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.

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Available from: John R Fike, Mar 21, 2014
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    • "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). "
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    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.
    Cellular and Molecular Neurobiology 12/2014; 35(1). DOI:10.1007/s10571-014-0144-8 · 2.51 Impact Factor
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    • "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]. "
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    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.
    PLoS ONE 04/2014; 9(4):e93650. DOI:10.1371/journal.pone.0093650 · 3.23 Impact Factor
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    • "One of the brain regions most densely populated with microglia is the hippocampus (Lawson et al., 1990); microglia activation in this region is a common landmark following stimulation with the bacterial endotoxin lipopolysaccharide (LPS; Rosi et al., 2005; Belarbi et al., 2012a,b), ionizing irradiation (Monje et al., 2002, 2003; Rola et al., 2008; Rosi et al., 2008; Belarbi et al., 2013), traumatic brain injury (Piao et al., 2013), brain ischemia (Liu et al., 2007), and kainic acid-induced or pilocarpine-induced brain seizure (Andersson et al., 1991; Borges et al., 2003; Turrin and Rivest, 2004; Vezzani et al., 2008). Microglia activation is also present in various models of neurodegenerative diseases associated with abnormal protein aggregation such as in genetically modified mouse models mimicking Alzheimer’s disease amyloid pathology (APP23: Stalder et al., 1999; Bornemann et al., 2001; PS/APP: Matsuoka et al., 2001; PS1 + APP: Gordon et al., 2002; Tg2576: Frautschy et al., 1998; Benzing et al., 1999; Sasaki et al., 2002) or tau pathology (P301S tau: Bellucci et al., 2004; Yoshiyama et al., 2007; TgTauP301L: Sasaki et al., 2008; Thy-Tau22: Belarbi et al., 2011). "
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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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