Trauma-induced alterations in cognition and Arc expression are reduced by previous exposure to 56Fe irradiation

Brain and Spinal Injury Center, University of California, San Francisco, California 94110, USA.
Hippocampus (Impact Factor: 4.16). 03/2012; 22(3):544-54. DOI: 10.1002/hipo.20920
Source: PubMed


Exposure to ionizing irradiation may affect brain functions directly, but may also change tissue sensitivity to a secondary insult such as trauma, stroke, or degenerative disease. To determine if a low dose of particulate irradiation sensitizes the brain to a subsequent injury, C56BL6 mice were exposed to brain only irradiation with 0.5 Gy of (56) Fe ions. Two months later, unilateral traumatic brain injury was induced using a controlled cortical impact system. Three weeks after trauma, animals received multiple BrdU injections and 30 days later were tested for cognitive performance in the Morris water maze. All animals were able to locate the visible and hidden platform during training; however, treatment effects were seen when spatial memory retention was assessed in the probe trial (no platform). Although sham and irradiated animals showed spatial memory retention, mice that received trauma alone did not. When trauma was preceded by irradiation, performance in the water maze was not different from sham-treated animals, suggesting that low-dose irradiation had a protective effect in the context of a subsequent traumatic injury. Measures of hippocampal neurogenesis showed that combined injury did not induce any changes greater that those seen after trauma or radiation alone. After trauma, there was a significant decrease in the percentage of neurons expressing the behaviorally induced immediate early gene Arc in both hemispheres, without associated neuronal loss. After combined injury there were no differences relative to sham-treated mice. Our results suggest that combined injury resulted in decreased alterations of our endpoints compared to trauma alone. Although the underlying mechanisms are not yet known, these results resemble a preconditioning, adaptive, or inducible-like protective response, where a sublethal or potentially injurious stimulus (i.e., irradiation) induces tolerance to a subsequent and potentially more damaging insult (trauma).

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    • "All mice, regardless of injury type, were subjected to this surgical procedure. Mice that were randomly selected for the trauma only (no irradiation) or RCI treatment groups were subjected to a controlled cortical impact (Rola et al. 2006, Rosi et al. 2012b). Th e lesion was produced with a pneumatic impact device using a 3-mm-diameter convex tip, mounted 20 ° from the vertical to account for the curvature of the mouse skull. "
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    ABSTRACT: Purpose: Uncontrolled radiation exposure due to radiological terrorism, industrial accidents or military circumstances is a continuing threat for the civilian population. Age plays a major role in the susceptibility to radiation; younger children are at higher risk of developing cognitive deterioration when compared to adults. Our objective was to determine if an exposure to radiation affected the vulnerability of the juvenile hippocampus to a subsequent moderate traumatic injury. Materials and methods: Three-week-old (juvenile) and eight-week-old young adult C57BL/J6 male mice received whole body cesium-137 (137Cs) irradiation with 4 gray (Gy). One month later, unilateral traumatic brain injury was induced using a controlled cortical impact system. Two months post-irradiation, animals were tested for hippocampus-dependent cognitive performance in the Morris water-maze. After cognitive testing, animals were euthanized and their brains frozen for immunohistochemical assessment of activated microglia and neurogenesis in the hippocampal dentate gyrus. Results: All animals were able to learn the water maze task; however, treatment effects were seen when spatial memory retention was assessed. Animals that received irradiation as juveniles followed by a moderate traumatic brain injury one month later did not show spatial memory retention, i.e., were cognitively impaired. In contrast, all groups of animals that were treated as adults showed spatial memory retention in the probe trials. Conclusion: Although the mechanisms involved are not clear, our results suggest that irradiation enhanced a young animal's vulnerability to develop cognitive injury following a subsequent traumatic injury.
    International Journal of Radiation Biology 10/2013; 90(3). DOI:10.3109/09553002.2014.859761 · 1.69 Impact Factor
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    • "Indeed, because neuroinflammation was shown to increase the proportion of granule cells expressing behaviorally induced Arc (Rosi et al., 2005), the decrease in new neurons expressing behaviorally induced Arc may be a compensatory mechanism to maintain an optimal level of neuronal activation and ensure the maintenance of pattern separation using a very sparse coding strategy (McNaughton et al., 1996; Rosi, 2011). Arc expression in new neurons as response to behavioral exploration was also reported in mice following exposure to low-dose irradiation combined or not with a subsequent traumatic brain injury in the presence of activated microglia (Rosi et al., 2012). Collectively, these findings show that while new neurons retain the capacity to be recruited into behaviorally relevant neural networks following brain injury, their recruitment is significantly decreased following classical microglia activation. "
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    ABSTRACT: Throughout life new neurons are continuously added to the hippocampal circuitry involved with spatial learning and memory. These new cells originate from neural precursors in the subgranular zone of the dentate gyrus, migrate into the granule cell layer, and integrate into neural networks encoding spatial and contextual information. This process can be influenced by several environmental and endogenous factors and is modified in different animal models of neurological disorders. Neuroinflammation, as defined by the presence of activated microglia, is a common key factor to the progression of neurological disorders. Analysis of the literature shows that microglial activation impacts not only the production, but also the migration and the recruitment of new neurons. The impact of microglia on adult-born neurons appears much more multifaceted than ever envisioned before, combining both supportive and detrimental effects that are dependent upon the activation phenotype and the factors being released. The development of strategies aimed to change microglia toward states that promote functional neurogenesis could therefore offer novel therapeutic opportunities against neurological disorders associated with cognitive deficits and neuroinflammation. The present review summarizes the current knowledge on how production, distribution, and recruitment of new neurons into behaviorally relevant neural networks are modified in the inflamed hippocampus.
    Frontiers in Cellular Neuroscience 09/2013; 7:145. DOI:10.3389/fncel.2013.00145 · 4.29 Impact Factor
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    • "Another factor that has been associated with cognitive performance is hippocampal neurogenesis, and data exist showing that neurogenic cells in the hippocampus are very radiosensitive, and are reduced by doses that are below the threshold for the lethal hematopoeitic or gastrointestinal radiation syndromes [8], [15]–[18]. Furthermore, changes in neurogenesis are associated with hippocampal dependent behavioral deficits [5]–[10], [20], [56]–[58]. Because traumatic brain injury shares specific neuropathologic characteristics with ionizing irradiation (i.e. "
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    ABSTRACT: Exposure to uncontrolled irradiation in a radiologic terrorism scenario, a natural disaster or a nuclear battlefield, will likely be concomitantly superimposed on other types of injury, such as trauma. In the central nervous system, radiation combined injury (RCI) involving irradiation and traumatic brain injury may have a multifaceted character. This may entail cellular and molecular changes that are associated with cognitive performance, including changes in neurogenesis and the expression of the plasticity-related immediate early gene Arc. Because traumatic stimuli initiate a characteristic early increase in polyamine metabolism, we hypothesized that treatment with the polyamine inhibitor alpha-difluoromethylornithine (DFMO) would reduce the adverse effects of single or combined injury on hippocampus structure and function. Hippocampal dependent cognitive impairments were quantified with the Morris water maze and showed that DFMO effectively reversed cognitive impairments after all injuries, particularly traumatic brain injury. Similar results were seen with respect to the expression of Arc protein, but not neurogenesis. Given that polyamines have been found to modulate inflammatory responses in the brain we also assessed the numbers of total and newly born activated microglia, and found reduced numbers of newly born cells. While the mechanisms responsible for the improvement in cognition after DFMO treatment are not yet clear, the present study provides new and compelling data regarding the potential use of DFMO as a potential countermeasure against the adverse effects of single or combined injury.
    PLoS ONE 01/2012; 7(1):e31094. DOI:10.1371/journal.pone.0031094 · 3.23 Impact Factor
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