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. The present project directly addresses the need for research with animal models on CNS risks that include likely changes in cognitive neurobehavioral function from solar particle events (SPE’s), galactic cosmic rays (GCR’s) or combined SPE and GCR irradiations. In addition, the project emphasizes differences in individual radiation sensitivity and likely changes in normal fluctuations in core body temperature and rest-activity patterns, two primary indices of circadian function, in addition to dopamine receptor-mediated behaviors and receptor function underlying these differences. It is critically important to assess whether radiation adversely affects brain functions by using new and more sensitive techniques to detect both short- and long-term cognitive neurobehavioral changes in animals. The use of such relevant systems for testing neurobehavioral function is critical to assessing radiation vulnerabilities for astronauts during long-duration lunar, NEA, and Mars missions.
Mitigating Neurobehavioral Vulnerabilities to Space Radiation (Career Advancement Award)
Catherine M. Davis, Ph.D.
The Johns Hopkins University School of Medicine
Aim: Assess the effects of radiation on core body temperature, spontaneous locomotor activity, and responses to dopamine D2/D3 receptor agonists in rats trained to perform the rodent psychomotor vigilance test (rPVT).
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 CNS leading to functional neurobehavioral changes during long-term space missions, and the development of effective countermeasures to such risks. The current project employs biotelemetry methods to determine if radiation alters core body temperature and rest-activity patterns (i.e., spontaneous locomotor activity) in a radiation sensitivity-dependent manner. These two indices were chosen because 1) they have similar circadian fluctuations in both humans and rats, 2) they have been, or continue to be, studied during spaceflight, and 3) they are altered by various environmental insults and physiological changes, including inflammation, therapeutic radiation exposure, and administration of dopaminergic compounds. For example, fatigue and changes in rest-activity patterns are known to be common side effects of cranial irradiation in cancer patients. Alterations in these functions following exposure to protons could be a major factor underlying radiation-sensitivity and would provide a wealth of information regarding what additional neurochemical systems might be involved.
Prior research has 1) identified rats that are sensitive to radiation-induced deficits in neurobehavioral function; 2) identified changes in the dopamine neurotransmitter system and dopamine-induced behaviors in radiation sensitive and insensitive rats; and 3) identified an increased inflammatory response in rats’ brains from 1-14 days post-irradiation. The current project is determining how the radiation-induced inflammatory response chronically alters thermoregulation. The severity of these changes are hypothesized to correlate with the severity of the neurobehavioral deficits in rPVT performance measures, such that rats classified as “radiation-sensitive” will have the most severe and/or sustained alterations in these measures. Since hypothermia is a dopamine D2 receptor-mediated behavior, radiation-induced increases in body temperature are hypothesized to also result in an attenuated hypothermic response following D2/3 agonist administration in radiation-sensitive rats only. An additional measure of dopaminergic activity in rats is the yawning reflex, which is a dopamine D3 receptor-mediated behavior. This measure will be employed to assess whether increased tissue levels and/or sensitivity of the D3 receptor are likely to occur only in the radiation-insensitive rats, primarily in those rats exposed to 100 cGy protons; such an effect will be evident as an upward shift of the ascending limb of the yawning dose-response curve. Differences in yawning are hypothesized to be apparent in other groups of irradiated rats following pretreatment with antagonists specific for other neurotransmitter systems involved in hippocampal control of the motor movements of yawning behavior (e.g., centrally acting anticholinergics).
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. 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.