Abstract 4754: Fractionated whole brain radiation-induced behavioral changes in athymic nude mice is associated with sustained neuroinflammation and microglial M1-phenotype

The objective of this study is to study the late-chronic effects of fractionated whole brain irradiation (fWBI) on cognitive impairment and associated cellular and molecular neuro-inflammatory mechanisms using clinically relevant and reliable mouse models. Microglia are recognized as the primary inn...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2017-07, Vol.77 (13_Supplement), p.4754-4754
Main Authors: Kanji, Suman, Johnson, Benjamin, Witcher, Kristina, Gulati, Pooja Gulati, Chen, Shannon, Godbout, Jonathan, Nelson, Randy J., Haque, Saikh, Chakravarti, Arnab
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container_issue 13_Supplement
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container_title Cancer research (Chicago, Ill.)
container_volume 77
creator Kanji, Suman
Johnson, Benjamin
Witcher, Kristina
Gulati, Pooja Gulati
Chen, Shannon
Godbout, Jonathan
Nelson, Randy J.
Haque, Saikh
Chakravarti, Arnab
description The objective of this study is to study the late-chronic effects of fractionated whole brain irradiation (fWBI) on cognitive impairment and associated cellular and molecular neuro-inflammatory mechanisms using clinically relevant and reliable mouse models. Microglia are recognized as the primary innate immune component of neuroinflammation. However, microglial contributions to radiation-induced cognitive impairment are poorly understood. Here, an athymic nude (Nu/Nu) mouse model was employed to address this issue. Mice were divided into two groups: radiation treatment (XRT) and no-treatment control (CTL). The whole brain of each XRT mouse received 30 Gy (3 Gy/fraction) of radiation over two weeks. XRT and CTL mice were assessed for cognitive and behavioral changes at 1, 4, and 6 months posttreatment using the novel object recognition test (for long-term, non-spatial memory), the free running Y-Maze (for short-term, spatial memory) and Barnes Maze (for spatial learning and memory). A significant decline in novel object recognition in the XRT group (P
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Microglia are recognized as the primary innate immune component of neuroinflammation. However, microglial contributions to radiation-induced cognitive impairment are poorly understood. Here, an athymic nude (Nu/Nu) mouse model was employed to address this issue. Mice were divided into two groups: radiation treatment (XRT) and no-treatment control (CTL). The whole brain of each XRT mouse received 30 Gy (3 Gy/fraction) of radiation over two weeks. XRT and CTL mice were assessed for cognitive and behavioral changes at 1, 4, and 6 months posttreatment using the novel object recognition test (for long-term, non-spatial memory), the free running Y-Maze (for short-term, spatial memory) and Barnes Maze (for spatial learning and memory). A significant decline in novel object recognition in the XRT group (P&lt;0.05) was seen at the 4 month time point and continued to persist at 6 months (P&lt;0.05). No significant changes in the Barnes maze or Y-maze were seen at these time points. Expression of neuroinflammatory mediator genes, from both whole brain and isolated microglia, were measured by RT-PCR. We found that markers of the M1-phenotype, which include TNF-α, and MHC II, were significantly upregulated (P&lt;0.05) and markers of the general M2 Phenotype, which include IL-4ra, IL-10ra, and TGF-β, were downregulated (P&lt;0.05) at 1 and 6 month time points. These results indicate that sustained neuroinflammation and microglial M1-polarization are associated with long-term cognitive impairment induced by fWBI. Radiotherapy is the most prevalent treatment for primary and metastatic brain tumors. Whereas previous studies that identified important mechanisms underlying XRT-induced cognitive decline had used treatment regimens that were not clinically relevant ones, we have employed a clinically relevant fractionation scheme to address the cellular and molecular deregulations in association with cognitive impairment. Citation Format: Suman Kanji, Benjamin Johnson, Kristina Witcher, Pooja Gulati Gulati, Shannon Chen, Jonathan Godbout, Randy J. Nelson, Saikh Haque, Arnab Chakravarti. Fractionated whole brain radiation-induced behavioral changes in athymic nude mice is associated with sustained neuroinflammation and microglial M1-phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. 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Microglia are recognized as the primary innate immune component of neuroinflammation. However, microglial contributions to radiation-induced cognitive impairment are poorly understood. Here, an athymic nude (Nu/Nu) mouse model was employed to address this issue. Mice were divided into two groups: radiation treatment (XRT) and no-treatment control (CTL). The whole brain of each XRT mouse received 30 Gy (3 Gy/fraction) of radiation over two weeks. XRT and CTL mice were assessed for cognitive and behavioral changes at 1, 4, and 6 months posttreatment using the novel object recognition test (for long-term, non-spatial memory), the free running Y-Maze (for short-term, spatial memory) and Barnes Maze (for spatial learning and memory). A significant decline in novel object recognition in the XRT group (P&lt;0.05) was seen at the 4 month time point and continued to persist at 6 months (P&lt;0.05). No significant changes in the Barnes maze or Y-maze were seen at these time points. Expression of neuroinflammatory mediator genes, from both whole brain and isolated microglia, were measured by RT-PCR. We found that markers of the M1-phenotype, which include TNF-α, and MHC II, were significantly upregulated (P&lt;0.05) and markers of the general M2 Phenotype, which include IL-4ra, IL-10ra, and TGF-β, were downregulated (P&lt;0.05) at 1 and 6 month time points. These results indicate that sustained neuroinflammation and microglial M1-polarization are associated with long-term cognitive impairment induced by fWBI. Radiotherapy is the most prevalent treatment for primary and metastatic brain tumors. Whereas previous studies that identified important mechanisms underlying XRT-induced cognitive decline had used treatment regimens that were not clinically relevant ones, we have employed a clinically relevant fractionation scheme to address the cellular and molecular deregulations in association with cognitive impairment. Citation Format: Suman Kanji, Benjamin Johnson, Kristina Witcher, Pooja Gulati Gulati, Shannon Chen, Jonathan Godbout, Randy J. Nelson, Saikh Haque, Arnab Chakravarti. Fractionated whole brain radiation-induced behavioral changes in athymic nude mice is associated with sustained neuroinflammation and microglial M1-phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. 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Microglia are recognized as the primary innate immune component of neuroinflammation. However, microglial contributions to radiation-induced cognitive impairment are poorly understood. Here, an athymic nude (Nu/Nu) mouse model was employed to address this issue. Mice were divided into two groups: radiation treatment (XRT) and no-treatment control (CTL). The whole brain of each XRT mouse received 30 Gy (3 Gy/fraction) of radiation over two weeks. XRT and CTL mice were assessed for cognitive and behavioral changes at 1, 4, and 6 months posttreatment using the novel object recognition test (for long-term, non-spatial memory), the free running Y-Maze (for short-term, spatial memory) and Barnes Maze (for spatial learning and memory). A significant decline in novel object recognition in the XRT group (P&lt;0.05) was seen at the 4 month time point and continued to persist at 6 months (P&lt;0.05). No significant changes in the Barnes maze or Y-maze were seen at these time points. Expression of neuroinflammatory mediator genes, from both whole brain and isolated microglia, were measured by RT-PCR. We found that markers of the M1-phenotype, which include TNF-α, and MHC II, were significantly upregulated (P&lt;0.05) and markers of the general M2 Phenotype, which include IL-4ra, IL-10ra, and TGF-β, were downregulated (P&lt;0.05) at 1 and 6 month time points. These results indicate that sustained neuroinflammation and microglial M1-polarization are associated with long-term cognitive impairment induced by fWBI. Radiotherapy is the most prevalent treatment for primary and metastatic brain tumors. Whereas previous studies that identified important mechanisms underlying XRT-induced cognitive decline had used treatment regimens that were not clinically relevant ones, we have employed a clinically relevant fractionation scheme to address the cellular and molecular deregulations in association with cognitive impairment. Citation Format: Suman Kanji, Benjamin Johnson, Kristina Witcher, Pooja Gulati Gulati, Shannon Chen, Jonathan Godbout, Randy J. Nelson, Saikh Haque, Arnab Chakravarti. Fractionated whole brain radiation-induced behavioral changes in athymic nude mice is associated with sustained neuroinflammation and microglial M1-phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4754. doi:10.1158/1538-7445.AM2017-4754</abstract><doi>10.1158/1538-7445.AM2017-4754</doi></addata></record>
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title Abstract 4754: Fractionated whole brain radiation-induced behavioral changes in athymic nude mice is associated with sustained neuroinflammation and microglial M1-phenotype
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