Executive function in rats is impaired by low (20 cGy) doses of 1 GeV/u (56)Fe particles.

Exposure to galactic cosmic radiation is a potential health risk in long-term space travel and represents a significant risk to the central nervous system. The most harmful component of galactic cosmic radiation is the HZE [high mass, highly charged (Z), high energy] particles, e.g., (56)Fe particle. In previous ground-based experiments, exposure to doses of HZE-particle radiation that an astronaut will receive on a deep space mission (i.e., ∼20 cGy) resulted in pronounced deficits in hippocampus-dependent learning and memory in rodents. Neurocognitive tasks that are dependent upon other regions of the brain, such as the striatum, are also impaired after exposure to low HZE-particle doses. These data raise the possibility that neurocognitive tasks regulated by the prefrontal cortex could also be impaired after exposure to mission relevant HZE-particle doses, which may prevent astronauts from performing complex executive functions. To assess the effects of mission relevant (20 cGy) doses of 1 GeV/u (56)Fe particles on executive function, male Wistar rats received either sham treatment or were irradiated and tested 3 months later for their ability to perform attentional set shifting. Compared to the controls, rats that received 20 cGy of 1 GeV/u (56)Fe particles showed significant impairments in their ability to complete the attentional set-shifting test, with only 17% of irradiated rats completing all stages as opposed to 78% of the control rats. The majority of failures (60%) occurred at the first reversal stage, and half of the remaining animals failed at the extra-dimensional shift phase of the studies. The irradiated rats that managed to complete the tasks did so with approximately the same ease as did the control rats. These observations suggest that exposure to mission relevant doses of 1 GeV/u (56)Fe particles results in the loss of functionality in several regions of the cortex: medical prefrontal cortex, anterior cingulated cortex, posterior cingulated cortex and the basal forebrain. Our observation that 20 cGy of 1 GeV/u (56)Fe particles is sufficient to impair the ability of rats to conduct attentional set-shifting raises the possibility that astronauts on prolonged deep space exploratory missions could subsequently develop deficits in executive function.

Low (20 cGy) doses of 1 GeV/u (56)Fe--particle radiation lead to a persistent reduction in the spatial learning ability of rats.

Exposure to galactic cosmic radiation (GCR) is considered to be a potential health risk in long-term space travel, and it represents a significant risk to the central nervous system (CNS). The most harmful component of GCR is the HZE [high-mass, highly charged (Z), high-energy] particles, e.g. (56)Fe. In previous ground-based experiments, exposure to high doses of HZE-particle radiation induced pronounced deficits in hippocampus-dependent learning and memory in rodents. Recent data suggest that glutamatergic transmission in hippocampal synaptosomes is impaired after low (60 cGy) doses of 1 GeV/u (56)Fe particles, which could lead to impairment of hippocampus-dependent spatial memory. To assess the effects of mission-relevant (20-60 cGy) doses of 1 GeV/u (56)Fe particles on hippocampus-dependent spatial memory, male Wistar rats either received sham treatment or were irradiated and tested 3 months later in the Barnes maze test. Compared to the controls, rats that received 20, 40 and 60 cGy 1 GeV/u (56)Fe particles showed significant impairments in their ability to locate the escape box in the Barnes maze, which was manifested by progressively increasing escape latency times over the 3 days of testing. However, this increase was not due to a lack of motivation of the rats to escape, because the total number of head pokes (and especially incorrect head pokes) remained constant over the test period. Given that rats exposed to X rays did not exhibit spatial memory impairments until >10 Gy was delivered, the RBE for 1 GeV/u (56)Fe-particle-induced hippocampal spatial memory impairment is ∼50. These data demonstrate that mission-relevant doses of 1 GeV/u (56)Fe particles can result in severe deficits in hippocampus-dependent neurocognitive tasks, and the extreme sensitivity of these processes to 1 GeV/u (56)Fe particles must arise due to the perturbation of multiple processes in addition to killing neuronal cells.

The identification of serum biomarkers of high-let radiation exposure and biological sequelae.

In the event of a nuclear detonation, thousands of people will be exposed to non-lethal radiation doses. There are multiple long-term health concerns for exposed individuals who receive non-lethal radiation exposures. Low doses of radiation, especially of high linear energy transfer (LET) radiation, can lead to the development of neurocognitive defects. The identification of serum biomarkers that can be used to monitor the emergence of the long-term biological sequelae of radiation exposure, such as neurocognitive defects, would greatly help the post-exposure health monitoring of the affected population. The authors have determined the impact that cranial irradiation with 2 Gy of high LET (150 keV um) has on the ability of rats to perform spatial memory tasks, and identified serum protein changes that are biomarkers of radiation exposure and of radiation-induced neurocognitive impairment. Matrix Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectroscopy (MALDI TOF-TOF) analysis of weak cation exchange (WCX) enriched serum protein preparations identified 23 proteins of interest: 10 were biomarkers of physical radiation dose, with six showing increased expression and four being undetectable in the irradiated rat serum. Four proteins were uniquely expressed in those rats that had good spatial memory and nine proteins were markers of bad spatial memory. This study provides proof of the concept that serum protein profiling can be used to identify biomarkers of radiation exposure and the emergence of radiation-sequelae in this rat model, and this approach could be easily applied to other systems to identify radiation biomarkers.

Comparison of the lateral tail vein and the retro-orbital venous sinus as routes of intravenous drug delivery in a transgenic mouse model.

In mice, intravenous injections are commonly administered in the lateral tail vein. This technique is sometimes difficult to carry out and may cause stress to mice. Though injection through the retro-orbital venous sinus can provide certain advantages over lateral tail vein injection, this method is poorly defined and infrequently used. To compare the efficacy of these two routes of drug delivery, the authors injected MAFIA transgenic mice with the depletion agent AP20187, which selectively induces apoptosis in macrophages. Each mouse received five consecutive daily injections through either the lateral tail vein or the retro-orbital venous sinus. The authors then compared macrophage depletion in different tissues (lung, spleen, bone marrow and peritoneal exudate cells). Both routes of injection were similarly effective. A separate experiment using BALB/c mice indicated that retro-orbital venous sinus injection was the less stressful of the two methods.

Lack of correlation of vaginal impedance measurements with hormone levels in the rat.

Hormone levels vary in female rats depending on estrous cycle stage. Vaginal cytology is a reliable method of staging female rats, but vaginal impedance offers an alternative depending on application. We sought to correlate vaginal impedance in cycling female rats with hormone levels. Vaginal cytology was the standard for comparison and verification of estrous cycle stage. Female rats (n = 41) were evaluated twice daily for 15 days via vaginal cytology and impedance to evaluate two or three estrous cycles per rat. During the last 5 days of the study, selected anesthetized sampling groups (n = 3 or 4 rats per group) were bled terminally at each time point to allow hormone determinations concurrently with vaginal cytology and impedance. Rats with abnormal vaginal smears or discharges (n = 5) were evaluated for reproductive tract histology. Rats classified in estrus by vaginal cytology had significantly higher vaginal impedance values than did nonestrus rats, but vaginal impedance and estrous cycle stage as determined by vaginal cytology did not correlate. Because of small sampling size in nonproestrus groups, correlation between vaginal impedance and hormone levels was evaluated only in proestrus rats (n = 22) and was nonsignificant. No correlation occurred between vaginal impedance and hormone levels in unstaged rats (n = 41). Two animals evaluated for reproductive tract histology showed evidence of pseudopregnancy. Vaginal impedance may be useful in distinguishing estrus from nonestrus rats but may be limited for chronic estrous cycle monitoring because of the possible risk of inducing pseudopregnancy.