapses in attention) and slows motor function. These findings support the success of the rPVT as a rodent model for studying the risks of living in the space radiation environment due to changes in neurobehavioral function.
Specific findings from the past year include:
1. Pre-exposure evaluations of a DA agonist and antagonist on FR/FI performance were completed. Following radiation, retests on the rPVT performances revealed ~30% of the animals to be classified as radiation-sensitive. Post-exposure pharmacological challenges with a DA agonist and antagonist are underway to determine whether radiation-induced changes in the DA system are linked to pre-radiation DA system changes (i.e., whether pre-radiation DA system sensitivities may be predictive of subsequent radiation sensitivity).
2. Drug-induced yawning is being used as a sensitive metric for determining subtle changes in D2 and D3 activity in rodents. A rising and falling pattern of DA-induced yawning in rodents is induced by activation of the D3 receptor on the ascending limb, and by inhibition by the D2 receptor on the descending limb. This differential modulation by D3 and D2 antagonists results in D3-preferring antagonists producing selective rightward shifts of the ascending limb, and D2-preferring antagonists producing selective shifts of the descending limb. Following 25-100 cGy proton exposures, differential shifts in the ascending limbs of these curves have been observed, suggesting that D3 receptor activity and/or tissue levels are altered by radiation.
3. A study (part of Catherine Davis' NSBRI Postdoctoral Fellowship) determined the degree to which radiation-induced deficits in neurobehavioral function differ as a function of changes in cytokine protein expression. Brain tissue of both F344 and LEW rPVT-trained rats were found to have differential changes in frontal cortex cytokine levels; several neurotrophic and putative pro-cognitive cytokines were significantly elevated in the LEW rats, which could underlie the lack of radiation-induced rPVT deficits in this strain. Western blot analyses of several different proteins important for dopamine neurotransmission (e.g., dopamine transporter, D2 receptor, tyrosine hydroxylase) and cell survival (e.g., Akt, p-Akt, CREB), in addition to various cytokines (e.g., TNF-a, Il-1a, Il-6, GM-CSF, CNTF, VEGF) in the frontal and parietal cortices of the F344 and LEW rats were found to be differentially altered following proton exposure.
4. Two new publications have appeared that demonstrate 1) Exposure to head-only proton irradiation differentially disrupts rPVT performance in a subgroup of radiation-sensitive animals, and that these deficits are correlated with changes in the levels of the dopamine transporter and the D2 receptor in this subgroup; and 2) following proton irradiation, rats performing an automated intra-dimensional set shifting task respond less and have elevated numbers of omitted trials during the first two performance stages, but show no effects of radiation on social recognition memory.
Plans for the Coming Year: Plans include completing 1) behavioral pharmacology studies to determine the degree to which pre-existing individual differences in neurotransmitter function may be predictive of the observed differential neurobehavioral susceptibility of individuals following radiation, 2) neurotransmitter protein level studies to determine the degree to which the observed neurotransmitter changes are restricted to specific brain regions, and 3) continued support of Dr. Catherine Davis' NSBRI Postdoctoral Fellowship studies designed to assess neurochemical changes in the brain following radiation.