title: Consequences of low dose ionizing radiation exposure on the hippocampal microenvironment.
abstract: The response of the brain to irradiation is complex, involving a multitude of stress inducible pathways that regulate neurotransmission within a dynamic microenvironment. While significant past work has detailed the consequences of CNS radiotherapy following relatively high doses (≥ 45 Gy), few studies have been conducted at much lower doses (≤ 2 Gy), where the response of the CNS (like many other tissues) may differ substantially from that expected from linear extrapolations of high dose data. Low dose exposure could elicit radioadaptive modulation of critical CNS processes such as neurogenesis, that provide cellular input into hippocampal circuits known to impact learning and memory. Here we show that mice deficient for chemokine signaling through genetic disruption of the CCR2 receptor exhibit a neuroprotective phenotype. Compared to wild type (WT) animals, CCR2 deficiency spared reductions in hippocampal neural progenitor cell survival and stabilized neurogenesis following exposure to low dose irradiation. While radiation-induced changes in microglia levels were not found in WT or CCR2 deficient animals, the number of Iba1+ cells did differ between each genotype at the higher dosing paradigms, suggesting that blockade of this signaling axis could moderate the neuroinflammatory response. Interestingly, changes in proinflammatory gene expression were limited in WT animals, while irradiation caused significant elevations in these markers that were attenuated significantly after radioadaptive dosing paradigms in CCR2 deficient mice. These data point to the importance of chemokine signaling under low dose paradigms, findings of potential significance to those exposed to ionizing radiation under a variety of occupational and/or medical scenarios.
authors.affiliation: Department of Radiation Oncology, University of California Irvine, Irvine, CA, 92697-2695, United States of America.
authors.forename: Munjal M
authors.initials: MM
authors.lastname: Acharya
authors.affiliation: Department of Radiation Oncology, University of California Irvine, Irvine, CA, 92697-2695, United States of America.
authors.forename: Neal H
authors.initials: NH
authors.lastname: Patel
authors.affiliation: Department of Radiation Oncology, University of California Irvine, Irvine, CA, 92697-2695, United States of America.
authors.forename: Brianna M
authors.initials: BM
authors.lastname: Craver
authors.affiliation: Department of Radiation Oncology, University of California Irvine, Irvine, CA, 92697-2695, United States of America.
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Tran
authors.affiliation: Department of Radiation Oncology, University of California Irvine, Irvine, CA, 92697-2695, United States of America.
authors.forename: Erich
authors.initials: E
authors.lastname: Giedzinski
authors.affiliation: Department of Radiation Oncology, University of California Irvine, Irvine, CA, 92697-2695, United States of America.
authors.forename: Bertrand P
authors.initials: BP
authors.lastname: Tseng
authors.affiliation: Department of Radiation Oncology, University of California Irvine, Irvine, CA, 92697-2695, United States of America.
authors.forename: Vipan K
authors.initials: VK
authors.lastname: Parihar
authors.affiliation: Department of Radiation Oncology, University of California Irvine, Irvine, CA, 92697-2695, United States of America.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Limoli
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D060833:Cellular Microenvironment / Q000528:radiation effects*; D002540:Cerebral Cortex / Q000378:metabolism / Q000528:radiation effects; D018891:Dentate Gyrus / Q000166:cytology; D004307:Dose-Response Relationship, Radiation; D005786:Gene Expression Regulation / Q000528:radiation effects; D006624:Hippocampus / Q000166:cytology* / Q000528:radiation effects*; D018836:Inflammation Mediators / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism / Q000528:radiation effects; D055495:Neurogenesis / Q000528:radiation effects; D000069079:Radiation Exposure; D011839:Radiation, Ionizing; D054390:Receptors, CCR2 / Q000172:deficiency / Q000378:metabolism
chemical_list: D015415:Biomarkers; C515335:Ccr2 protein, mouse; D018836:Inflammation Mediators; D054390:Receptors, CCR2