Cranial Irradiation Alters the Behaviorally Induced Immediate-Early Gene Arc (Activity-Regulated Cytoskeleton-Associated Protein)

Brain and Spinal Injury Center, Department of Physical Therapy and Rehabilitation Sciences, University of California, San Francisco, San Francisco, California 94110, USA.
Cancer Research (Impact Factor: 9.33). 01/2009; 68(23):9763-70. DOI: 10.1158/0008-5472.CAN-08-1861
Source: PubMed


Therapeutic irradiation of the brain is commonly used to treat brain tumors but can induce cognitive impairments that can severely affect quality of life. The underlying mechanisms responsible for radiation-induced cognitive deficits are unknown but likely involve alterations in neuronal activity. To gain some mechanistic insight into how irradiation may affect hippocampal neurons known to be associated with cognitive function, we quantitatively assessed the molecular distribution of the behaviorally induced immediate-early gene Arc (activity-regulated cytoskeleton-associated protein) at the level of mRNA and the protein. Young adult C57BL/6J mice received whole-brain irradiation with 0 or 10 Gy, and 1 week or 2 months later, exploration of a novel environment was used to induce Arc expression. The fractions of neurons expressing Arc mRNA and Arc protein were detected using fluorescence in situ hybridization and immunocytochemistry, respectively. Our results showed that there was a significant reduction in the percentage of neurons expressing Arc protein 1 week after irradiation, whereas 2 months after irradiation, there was a reduction in the percentage of neurons expressing both Arc mRNA and Arc protein. Importantly, radiation-induced changes in Arc expression were not a result of neuronal cell loss. The changes observed at 2 months were associated with a significant increase in the number of activated microglia, supporting the idea that inflammation may contribute to neuronal dysfunction. These findings are the first to show that local brain irradiation initiates changes in hippocampal neurons that disrupt the activity patterns (Arc expression) associated with neuroplasticity and memory.

Download full-text


Available from: John R Fike, Mar 21, 2014
  • Source
    • "Interestingly, in a previous study we showed that mice that received head-only 56 Fe (1 Gy) irradiation showed a lower fraction of neurons expressing activity-regulated cytoskeleton-associated protein (Arc) in the free blade of the dentate gyrus than sham-irradiated mice [34]. Together, these data suggest that neurons normally showing increased spine density following exploratory behavior and having this ability being affected by 56 Fe irradiation might be expressing the immediate early gene Arc that is enriched in neuronal dendrites [39] and affected by cranial irradiation [40]. The trend toward a behavioral testing × radiation interaction for apical dendrites in the CA3 region of the hippocampus is remarkable based on the retraction and simplification of apical dendrites in the CA3 region of the hippocampus following chronic restraint stress [41,42]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A unique feature of the space radiation environment is the presence of high-energy charged particles, including 56Fe ions, which can present a significant hazard to space flight crews during and following a mission. 56Fe irradiation-induced cognitive changes often involve alterations in hippocampal function. These alterations might involve changes in spine morphology and density. In addition to irradiation, performing a cognitive task can also affect spine morphology. Therefore, it is often hard to determine whether changes in spine morphology and density are due to an environmental challenge or group differences in performance on cognitive tests. In this study, we tested the hypothesis that the ability of exploratory behavior to increase specific measures of hippocampal spine morphology and density is affected by 56Fe irradiation. In sham-irradiated mice, exploratory behavior increased basal spine density in the CA1 region of the hippocampus and the enclosed blade of the dentate gyrus. These effects were not seen in irradiated mice. In addition, following exploratory behavior, there was a trend towards a decrease in the percent stubby spines on apical dendrites in the CA3 region of the hippocampus in 56Fe-irradiated, but not sham-irradiated, mice. Other hippocampal regions and spine measures affected by 56Fe irradiation showed comparable radiation effects in behaviorally naïve and cognitively tested mice. Thus, the ability of exploratory behavior to alter spine density and morphology in specific hippocampal regions is affected by 56Fe irradiation.
    Full-text · Article · Jan 2016 · Behavioural brain research
  • Source
    • "The underlying mechanisms responsible for radiationinduced cognitive impairment remain, however, elusive. The possible mechanism includes alterations in the neurogenic cell populations in GD (Rola et al. 2004; Winocur et al. 2006; Monje and Palmer 2003; Saxe et al. 2006), loss of mature neurons in GD (Raber et al. 2004; Fan et al. 2007), alterations in NMDA receptor subunits (Shi et al. 2006), genetic risk factors (Villasana et al. 2006) and lower expression of the immediate-early gene Arc (activity-regulated cytoskeleton-associated protein) (Rosi et al. 2008). These cognitive dysfunctions often manifest as deficits in hippocampal-dependent learning and memory, including spatial information processing (Abayomi 1996; Crossen et al. 1994; Roman and Sperduto 1995; Surma-aho et al. 2001). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The intrauterinal development in mammals represents a very sensitive period of life in relation to many environmental factors, including ionizing radiation (IR). The developing nervous system is particularly vulnerable to IR, and the consequences of exposure are of importance because of its potential health risks. The aim of our work was to assess whether prenatal irradiation of rats on the 17th day of embryonic development with a dose of 1 Gy would affect the formation of new cells and the number of mature neurons in the hippocampus and the selected forms of behaviour in the postnatal period. Male progeny of irradiated and control females was tested at ages of 3 weeks, 2 and 3 months. The number of mitotically active cells in the gyrus dentatus (GD) of the hippocampus was significantly reduced in irradiated rats aged 3 weeks. In irradiated rats aged 2 months, a significant reduction of mature neurons in CA1 area and in GD of the hippocampus was observed. The IR negatively influenced the spatial memory in Morris water maze, significantly decreased the exploratory behaviour and increased the anxiety-like behaviour in elevated plus-maze in rats aged 2 months. No significant differences were observed in animals aged 3 months compared with controls of the same age. A significant correlation between the number of mature neurons in the hilus and of the cognitive performances was found. Our results show that a low dose of radiation applied during the sensitive phase of brain development can influence the level of neurogenesis in the subgranular zone of GD and cause an impairment of the postnatal development of mental functions.
    Full-text · Article · Dec 2014 · Cellular and Molecular Neurobiology
  • Source
    • "Specifically, irradiation of the temporal lobe can profoundly affect the cellular structures mediating learning and memory [2]–[4]. Ionizing radiation has been consistently shown to affect multiple neuroinflammatory signaling cascades [5]–[7] ultimately causing disruptions in hippocampal function [3]–[5], [8], [9]. Importantly, broad-spectrum anti-inflammatory treatment has been shown to abrogate certain aspects of radiation-induced hippocampal functional deficits [4], [9]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Therapeutic irradiation is commonly used to treat primary or metastatic central nervous system tumors. It is believed that activation of neuroinflammatory signaling pathways contributes to the development of common adverse effects, which may ultimately contribute to cognitive dysfunction. Recent studies identified the chemokine (C-C motif) receptor (CCR2), constitutively expressed by cells of the monocyte-macrophage lineage, as a mediator of cognitive impairments induced by irradiation. In the present study we utilized a unique reporter mouse (CCR2RFP/+CX3CR1GFP/+) to accurately delineate the resident (CX3CR1+) versus peripheral (CCR2+) innate immune response in the brain following cranial irradiation. Our results demonstrate that a single dose of 10Gy cranial γ-irradiation induced a significant decrease in the percentage of resident microglia, while inducing an increase in the infiltration of peripherally derived CCR2+ macrophages. Although reduced in percentage, there was a significant increase in F4/80+ activated macrophages in irradiated animals compared to sham. Moreover, we found that there were altered levels of pro-inflammatory cytokines, chemokines, adhesion molecules, and growth factors in the hippocampi of wild type irradiated mice as compared to sham. All of these molecules are implicated in the recruitment, adhesion, and migration of peripheral monocytes to injured tissue. Importantly, there were no measureable changes in the expression of multiple markers associated with blood-brain barrier integrity; implicating the infiltration of peripheral CCR2+ macrophages may be due to inflammatory induced chemotactic signaling. Cumulatively, these data provide evidence that therapeutic levels of cranial radiation are sufficient to alter the brain's homeostatic balance and permit the influx of peripherally-derived CCR2+ macrophages as well as the regional susceptibility of the hippocampal formation to ionizing radiation.
    Full-text · Article · Apr 2014 · PLoS ONE
Show more