苯并[a]芘暴露对小鼠条件性恐惧记忆的影响
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摘要
目的:研究苯并[a]芘染毒对小鼠条件性恐惧记忆的影响。方法:健康8周龄雄性C57/BL6小鼠随机分为3组:染毒组、溶剂对照组和生理盐水对照组,每组12只。各组分别连续腹腔注射苯并芘(2 mg/kg)、等体积植物油和等体积生理盐水10 d,在染毒结束后第2周和第4周各取6只分别进行条件性恐惧记忆测试和开放旷场测试。结果:条件性恐惧记忆测试结果显示,染毒后第2周和第4周,染毒组小鼠在训练阶段僵立时间百分比与对照组无明显差异;在背景提示阶段染毒组小鼠僵立时间百分比显著低于对照组(P <0. 05);在声音提示阶段染毒组小鼠僵立时间百分比同样显著低于对照组(P <0. 05)。在整个条件性恐惧记忆测试过程中,各组动物僵立时间百分比的变化趋势也存在显著性差异(P <0. 05)。开放旷场测试结果显示,染毒后第2周和第4周,各组动物条件性恐惧记忆刺激前后对比,对照组在中心区域停留的时间占比显著降低(P <0. 05),而染毒组前后对比无显著性差异。结论:苯并[a]芘暴露对小鼠的恐惧记忆水平具有显著的抑制作用,并因此减少恐惧伴随情绪-焦虑的产生。
Objective: To investigate the effect of benzo[a]pyrene on conditional fear memory in mice. Methods:Thirty-six healthy male C57/BL6 mice were randomly divided into 3 groups: the exposed group,the solvent control group and the saline control group,with 12 mouse in each group. They were continuously intraperitoneally injected with benzopyrene( 2 mg/kg),an equal volume of vegetable oil and an equal volume of physiological saline for 10 days,and then continued to be kept. At the 2nd week and the 4th week post injection,6 mice in each group were started to behavioral testing for contextual and cued fear conditioning test and open field test,respectively. Results: The contextual and cued fear conditioning test showed that there was no significant difference between the percentage of freezing time of the mouse in the exposed group and the control group during the training phase; During the contextual phase,the percentage of freezing time of the mouse in the exposed group was significantly lower than that of the control group( P < 0. 05);During the cued phase,the percentage of freezing time of the mouse in the exposed group was also significantly lowerthan that of the control group( P < 0. 05); there was also a significant difference in the change trend of percentage of freezing time in the whole contextual and cued fear conditioning test( P < 0. 05). The open field test showed that the proportion of time spent in the central area was significantly lower in the control group before and after the conditional fear memory stimulation( P < 0. 05),and there was no significant difference in exposed group before and after stimulation. Conclusion: Benzo[a]pyrene exposure has a significant inhibition on fear memory in mouse,and thus reduces fear associated with mood-anxiety.
Objective: To investigate the effect of benzo[a]pyrene on conditional fear memory in mice. Methods:Thirty-six healthy male C57/BL6 mice were randomly divided into 3 groups: the exposed group,the solvent control group and the saline control group,with 12 mouse in each group. They were continuously intraperitoneally injected with benzopyrene( 2 mg/kg),an equal volume of vegetable oil and an equal volume of physiological saline for 10 days,and then continued to be kept. At the 2nd week and the 4th week post injection,6 mice in each group were started to behavioral testing for contextual and cued fear conditioning test and open field test,respectively. Results: The contextual and cued fear conditioning test showed that there was no significant difference between the percentage of freezing time of the mouse in the exposed group and the control group during the training phase; During the contextual phase,the percentage of freezing time of the mouse in the exposed group was significantly lower than that of the control group( P < 0. 05);During the cued phase,the percentage of freezing time of the mouse in the exposed group was also significantly lowerthan that of the control group( P < 0. 05); there was also a significant difference in the change trend of percentage of freezing time in the whole contextual and cued fear conditioning test( P < 0. 05). The open field test showed that the proportion of time spent in the central area was significantly lower in the control group before and after the conditional fear memory stimulation( P < 0. 05),and there was no significant difference in exposed group before and after stimulation. Conclusion: Benzo[a]pyrene exposure has a significant inhibition on fear memory in mouse,and thus reduces fear associated with mood-anxiety.
引文
[1]杨凯,秦启忠,涂白杰.苯并[a]芘与铅对小鼠学习记忆能力影响协同效应[J].中国公共卫生,2016,32(1):85-88.DOI:10. 11847/zgggws2016-32-01-25.
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[15]Kuniishi H,Ichisaka S,Yamamoto M,et al. Early deprivation increases high-leaning behavior,a novel anxiety-like behavior,in the open field test in rats[J]. Neurosci Res,2017,123:27-35.DOI:10. 1016/j. neures. 2017. 04. 012.
[16]Zhang W,Tian F,Zheng J,et al. Chronic administration of benzo(a)pyrene induces memory impairment and anxiety-Like behavior and increases of NR2B DNA methylation[J]. Plo S One,2016,11(2):e0149574. DOI:10. 1371/journal. pone. 0149574.
[17]Li C,Wang J,Su Q,et al. Postnatal subacute benzo(a)Pyrene exposure caused neurobehavioral impairment and metabolomic changes of cerebellum in the early adulthood period of sprague-Dawley rats[J]. Neurotox Res,2018,33(4):812-823. DOI:10. 1007/s12640-017-9832-8.
[18]He C,Wang C,Zhou Y,et al. Embryonic exposure to benzo(a)pyrene influences neural development and function in rockfish(Sebastiscus marmoratus)[J]. Neurotoxicology,2012,33(4):758-762. DOI:10. 1016/j. neuro. 2012. 01. 002.
[19] Mohanty R,Das SK,Patri M. Modulation of Benzo[a]Pyrene induced anxiolytic-like behavior by retinoic acid in zebrafish:Involvement of oxidative stress and antioxidant defense system[J].Neurotox Res,2017,31(4):493-504. DOI:10. 1007/s12640-016-9694-5.
[20]He J,Ji X,Li Y,et al. Subchronic exposure of benzo(a)pyrene interferes with the expression of Bcl-2,Ki-67,C-myc and p53,Bax,Caspase-3 in sub-regions of cerebral cortex and hippocampus[J]. Experimental and Toxicologic Pathology:official journal of the Gesellschaft fur Toxikologische Pathologie,2016,68(2-3):149-156. DOI:10. 1016/j. etp. 2015. 11. 007.
[21]Sotres-Bayon F,Sierra-Mercado D,Pardilla-Delgado E,et al. Gating of fear in prelimbic cortex by hippocampal and amygdala inputs[J]. Neuron,2012,76(4):804-812. DOI:10. 1016/j. neuron.2012. 09. 028.
[22]Felix-Ortiz AC,Beyeler A,Seo C,et al. BLA to v HPC inputs modulate anxiety-related behaviors[J]. Neuron,2013,79(4):658-664. DOI:10. 1016/j. neuron. 2013. 06. 016.
[2]Kasala ER,Bodduluru LN,Barua CC,et al. Antioxidant and antitumor efficacy of Luteolin,a dietary flavone on benzo(a)pyrene-induced experimental lung carcinogenesis[J]. Biomed Pharmacother,2016,82:568-577. DOI:10. 1016/j. biopha. 2016. 05.042.
[3]Liamin M,Boutet-Robinet E,Jamin EL,et al. Benzo[a]pyrene-induced DNA damage associated with mutagenesis in primary human activated T lymphocytes[J]. Biochemical Pharmacology,2017,137:113-124. DOI:10. 1016/j. bcp. 2017. 04. 025.
[4]Winn LM,Wells PG. Evidence for embryonic prostaglandin H synthase-catalyzed bioactivation and reactive oxygen species-mediated oxidation of cellular macromolecules in phenytoin and benzo[a]pyrene teratogenesis[J]. Free Radical Biology&Medicine,1997,22(4):607-621. DOI:10. 1016/S0891-5849(96)00340-1.
[5]Maciel ES,Biasibetti R,Costa AP,et al. Subchronic oral administration of Benzo[a]pyrene impairs motor and cognitive behavior and modulates S100B levels and MAPKs in rats[J]. Neurochem Res,2014,39(4):731-740. DOI:10. 1007/s11064-014-1261-y.
[6]Liang X,Tang Y,Duan L,et al. Adverse effect of sub-chronic exposure to benzo(a)pyrene and protective effect of butylated hydroxyanisole on learning and memory ability in male SpragueDawley rat[J]. Toxicol Sci,2014,39(5):739-748. DOI:10.2131/jts. 39. 739.
[7]Knecht AL,Truong L,Simonich MT,et al. Developmental benzo[a]pyrene(B[a]P)exposure impacts larval behavior and impairs adult learning in zebrafish[J]. Neurotoxicology and Teratology,2017,59:27-34. DOI:10. 1016/j. ntt. 2016. 10. 006.
[8]Perera FP,Rauh V,Whyatt RM,et al. Effect of prenatal exposure to airborne polycyclic aromatic hydrocarbons on neurodevelopment in the first 3 years of life among inner-city children[J]. Environmental Health Perspectives,2006,114(8):1287-1292. DOI:10.1289/ehp. 9084.
[9]Shu H,Zheng GQ,Wang X,et al. Activation of matrix metalloproteinase in dorsal hippocampus drives improvement in spatial working memory after intra-VTA nicotine infusion in rats[J]. Neurochem,2015,135(2):357-367. DOI:10. 1111/jnc. 13283.
[10]Maharjan DM,Dai YY,Glantz EH,et al. Disruption of dorsal hippocampal-prefrontal interactions using chemogenetic inactivation impairs spatial learning[J]. Neurobiol Learn Mem,2018,155:351-360. DOI:10. 1016/j. nlm. 2018. 08. 023.
[11]Sierra-Mercado D,Padilla-Coreano N,Quirk GJ. Dissociable roles of prelimbic and infralimbic cortices,ventral hippocampus,and basolateral amygdala in the expression and extinction of conditioned fear[J]. Neuropsychopharmacology:official publication of the American College of Neuropsychopharmacology,2011,36(2):529-538. DOI:10. 1038/npp. 2010. 184.
[12]Cullen PK,Gilman TL,Winiecki P,et al. Activity of the anterior cingulate cortex and ventral hippocampus underlie increases in contextual fear generalization[J]. Neurobiol Learn Mem,2015,124:19-27. DOI:10. 1016/j. nlm. 2015. 07. 001.
[13]Shoji H,Takao K,Hattori S,et al. Contextual and cued fear conditioning test using a video analyzing system in mice[J]. Journal of Visualized Experiments:Jo VE, 2014(85). DOI:10. 3791/50871.
[14] Mc Dermott CM,Liu D,Ade C,et al. Estradiol replacement enhances fear memory formation, impairs extinction and reduces COMT expression levels in the hippocampus of ovariectomized female mice[J]. Neurobiol Learn and Mem,2015,118:167-177. DOI:10. 1016/j. nlm. 2014. 12. 009.
[15]Kuniishi H,Ichisaka S,Yamamoto M,et al. Early deprivation increases high-leaning behavior,a novel anxiety-like behavior,in the open field test in rats[J]. Neurosci Res,2017,123:27-35.DOI:10. 1016/j. neures. 2017. 04. 012.
[16]Zhang W,Tian F,Zheng J,et al. Chronic administration of benzo(a)pyrene induces memory impairment and anxiety-Like behavior and increases of NR2B DNA methylation[J]. Plo S One,2016,11(2):e0149574. DOI:10. 1371/journal. pone. 0149574.
[17]Li C,Wang J,Su Q,et al. Postnatal subacute benzo(a)Pyrene exposure caused neurobehavioral impairment and metabolomic changes of cerebellum in the early adulthood period of sprague-Dawley rats[J]. Neurotox Res,2018,33(4):812-823. DOI:10. 1007/s12640-017-9832-8.
[18]He C,Wang C,Zhou Y,et al. Embryonic exposure to benzo(a)pyrene influences neural development and function in rockfish(Sebastiscus marmoratus)[J]. Neurotoxicology,2012,33(4):758-762. DOI:10. 1016/j. neuro. 2012. 01. 002.
[19] Mohanty R,Das SK,Patri M. Modulation of Benzo[a]Pyrene induced anxiolytic-like behavior by retinoic acid in zebrafish:Involvement of oxidative stress and antioxidant defense system[J].Neurotox Res,2017,31(4):493-504. DOI:10. 1007/s12640-016-9694-5.
[20]He J,Ji X,Li Y,et al. Subchronic exposure of benzo(a)pyrene interferes with the expression of Bcl-2,Ki-67,C-myc and p53,Bax,Caspase-3 in sub-regions of cerebral cortex and hippocampus[J]. Experimental and Toxicologic Pathology:official journal of the Gesellschaft fur Toxikologische Pathologie,2016,68(2-3):149-156. DOI:10. 1016/j. etp. 2015. 11. 007.
[21]Sotres-Bayon F,Sierra-Mercado D,Pardilla-Delgado E,et al. Gating of fear in prelimbic cortex by hippocampal and amygdala inputs[J]. Neuron,2012,76(4):804-812. DOI:10. 1016/j. neuron.2012. 09. 028.
[22]Felix-Ortiz AC,Beyeler A,Seo C,et al. BLA to v HPC inputs modulate anxiety-related behaviors[J]. Neuron,2013,79(4):658-664. DOI:10. 1016/j. neuron. 2013. 06. 016.