Executive Function in Rats is Impaired by Low (20 cGy) Doses of 1 GeV/u Fe-56 Particles

a Department of Pathology and Anatomy.
Radiation Research (Impact Factor: 2.91). 08/2012; 178(4):289-94. DOI: 10.2307/41679874
Source: PubMed


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.

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    • "While the tasks used in the current study are not thought to explicitly require the hippocampus, there is evidence in the literature regarding the interaction of the hippocampus with numerous areas of the brain involved in performance of these tasks, including the medial prefrontal cortex, basal forebrain, both anterior and posterior cingulate cortices, and the perirhinal cortex [23], [24]. For example, afferent and efferent pathways connect the hippocampus to the medial prefrontal cortex, and while damage alone to this area could impact simple discrimination, the fact that these areas are part of an interconnected network suggests that damage to either area could cause deficits in attentional set shifting. "
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    ABSTRACT: The present report describes an animal model for examining the effects of radiation on a range of neurocognitive functions in rodents that are similar to a number of basic human cognitive functions. Fourteen male Long-Evans rats were trained to perform an automated intra-dimensional set shifting task that consisted of their learning a basic discrimination between two stimulus shapes followed by more complex discrimination stages (e.g., a discrimination reversal, a compound discrimination, a compound reversal, a new shape discrimination, and an intra-dimensional stimulus discrimination reversal). One group of rats was exposed to head-only X-ray radiation (2.3 Gy at a dose rate of 1.9 Gy/min), while a second group received a sham-radiation exposure using the same anesthesia protocol. The irradiated group responded less, had elevated numbers of omitted trials, increased errors, and greater response latencies compared to the sham-irradiated control group. Additionally, social odor recognition memory was tested after radiation exposure by assessing the degree to which rats explored wooden beads impregnated with either their own odors or with the odors of novel, unfamiliar rats; however, no significant effects of radiation on social odor recognition memory were observed. These data suggest that rodent tasks assessing higher-level human cognitive domains are useful in examining the effects of radiation on the CNS, and may be applicable in approximating CNS risks from radiation exposure in clinical populations receiving whole brain irradiation.
    PLoS ONE 08/2014; 9(8):e104393. DOI:10.1371/journal.pone.0104393 · 3.23 Impact Factor
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    • "(Britten et al. 2012; Lonart et al. 2012; Tseng et al. 2013). Thus, whether at lower or higher dosing paradigms, exposure of the CNS is associated with an increased risk of developing acute and longer-term cognitive decrements (Greene-Schloesser et al. 2012; Lonart et al. 2012). The foregoing has become an increasing concern for those exposed under a variety of scenarios, not only due to the increasing numbers of cancer survivors, but also due to the conspicuous lack of any satisfactory long-term solutions for this serious side effect of radiation exposure to the CNS. "
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    ABSTRACT: Cranial radiotherapy is used routinely to control the growth of primary and secondary brain tumors, but often results in serious and debilitating cognitive dysfunction. In part due to the beneficial dose depth distributions that may spare normal tissue damage, the use of protons to treat CNS and other tumor types is rapidly gaining popularity. Astronauts exposed to lower doses of protons in the space radiation environment are also at risk for developing adverse CNS complications. To explore the consequences of whole body proton irradiation, mice were subjected to 0.1 and 1 Gy and analyzed for morphometric changes in hippocampal neurons 10 and 30 days following exposure. Significant dose-dependent reductions (~33 %) in dendritic complexity were found, when dendritic length, branching and area were analyzed 30 days after exposure. At equivalent doses and times, significant reductions in the number (~30 %) and density (50-75 %) of dendritic spines along hippocampal neurons of the dentate gyrus were also observed. Immature spines (filopodia, long) exhibited the greatest sensitivity (1.5- to 3-fold) to irradiation, while more mature spines (mushroom) were more resistant to changes over a 1-month post-irradiation timeframe. Irradiated granule cell neurons spanning the subfields of the dentate gyrus showed significant and dose-responsive reductions in synaptophysin expression, while the expression of postsynaptic density protein (PSD-95) was increased significantly. These findings corroborate our past work using photon irradiation, and demonstrate for the first time, dose-responsive changes in dendritic complexity, spine density and morphology and synaptic protein levels following exposure to low-dose whole body proton irradiation.
    Brain Structure and Function 01/2014; 220(2). DOI:10.1007/s00429-014-0709-9 · 5.62 Impact Factor
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    ABSTRACT: Significant past work has linked radiation exposure of the CNS to elevated levels of oxidative stress and inflammation. These secondary reactive processes are both dynamic and persistent and are believed to compromise the functionality of the CNS, in part, by disrupting endogenous neurogenesis in the hippocampus. While evidence has shown neurogenesis to be sensitive to irradiation and redox state, the mechanistic basis underlying these effects is incompletely understood. To clarify the role of reactive oxygen species (ROS) in mediating radiation-induced changes in neurogenesis we have analyzed transgenic mice that overexpress human catalase localized to the mitochondria. With this model, we investigated the consequences of low dose and clinically relevant proton irradiation on neurogenesis, and how that process is modified in response to genetic disruption of mitochondrial ROS levels. In unirradiated animals, basal neurogenesis was improved significantly by reductions in mitochondrial ROS. In animals subjected to proton exposure, hippocampal progenitor cell proliferation was attenuated significantly by overexpression of human catalase in the mitochondria. Furthermore, expression of the MCAT transgene significantly improved neurogenesis in WT animals after low-dose proton exposure (0.5 Gy), with similar trends observed at higher dose (2 Gy). Our report documents for the first time the impact of proton irradiation on hippocampal neurogenesis, and the neuroprotective properties of reducing mitochondrial ROS through the targeted overexpression of catalase.
    Radiation Research 05/2013; 180(1). DOI:10.1667/RR3339.1 · 2.91 Impact Factor
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