Objective To investigate the effects of relatively low dose of ionizing radiation on adult cognition and hippocampal neurogenesis in juvenile mice, and to illuminate the relationship between relatively low dose of irradiation, cognitive function and neurogenesis. Methods 20 Kunming mice were randomly divided into two groups at postnatal 21 days: a radiation group and a control group (P21) (n = 10 each group). The radiation group was exposured with an acute whole body irradiation with a dose of 5 Gy at P21, the normal control group was sham irradiated. The two groups of mice were weighed before being exposured, at 2 months old and 4 months old, respectively. At 4-month-old, each mouse was experimented with open field test (OPT), new object recognition experiment (NOR), fear conditioning test (FC) and Morris Water Maze test (MWM). Brain sections were then immunostaining for different markers including Ki67 (mark proliferation neuron), doublecortin (DCX, mark differentiation and migration neuron), calbindin (CB, mark interneuron), and parvalbumin (PV, mark interneuron) in hippocampal dentate gyrus (DG). Results (1) In the body weight test, both at 2 and 4 months of age, the percentage of mice’ body weight gain in the radiated group was significantly lower than that of the control group (t=3.02, P<0.05; t=4.22, P<0.01). (2) There were no significant differences in the distance traveled within 5 min in OPT ( t=-1.672, P＞0.05), the DI in NOR (t=0.753, P>0.05), the contextual memory related freezing time ( t=-0.885，P>0.05) and the clued memory related freezing time (t=0.15, P>0.05) in FC, the average escape latency (F=2.30，P>0.05) in MWM and the times of crossing platform (t=-1.07, P>0.05) between the two groups. (3) However, Ki67, DCX, CB and PV labeled neurons number in DG in irradiation group were significantly lower than that of the control group (Ki67, t=2.80, P<0.05; DCX, t=6.63, P<0.001;CB, t=3.75, P<0.01; PV, t=5.39, P<0.001). Conclusions (1) Relatively low doses (5 Gy) of ionizing radiation in juvenile stage cause slow body weight gain in mice. (2) Relatively low doses (5 Gy) of irradiation exposure to juvenile mice do not cause learning and memory disorder when mice were tested in adult, but it resulted in declining of neurogenesis in SGZ. (3) The decreasing of neurogenesis induced by irradiation includes injury of a series of processes such as proliferation, division, differentiation, migration and maturation of neurons.
[1] Ehrhardt MJ, Mulrooney DA. Metabolic syndrome in adult survivors of childhood cancer: the intersection of oncology, endocrinology, and cardiology[J]. Lancet Diabetes Endocrinol, 2015, 3(7): 494-496. DOI: 10.1016/s2213-8587(15)00031-5.
[2] Cairncross G, Wang M, Shaw E, et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402[J]. J Clin Oncol, 2013, 31(3): 337-343. DOI: 10.1200/jco.2012.43.2674.
[3] Soussain C, Ricard D, Fike JR, et al. CNS complications of radiotherapy and chemotherapy[J]. Lancet, 2009, 374(9701): 1639-1651. DOI: 10.1016/s0140-6736(09)61299-x.
[4] Schnegg CI, Greene-Schloesser D, Kooshki M, et al. The PPARdelta agonist GW0742 inhibits neuroinflammation, but does not restore neurogenesis or prevent early delayed hippocampal-dependent cognitive impairment after whole-brain irradiation[J]. Free Radic Biol Med, 2013, 61(3): 1-9. DOI: 10.1016/j.freeradbiomed.2013.03.002.
[5] Pereira Dias G, Hollywood R, Bevilaqua MC, et al. Consequences of cancer treatments on adult hippocampal neurogenesis: implications for cognitive function and depressive symptoms[J]. Neuro Oncol, 2014, 16(4): 476-492. DOI: 10.1093/neuonc/not321.
[6] Son Y, Yang M, Kim JS, et al. Hippocampal dysfunction during the chronic phase following a single exposure to cranial irradiation[J]. Exp Neurol, 2014, 254(4): 134-144. DOI: 10.1016/j.expneurol.2014.01.018.
[7] Son Y, Yang M, Wang H, et al. Hippocampal dysfunctions caused by cranial irradiation: a review of the experimental evidence[J]. Brain Behav Immun, 2015, 45(3): 287-296. DOI: 10.1016/j.bbi.2015.01.007.
[8] Cameron HA, Glover LR. Adult neurogenesis: beyond learning and memory[J]. Annu Rev Psychol, 2015, 66(1): 53-81. DOI: 10.1146/annurev-psych-010814-015006.
[9]Yousuf S, Brat DJ, Shu HK, et al. Progesterone improves neurocognitive outcomes following therapeutic cranial irradiation in mice[J]. Horm Behav, 2017, 96(11): 21-30. DOI: 10.1016/j.yhbeh.2017.08.004.
[10]Cacao ECucinotta FA. Modeling Heavy-Ion Impairment of Hippocampal Neurogenesis after Acute and Fractionated Irradiation[J]. Radiat Res, 2016, 186(6): 624-637. DOI: 10.1667/rr14569.1.
[11] Tang FR, Loke WK, Wong P, et al. Radioprotective effect of ursolic acid in radiation-induced impairment of neurogenesis, learning and memory in adolescent BALB/c mouse[J]. Physiol Behav, 2017, 175(6): 37-46. DOI: 10.1016/j.physbeh.2017.03.027.
[12]Tang FR, Loke WK, Khoo BC. Postnatal irradiation-induced hippocampal neuropathology, cognitive impairment and aging[J]. Brain Dev, 2017, 39(4): 277-293. DOI: 10.1016/j.braindev.2016.11.001.
[13] Pearce MS, Salotti JA, Little MP, et al. Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study[J]. Lancet, 2012, 380(9840): 499-505. DOI: 10.1016/s0140-6736(12)60815-0.
[14] Monje ML, Mizumatsu S, Fike JR, et al. Irradiation induces neural precursor-cell dysfunction[J]. Nat Med, 2002, 8(9): 955-962. DOI: 10.1038/nm749.
[15] Monje ML, Toda H Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis[J]. Science, 2003, 302(5651): 1760-1765. DOI: 10.1126/science.1088417.
[16] Alexander TC, Butcher H, Krager K, et al. Behavioral Effects of Focal Irradiation in a Juvenile Murine Model[J]. Radiat Res, 2018, 189(6): 605-617. DOI: 10.1667/rr14847.1.
[17]Yang B, Ren BX, Tang FR. Prenatal irradiation-induced brain neuropathology and cognitive impairment[J]. Brain Dev, 2017, 39(1): 10-22. DOI: 10.1016/j.braindev.2016.07.008.
[18] Peng S, Yang B, Duan MY, et al. The Disparity of Impairment of Neurogenesis and Cognition After Acute or Fractionated Radiation Exposure in Adolescent BALB/c Mice[J]. Dose Response, 2019, 17(1): 1559325818822574. DOI: 10.1177/1559325818822574.
[19] Wang SW, Ren BX, Qian F, et al. Radioprotective effect of epimedium on neurogenesis and cognition after acute radiation exposure[J]. Neurosci Res, 2019, 145(8): 46-53. DOI: 10.1016/j.neures.2018.08.011.
[20]Moy SS, Nadler JJ, Young NB, et al. Mouse behavioral tasks relevant to autism: phenotypes of 10 inbred strains[J]. Behav Brain Res, 2007, 176(1): 4-20. DOI: 10.1016/j.bbr.2006.07.030.
[21] Win-Shwe TT, Fujitani Y, Kyi-Tha-Thu C, et al. Effects of diesel engine exhaust origin secondary organic aerosols on novel object recognition ability and maternal behavior in BALB/c mice[J]. Int J Environ Res Public Health, 2014, 11(11): 11286-11307. DOI: 10.3390/ijerph111111286.
[22]Bhattacharya TK, Pence BD, Ossyra JM, et al. Exercise but not (-)-epigallocatechin-3-gallate or beta-alanine enhances physical fitness, brain plasticity, and behavioral performance in mice[J]. Physiol Behav, 2015, 145(3): 29-37. DOI: 10.1016/j.physbeh.2015.03.023.
[23] Torres LH, Garcia RC, Blois AM, et al. Exposure of Neonatal Mice to Tobacco Smoke Disturbs Synaptic Proteins and Spatial Learning and Memory from Late Infancy to Early Adulthood[J]. PLoS One, 2015, 10(8): 136-399. DOI: 10.1371/journal.pone.0136399.
[24] Peiffer AM, Creer RM, Linville C, et al. Radiation-induced cognitive impairment and altered diffusion tensor imaging in a juvenile rat model of cranial radiotherapy[J]. Int J Radiat Biol, 2014, 90(9): 799-806. DOI: 10.3109/09553002.2014.938278.
[25] Ji S, Tian Y, Lu Y, et al. Irradiation-induced hippocampal neurogenesis impairment is associated with epigenetic regulation of bdnf gene transcription[J]. Brain Res, 2014, 1577(6): 77-88. DOI: 10.1016/j.brainres.2014.06.035.
[26] Rola R, Raber J, Rizk A, et al. Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice[J]. Exp Neurol, 2004, 188(2): 316-330. DOI: 10.1016/j.expneurol.2004.05.005.
[27] Impey S, Jopson T, Pelz C, et al. Short- and long-term effects of (56)Fe irradiation on cognition and hippocampal DNA methylation and gene expression[J]. BMC Genomics, 2016, 17(1): 825. DOI: 10.1186/s12864-016-3110-7.
[28]Greene-Schloesser D, Robbins ME, Peiffer AM, et al. Radiation-induced brain injury: a review[J]. Front Oncol, 2012, 2(6): 73. DOI: 10.3389/fonc.2012.00073.
[29] Rao AA, Ye H, Decker PA, et al. Therapeutic doses of cranial irradiation induce hippocampus-dependent cognitive deficits in young mice[J]. J Neurooncol, 2011, 105(2): 191-198. DOI: 10.1007/s11060-011-0582-9.
[30] Zhou H, Liu Z, Liu J, et al. Fractionated radiation-induced acute encephalopathy in a young rat model: cognitive dysfunction and histologic findings[J]. AJNR Am J Neuroradiol, 2011, 32(10): 1795-1800. DOI: 10.3174/ajnr.A2643.
[31] Silasi G, Diaz-Heijtz R, Besplug J, et al. Selective brain responses to acute and chronic low-dose X-ray irradiation in males and females[J]. Biochem Biophys Res Commun, 2004, 325(4): 1223-1235. DOI: 10.1016/j.bbrc.2004.10.166.
[32] Kim JS, Lee HJ, Kim JC, et al. Transient impairment of hippocampus-dependent learning and memory in relatively low-dose of acute radiation syndrome is associated with inhibition of hippocampal neurogenesis[J]. J Radiat Res, 2008, 49(5): 517-526. DOI: 10.1269/jrr.08020.
[33] Scholzen TGerdes J. The Ki-67 protein: from the known and the unknown[J]. J Cell Physiol, 2000, 182(3): 311-322. DOI: 10.1002/(sici)1097-4652(200003)182:3<311::aid-jcp1>3.0.co;2-9.
[34]Francis F, Koulakoff A, Boucher D, et al. Doublecortin is a developmentally regulated, microtubule-associated protein expressed in migrating and differentiating neurons[J]. Neuron, 1999, 23(2): 247-256. DOI: 10.1016/s0896-6273(00)80777-1.
[35]Freund TF, Buzsaki G. Interneurons of the hippocampus[J]. Hippocampus, 1996, 6(4): 347-470. DOI: 10.1002/(sici)1098-1063(1996)6:4<347::aid-hipo1>3.0.co;2-i.
