丰富环境改善小鼠放射性认知功能障碍
|
摘要
探讨丰富环境(Environmental Enrichment, EE)对电离辐射所致小鼠认知功能障碍的保护作用及其可能机制。将36只雌性昆明小鼠随机分为对照组(Control)、辐射组(IR)和辐射丰富环境组(IR+EE)。IR组和IR+EE组小鼠采用137Csγ射线进行全身辐照至吸收剂量4 Gy;IR+EE组小鼠辐照后给予连续35 d EE刺激。采用新物体识别实验检测小鼠认知功能;免疫组织化学方法检测海马区神经发生标记物双皮质素(Doublecortin, DCX)及磷酸化环磷酸腺苷应答元件结合蛋白(Phosphorylatedcyclicadenosinemonophosphate(cAMP)response element-binding protein, p-CREB)的表达;Western blot方法检测海马区CREB及p-CREB蛋白的表达。结果表明:与对照组相比,IR组小鼠新物体分辨率明显降低(45.55±5.80 vs. 2.99±6.18,p<0.05),海马区DCX阳性细胞数明显减少(123.8±9.3 vs. 70.2±5.9,p<0.05),p-CREB/CREB表达下调(1.007±0.058 vs. 0.772±0.039,p<0.05);而予以EE刺激后小鼠新物体分辨率明显回升(2.99±6.18 vs. 28.31±7.30,p<0.05),海马区DCX阳性细胞数明显增加(70.2±5.9 vs. 95.7±6.5,p<0.05),p-CREB/CREB表达上调(0.772±0.039 vs. 1.014±0.093,p<0.05)。结果提示EE可能是通过上调海马区p-CREB的表达,保护海马神经发生,进而改善辐射所致的小鼠认知功能障碍。
To investigate the protective effect and potential mechanism of environmental enrichment(EE) on irradiation-induced cognitive dysfunction in mice, thirty-six female Kunming mice were randomly divided into three groups administered different treatments: control, Irradiation(IR), and IR+EE. The mice in IR group and IR+EE group were irradiated with 137 Cs γ rays at an absorbed dose of 4.0 Gy. Mice in the IR+EE group were housed in EE for 35 d following irradiation. The object recognition task was used to evaluate the cognitive function of mice. The expression of the neurogenesis marker doublecortin(DCX), and phosphorylated cAMP response element-binding protein(p-CREB) was detected by using immunohistochemical staining. The expression of the cAMP response element-binding protein(CREB) and p-CREB proteins in hippocampus was assayed by using western blotting. The results showed that compared with control group, the irradiation group had a low discrimination ratio in the object recognition task(45.55 ± 5.80 vs. 2.99 ± 6.18, p<0.05), had fewer DCX positive cells(123.8 ± 9.3 vs. 70.2 ± 5.9, p<0.05), and had a remarkably lower level of p-CREB/CREB(1.007 ± 0.058 vs. 0.772 ± 0.039, p<0.05). Compared with the IR group, the IR+EE group had an enhanced discrimination ratio(2.99 ± 6.18 vs. 28.31 ± 7.30, p<0.05), more DCX positive cells(70.2 ± 5.9 vs. 95.7 ± 6.5, p<0.05), and up-regulated the expression of p-CREB/CREB(0.772 ± 0.039 vs. 1.014 ± 0.093, p<0.05). The results suggest that EE may alleviate irradiation-induced cognitive dysfunction and impair neurogenesis via enhancing hippocampal p-CREB expression.
To investigate the protective effect and potential mechanism of environmental enrichment(EE) on irradiation-induced cognitive dysfunction in mice, thirty-six female Kunming mice were randomly divided into three groups administered different treatments: control, Irradiation(IR), and IR+EE. The mice in IR group and IR+EE group were irradiated with 137 Cs γ rays at an absorbed dose of 4.0 Gy. Mice in the IR+EE group were housed in EE for 35 d following irradiation. The object recognition task was used to evaluate the cognitive function of mice. The expression of the neurogenesis marker doublecortin(DCX), and phosphorylated cAMP response element-binding protein(p-CREB) was detected by using immunohistochemical staining. The expression of the cAMP response element-binding protein(CREB) and p-CREB proteins in hippocampus was assayed by using western blotting. The results showed that compared with control group, the irradiation group had a low discrimination ratio in the object recognition task(45.55 ± 5.80 vs. 2.99 ± 6.18, p<0.05), had fewer DCX positive cells(123.8 ± 9.3 vs. 70.2 ± 5.9, p<0.05), and had a remarkably lower level of p-CREB/CREB(1.007 ± 0.058 vs. 0.772 ± 0.039, p<0.05). Compared with the IR group, the IR+EE group had an enhanced discrimination ratio(2.99 ± 6.18 vs. 28.31 ± 7.30, p<0.05), more DCX positive cells(70.2 ± 5.9 vs. 95.7 ± 6.5, p<0.05), and up-regulated the expression of p-CREB/CREB(0.772 ± 0.039 vs. 1.014 ± 0.093, p<0.05). The results suggest that EE may alleviate irradiation-induced cognitive dysfunction and impair neurogenesis via enhancing hippocampal p-CREB expression.
引文
1 Gan H K,Bernstein L J,Brown J,et al.Cognitive functioning after radiotherapy or chemoradiotherapy for head-and-neck cancer[J].International Journal of Radiation Oncology Biology Physics,2011,81(1):126-134.DOI:10.1016/j.ijrobp.2010.05.004.
2 Van Praag H,Kempermann G,Gage F H.Neural consequences of environmental enrichment[J].Nature Reviews Neuroscience,2000,1(3):191-198.DOI:10.1038/35044558.
3 Lee E H,Hsu W L,Ma Y L,et al.Enrichment enhances the expression of sgk,a glucocorticoid-induced gene,and facilitates spatial learning through glutamate AMPAreceptor mediation[J].European Journal of Neuroscience,2003,18(10):2842-2852.DOI:10.1046/j.1460-9568.2003.03032.x.
4乃爱桃,王贞,曹文宇,等.丰富环境对辐射诱导小鼠认知障碍的保护作用及可能机制[J].中华放射医学与防护杂志,2018,38(6):401-406.DOI:10.3760/cma.j.issn.0254-5098.2018.06.001.NAI Aitao,WANG Zhen,CAO Wenyu,et al.The protective effect of environmental enrichment on radiation induced cognitive dysfunction and underlying mechanism[J].Chinese Journal of Radiological Medicine and Protect,2018,38(6):401-406.DOI:10.3760/cma.j.issn.0254-5098.2018.06.001.
5胡雅梦,刘琅嬛,刘宝婵,等.黄芪甲苷对肝细胞的辐射防护作用[J].辐射研究与辐射工艺学报,2015,33(6):060202.DOI:10.11889/j.1000-3436.2015.rrj.33.060202.HU Yameng,LIU Langhuan,LIU Baochan,et al.Radioprotective effects of astragaloside IV on the liver cell[J].Journal of Radiation Research and Radiation Processing,2015,33(6):060202.DOI:10.11889/j.1000-3436.2015.rrj.33.060202.
6 Cao W Y,Hu Z L,Xu Y,et al.Role of early environmental enrichment on the social dominance tube test at adulthood in the rat[J].Psychopharmacology(Berl),2017,234(22):3321-3334.DOI:10.1007/s00213-017-4717-3.
7 Xu Y,Cao W,Zhou M,et al.Inactivation of BRD7 results in impaired cognitive behavior and reduced synaptic plasticity of the medial prefrontal cortex[J].Behavioural Brain Research,2015,286:1-10.DOI:10.1016/j.bbr.2015.02.031.
8 Cao W,Duan J,Wang X,et al.Early enriched environment induces an increased conversion of pro BDNF to BDNF in the adult rat's hippocampus[J].Behavioural Brain Research,2014,265:76-83.DOI:10.1016/j.bbr.2014.02.022.
9 Achanta P,Fuss M,Martinez J J.Ionizing radiation impairs the formation of trace fear memories and reduces hippocampal neurogenesis[J].Behavioral Neuroscience,2009,123(5):1036-1045.DOI:10.1037/a0016870.
10 Abrous D N,Koehl M,Moal M L.Adult neurogenesis:from precursors to network and physiology[J].Physiological Reviews,2005,85(2):523-569.DOI:10.1152/physrev.00055.2003.
11 Kalm M,Roughton K,Blomgren K.Lipopolysaccharide sensitized male and female juvenile brains to ionizing radiation[J].Cell Death and Disease,2013,4:e962.DOI:10.1038/cddis.2013.482.
12 Sweet T B,Hurley S D,Wu M D,et al.Neurogenic effects of low-dose whole-body HZE(Fe)ion and gamma irradiation[J].Radiation Research,2016,186(6):614-623.DOI:10.1667/RR14530.1.
13 Monje M L,Vogel H,Masek M,et al.Impaired human hippocampal neurogenesis after treatment for central nervous system malignancies[J].Ann Neurol,2007,62(5):515-520.DOI:10.1002/ana.21214.
14 Raber J,Rola R,LeFevour A,et al.Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis[J].Radiation Research,2004,162(1):39-47.DOI:10.1667/RR3206.
15 Monteiro B M,Moreira F A,Massensini A R,et al.Enriched environment increases neurogenesis and improves social memory persistence in socially isolated adult mice[J].Hippocampus,2014,24(2):239-248.DOI:10.1002/hipo.22218.
16 Speisman R B,Kumar A,Rani A,et al.Environmental enrichment restores neurogenesis and rapid acquisition in aged rats[J].Neurobiology of Aging,2013,34(1):263-274.DOI:10.1016/j.neurobiolaging.2012.05.023.
17 Shen J,Zhang J J,Deng M,et al.The antidepressant effect of Angelica sinensis extracts on chronic unpredictable mild stress-induced depression is mediated via the upregulation of the BDNF signaling pathway in rats[J].Evidence-Based Complementary and Alternative Medicine,2016(2):1-8.DOI:10.1155/2016/7434692.
18 Shindo T,Matsumoto Y,Wang Q,et al.Differences in the neuronal stem cells survival,neuronal differentiation and neurological improvement after transplantation of neural stem cells between mild and severe experimental traumatic brain injury[J].Journal of Medical Investigation,2006,53(1-2):42-51.
19 Yang S N,Huang L T,Wang C L,et al.Prenatal administration of morphine decreases CREB Serine-133phosphorylation and synaptic plasticity range mediated by glutamatergic transmission in the hippocampal CA1 area of cognitive-deficient rat offspring[J].Hippocampus,2003,13(8):915-921.DOI:10.1002/hipo.10137.
2 Van Praag H,Kempermann G,Gage F H.Neural consequences of environmental enrichment[J].Nature Reviews Neuroscience,2000,1(3):191-198.DOI:10.1038/35044558.
3 Lee E H,Hsu W L,Ma Y L,et al.Enrichment enhances the expression of sgk,a glucocorticoid-induced gene,and facilitates spatial learning through glutamate AMPAreceptor mediation[J].European Journal of Neuroscience,2003,18(10):2842-2852.DOI:10.1046/j.1460-9568.2003.03032.x.
4乃爱桃,王贞,曹文宇,等.丰富环境对辐射诱导小鼠认知障碍的保护作用及可能机制[J].中华放射医学与防护杂志,2018,38(6):401-406.DOI:10.3760/cma.j.issn.0254-5098.2018.06.001.NAI Aitao,WANG Zhen,CAO Wenyu,et al.The protective effect of environmental enrichment on radiation induced cognitive dysfunction and underlying mechanism[J].Chinese Journal of Radiological Medicine and Protect,2018,38(6):401-406.DOI:10.3760/cma.j.issn.0254-5098.2018.06.001.
5胡雅梦,刘琅嬛,刘宝婵,等.黄芪甲苷对肝细胞的辐射防护作用[J].辐射研究与辐射工艺学报,2015,33(6):060202.DOI:10.11889/j.1000-3436.2015.rrj.33.060202.HU Yameng,LIU Langhuan,LIU Baochan,et al.Radioprotective effects of astragaloside IV on the liver cell[J].Journal of Radiation Research and Radiation Processing,2015,33(6):060202.DOI:10.11889/j.1000-3436.2015.rrj.33.060202.
6 Cao W Y,Hu Z L,Xu Y,et al.Role of early environmental enrichment on the social dominance tube test at adulthood in the rat[J].Psychopharmacology(Berl),2017,234(22):3321-3334.DOI:10.1007/s00213-017-4717-3.
7 Xu Y,Cao W,Zhou M,et al.Inactivation of BRD7 results in impaired cognitive behavior and reduced synaptic plasticity of the medial prefrontal cortex[J].Behavioural Brain Research,2015,286:1-10.DOI:10.1016/j.bbr.2015.02.031.
8 Cao W,Duan J,Wang X,et al.Early enriched environment induces an increased conversion of pro BDNF to BDNF in the adult rat's hippocampus[J].Behavioural Brain Research,2014,265:76-83.DOI:10.1016/j.bbr.2014.02.022.
9 Achanta P,Fuss M,Martinez J J.Ionizing radiation impairs the formation of trace fear memories and reduces hippocampal neurogenesis[J].Behavioral Neuroscience,2009,123(5):1036-1045.DOI:10.1037/a0016870.
10 Abrous D N,Koehl M,Moal M L.Adult neurogenesis:from precursors to network and physiology[J].Physiological Reviews,2005,85(2):523-569.DOI:10.1152/physrev.00055.2003.
11 Kalm M,Roughton K,Blomgren K.Lipopolysaccharide sensitized male and female juvenile brains to ionizing radiation[J].Cell Death and Disease,2013,4:e962.DOI:10.1038/cddis.2013.482.
12 Sweet T B,Hurley S D,Wu M D,et al.Neurogenic effects of low-dose whole-body HZE(Fe)ion and gamma irradiation[J].Radiation Research,2016,186(6):614-623.DOI:10.1667/RR14530.1.
13 Monje M L,Vogel H,Masek M,et al.Impaired human hippocampal neurogenesis after treatment for central nervous system malignancies[J].Ann Neurol,2007,62(5):515-520.DOI:10.1002/ana.21214.
14 Raber J,Rola R,LeFevour A,et al.Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis[J].Radiation Research,2004,162(1):39-47.DOI:10.1667/RR3206.
15 Monteiro B M,Moreira F A,Massensini A R,et al.Enriched environment increases neurogenesis and improves social memory persistence in socially isolated adult mice[J].Hippocampus,2014,24(2):239-248.DOI:10.1002/hipo.22218.
16 Speisman R B,Kumar A,Rani A,et al.Environmental enrichment restores neurogenesis and rapid acquisition in aged rats[J].Neurobiology of Aging,2013,34(1):263-274.DOI:10.1016/j.neurobiolaging.2012.05.023.
17 Shen J,Zhang J J,Deng M,et al.The antidepressant effect of Angelica sinensis extracts on chronic unpredictable mild stress-induced depression is mediated via the upregulation of the BDNF signaling pathway in rats[J].Evidence-Based Complementary and Alternative Medicine,2016(2):1-8.DOI:10.1155/2016/7434692.
18 Shindo T,Matsumoto Y,Wang Q,et al.Differences in the neuronal stem cells survival,neuronal differentiation and neurological improvement after transplantation of neural stem cells between mild and severe experimental traumatic brain injury[J].Journal of Medical Investigation,2006,53(1-2):42-51.
19 Yang S N,Huang L T,Wang C L,et al.Prenatal administration of morphine decreases CREB Serine-133phosphorylation and synaptic plasticity range mediated by glutamatergic transmission in the hippocampal CA1 area of cognitive-deficient rat offspring[J].Hippocampus,2003,13(8):915-921.DOI:10.1002/hipo.10137.