调肝方药对慢性应激性抑郁大鼠海马齿状回神经发生的调控作用
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摘要
研究目的
当前临床中治疗抑郁症的药物多数为生物合成制剂,病人容易耐受、成瘾、毒副作用较大。抑郁症的发病与慢性应激有关。海马是应激反应的高位调节中枢,对应激反应非常敏感且易损。海马齿状回区域的神经发生对于维持海马的结构和功能具有重要的作用。不良应激会抑制海马齿状回区域的神经发生,减少齿状回区域神经元的数目。传统中医当中虽然没有应激这一概念,但中医的藏象理论及有关情志致病的论述与现代应激理论之间有许多相似之处。调肝方药是根据中医藏象理论学说“肝主疏泄”的理论所创制的一系列方药,一直被广泛地应用于情志疾病的治疗。调肝中药复方所显示出来的独有的整体调节作用,克服了生物合成制剂所固有的缺陷,具有良好的科研和开发应用前景。本研究从慢性应激时海马齿状回区域神经细胞增殖与凋亡失衡的角度,观察调肝中药复方XYS和JWSNS对慢性应激性抑郁的作用并探讨其中的一些可能机制,为今后运用中医药防治应激因素所致神经精神疾患、延缓应激衰老以及研制抗应激性损伤的中药新药提供实验基础。
研究方法
复制慢性应激性抑郁动物模型。与复制模型同步使用调肝中药复方逍遥散和加味四逆散干预。最后运用免疫组化、原位杂交等实验技术检测相关指标的变化,观察调肝方药对慢性应激性抑郁大鼠海马齿状回神经发生的作用并探讨可能的机制。
1、复制和验证慢性温和应激模型;
2、观察糖水偏爱度和强迫游泳的不动时间;
3、取各实验组大鼠脑部冰冻切片:使用荧光标记的免疫组化方法检测海马齿状回区域神经元特异核蛋白(NeuN)、5-溴脱氧尿嘧啶核苷(BrdU)表达水平;使用DNA片段化原位末端标记法检测海马齿状回区域细胞的调亡水平;使用荧光标记的免疫组化方法检测海马齿状回区域脑源性神经营养因子(BDNF)表达水平;使用原位杂交技术检测海马齿状回区域BDNF mRNA表达水平;使用荧光标记的免疫组化方法检测海马齿状回区域磷酸化cAMP反应元件结合蛋白(pCREB)表达水平;使用荧光标记的免疫组化方法检测海马齿状回区域N-甲基-D-天冬氨酸1型受体(NMDA R1)表达水平。
研究结果
1、调肝方药治疗组强迫游泳的平均不动时间短于模型组(调肝1组P＜0.01,调肝2组P＜0.05)。
2、调肝方药组NeuN标记平均荧光强度值明显高于模型组(P＜0.05)和西药组(P＜0.01)。
3、调肝方药组BrdU标记的平均荧光强度值明显高于模型组(P＜0.01),调肝方药组BrdU-NeuN联合标记的平均荧光强度值与BrdU标记的平均荧光强度值的比值低于模型组(P＜0.01)
4、调肝方药组凋亡细胞调亡标记的平均荧光强度值与总细胞DAPI标记的平均荧光强度值的比值明显低于模型组(P＜0.01)。
5、调肝方药组BDNF平均荧光强度值高于模型组(P＜0.05)。
6、调肝方药组BDNF mRNA的平均光密度值明显高于模型组(P＜0.01)。
7、调肝方药组pCREB的平均荧光强度值明显高于模型组(P＜0.01)。
8、调肝方药组NMDA R1的平均荧光强度值明显低于模型组(P＜0.01)。
研究结论
1、慢性应激可以引起海马DG区域细胞增殖的减少和凋亡的增多,使DG区域神经元的数量下降,即可以抑制DG区域的神经发生。
2、调肝方药能够通过促进慢性应激条件下海马DG区域神经细胞的增殖、抑制神经细胞的凋亡,增加DG区域神经元的数目来发挥抗慢性应激性抑郁的作用。
3、调肝方药能够通过上调慢性应激条件下海马DG区域pCREB - BDNF mRNA -BDNF的表达、下调NMDA R1的表达,来对抗慢性应激引起的DG区域神经发生受抑制的状况。
Objective:Currently,we treat the depression more depend on biosynthesis preparation, while some of the drugs has the shortage of addiction and some has the shortage of side affect that has been abused in the clinic.Research proves that chronic stress related to depression.Neurogenesis happening in the dentate gyrus(DG) region is important for maintaining the structure and function of hippocampus.Harmful chronic stress can depress the neurogenesis,and reduce the number of neurons.There has no glossaries in TCM for stress,but the Theory of zang-manifestations and emotion disorder is similar with modern stress theory.Liver-regulating compound recipe is based on the theory of zang-manifestations,and has been used in the clinic widely and effectively for treating the Qingzhi disease.Liver-regulating compound recipe have the whole regulation function, which overcomes some of the shortage of biosynthesis preparation and shows the prospect of development.In this study,we try to find out the effect of liver-regulating compound recipe on depression that stimulated by chronic stress and try to find out some of the mechanisms that behind it in view of imbalance of proliferation and apoptosis happened under chronic stress.
Methods:we copy the model of chronic mild stress using Wister Rat in our research, and treating the rats by XYS and JWSNS along with the copying.Get the frozen sections of the brain in the range of target and detect the expressions of the indexes that can be used to detect the effect and explain what we see by insituhybridization and fluorescence Immunohistochemsitry.
1,Copy and validate the chronic mild stress(CMS) model;
2,Observe the result of Sucrose consumption and Forced swimming;
3,Take the frozen sections of rat brains to detect the expression levels of NeuN,BrdU in DG region by fluorescent-labeled Immunohistochemistry;detect the expression levels of apoptosis in DG region by Fluorescein FragEL~(TM) DNA Fragmentation Detection Kit;detect the expression levels of BDNF in DG region by fluorescent-labeled Immunohistochemistry; detect the expression levels of BDNF mRNA by insituhybridization;detect the expression levels of pCREB in DG region by fluorescent-labeled Immunohistochemistry;detect the expression levels of NMDA R1 in DG region by fluorescent-labeled Immunohistochemistry.
Result:
1,The average forced swimming immobility time of liver-regulating compound recipe group is obviously shorter than the model group(liver-regulating compound recipe group1 P <0.01,liver-regulating compound recipe group 2 P <0.05).
2,The average intensity of fluorescence of NeuN in liver-regulating compound recipe group is obviously higher than the model group(P <0.05) and western medicine group(P <0.01).
3,The average intensity of fluorescence of BrdU in liver-regulating compound recipe group is obviously higher than the model group(P <0.01).
4,The ratio of the average intensity of fluorescence marking by apoptosis and the average intensity of DAPI which marking all the cells in liver-regulating compound recipe group is obviously lower than that of the model group(P <0.01).
5,The average intensity of fluorescence marking by BDNF in liver-regulating compound recipe group is obviously higher than the model group(P <0.01).
6,The average intensity of BDNF mRNA in liver-regulating compound recipe group is obviously higher than the model group(P <0.01).
7,The average intensity of fluorescence marking by pCREB in liver-regulating compound recipe group is obviously higher than the model group(P <0.01).
8,The average intensity of fluorescence of NMDAR1 in liver-regulating compound recipe group is obviously lower than the model group(P <0.01).
Conclusion:In our study,we make three conclusions.First,the chronic stress can decreae the proliferation of the neurons,increse the apoptosis of the neurons and decrease the number of the neurons in DG region,which means the chronic stress inhibits the neurogenesis in DG gegion.Second,the liver-regulating compound recipe can accelerate the proliferation of the neurons,depress the apoptosis of the neurons,and increase the number of neurons in DG region to play an important role in anti-depression. Third,the liver-regulating compound recipe can also up-regulate the expression of pCREB, BDNF mRNA,and BDNF in DG region under chronic mild stress,down-regulate the expression of NMDA R1 in DG region,which plays an important role in regulating the neurogenesis in DG region.
当前临床中治疗抑郁症的药物多数为生物合成制剂,病人容易耐受、成瘾、毒副作用较大。抑郁症的发病与慢性应激有关。海马是应激反应的高位调节中枢,对应激反应非常敏感且易损。海马齿状回区域的神经发生对于维持海马的结构和功能具有重要的作用。不良应激会抑制海马齿状回区域的神经发生,减少齿状回区域神经元的数目。传统中医当中虽然没有应激这一概念,但中医的藏象理论及有关情志致病的论述与现代应激理论之间有许多相似之处。调肝方药是根据中医藏象理论学说“肝主疏泄”的理论所创制的一系列方药,一直被广泛地应用于情志疾病的治疗。调肝中药复方所显示出来的独有的整体调节作用,克服了生物合成制剂所固有的缺陷,具有良好的科研和开发应用前景。本研究从慢性应激时海马齿状回区域神经细胞增殖与凋亡失衡的角度,观察调肝中药复方XYS和JWSNS对慢性应激性抑郁的作用并探讨其中的一些可能机制,为今后运用中医药防治应激因素所致神经精神疾患、延缓应激衰老以及研制抗应激性损伤的中药新药提供实验基础。
研究方法
复制慢性应激性抑郁动物模型。与复制模型同步使用调肝中药复方逍遥散和加味四逆散干预。最后运用免疫组化、原位杂交等实验技术检测相关指标的变化,观察调肝方药对慢性应激性抑郁大鼠海马齿状回神经发生的作用并探讨可能的机制。
1、复制和验证慢性温和应激模型;
2、观察糖水偏爱度和强迫游泳的不动时间;
3、取各实验组大鼠脑部冰冻切片:使用荧光标记的免疫组化方法检测海马齿状回区域神经元特异核蛋白(NeuN)、5-溴脱氧尿嘧啶核苷(BrdU)表达水平;使用DNA片段化原位末端标记法检测海马齿状回区域细胞的调亡水平;使用荧光标记的免疫组化方法检测海马齿状回区域脑源性神经营养因子(BDNF)表达水平;使用原位杂交技术检测海马齿状回区域BDNF mRNA表达水平;使用荧光标记的免疫组化方法检测海马齿状回区域磷酸化cAMP反应元件结合蛋白(pCREB)表达水平;使用荧光标记的免疫组化方法检测海马齿状回区域N-甲基-D-天冬氨酸1型受体(NMDA R1)表达水平。
研究结果
1、调肝方药治疗组强迫游泳的平均不动时间短于模型组(调肝1组P＜0.01,调肝2组P＜0.05)。
2、调肝方药组NeuN标记平均荧光强度值明显高于模型组(P＜0.05)和西药组(P＜0.01)。
3、调肝方药组BrdU标记的平均荧光强度值明显高于模型组(P＜0.01),调肝方药组BrdU-NeuN联合标记的平均荧光强度值与BrdU标记的平均荧光强度值的比值低于模型组(P＜0.01)
4、调肝方药组凋亡细胞调亡标记的平均荧光强度值与总细胞DAPI标记的平均荧光强度值的比值明显低于模型组(P＜0.01)。
5、调肝方药组BDNF平均荧光强度值高于模型组(P＜0.05)。
6、调肝方药组BDNF mRNA的平均光密度值明显高于模型组(P＜0.01)。
7、调肝方药组pCREB的平均荧光强度值明显高于模型组(P＜0.01)。
8、调肝方药组NMDA R1的平均荧光强度值明显低于模型组(P＜0.01)。
研究结论
1、慢性应激可以引起海马DG区域细胞增殖的减少和凋亡的增多,使DG区域神经元的数量下降,即可以抑制DG区域的神经发生。
2、调肝方药能够通过促进慢性应激条件下海马DG区域神经细胞的增殖、抑制神经细胞的凋亡,增加DG区域神经元的数目来发挥抗慢性应激性抑郁的作用。
3、调肝方药能够通过上调慢性应激条件下海马DG区域pCREB - BDNF mRNA -BDNF的表达、下调NMDA R1的表达,来对抗慢性应激引起的DG区域神经发生受抑制的状况。
Objective:Currently,we treat the depression more depend on biosynthesis preparation, while some of the drugs has the shortage of addiction and some has the shortage of side affect that has been abused in the clinic.Research proves that chronic stress related to depression.Neurogenesis happening in the dentate gyrus(DG) region is important for maintaining the structure and function of hippocampus.Harmful chronic stress can depress the neurogenesis,and reduce the number of neurons.There has no glossaries in TCM for stress,but the Theory of zang-manifestations and emotion disorder is similar with modern stress theory.Liver-regulating compound recipe is based on the theory of zang-manifestations,and has been used in the clinic widely and effectively for treating the Qingzhi disease.Liver-regulating compound recipe have the whole regulation function, which overcomes some of the shortage of biosynthesis preparation and shows the prospect of development.In this study,we try to find out the effect of liver-regulating compound recipe on depression that stimulated by chronic stress and try to find out some of the mechanisms that behind it in view of imbalance of proliferation and apoptosis happened under chronic stress.
Methods:we copy the model of chronic mild stress using Wister Rat in our research, and treating the rats by XYS and JWSNS along with the copying.Get the frozen sections of the brain in the range of target and detect the expressions of the indexes that can be used to detect the effect and explain what we see by insituhybridization and fluorescence Immunohistochemsitry.
1,Copy and validate the chronic mild stress(CMS) model;
2,Observe the result of Sucrose consumption and Forced swimming;
3,Take the frozen sections of rat brains to detect the expression levels of NeuN,BrdU in DG region by fluorescent-labeled Immunohistochemistry;detect the expression levels of apoptosis in DG region by Fluorescein FragEL~(TM) DNA Fragmentation Detection Kit;detect the expression levels of BDNF in DG region by fluorescent-labeled Immunohistochemistry; detect the expression levels of BDNF mRNA by insituhybridization;detect the expression levels of pCREB in DG region by fluorescent-labeled Immunohistochemistry;detect the expression levels of NMDA R1 in DG region by fluorescent-labeled Immunohistochemistry.
Result:
1,The average forced swimming immobility time of liver-regulating compound recipe group is obviously shorter than the model group(liver-regulating compound recipe group1 P <0.01,liver-regulating compound recipe group 2 P <0.05).
2,The average intensity of fluorescence of NeuN in liver-regulating compound recipe group is obviously higher than the model group(P <0.05) and western medicine group(P <0.01).
3,The average intensity of fluorescence of BrdU in liver-regulating compound recipe group is obviously higher than the model group(P <0.01).
4,The ratio of the average intensity of fluorescence marking by apoptosis and the average intensity of DAPI which marking all the cells in liver-regulating compound recipe group is obviously lower than that of the model group(P <0.01).
5,The average intensity of fluorescence marking by BDNF in liver-regulating compound recipe group is obviously higher than the model group(P <0.01).
6,The average intensity of BDNF mRNA in liver-regulating compound recipe group is obviously higher than the model group(P <0.01).
7,The average intensity of fluorescence marking by pCREB in liver-regulating compound recipe group is obviously higher than the model group(P <0.01).
8,The average intensity of fluorescence of NMDAR1 in liver-regulating compound recipe group is obviously lower than the model group(P <0.01).
Conclusion:In our study,we make three conclusions.First,the chronic stress can decreae the proliferation of the neurons,increse the apoptosis of the neurons and decrease the number of the neurons in DG region,which means the chronic stress inhibits the neurogenesis in DG gegion.Second,the liver-regulating compound recipe can accelerate the proliferation of the neurons,depress the apoptosis of the neurons,and increase the number of neurons in DG region to play an important role in anti-depression. Third,the liver-regulating compound recipe can also up-regulate the expression of pCREB, BDNF mRNA,and BDNF in DG region under chronic mild stress,down-regulate the expression of NMDA R1 in DG region,which plays an important role in regulating the neurogenesis in DG region.
引文
[1]Abrous D.N.,Koehl M.,Le Moal M.Adult neurogenesis:from precursors to network and physiology[J].Physiol Rev,2005,85(2):523-69.
[2]Lowenstein D.H.,Parent J.M.Brain,heal thyself[J].Science,1999,283(5405):1126-7.
[3]Altman J.Are new neurons formed in the brains of adult mammals?[J].Science,1962,135(1127-8.
[4]Airman J.,Das G.D.Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats[J].J Comp Neurol,1965,124(3):319-35.
[5]Reynolds B.A.,Weiss S.Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system[J].Science,1992,255(5052):1707-10.
[6]Eriksson P.S.,Perfilieva E.,Bjork-Eriksson T.,et al.Neurogenesis in the adult human hippocampus[J].Nat Med,1998,4(11 ):1313-7.
[7]范晓棠.Noggin与BMP4在大鼠中枢神经系统的发育学表达及与学习记忆的相关性研究[D].第三军医大学,2002.
[8]Carleton A.,Petreanu L.T.,Lansford R.,et al.Becoming a new neuron in the adult olfactory bulb[J[.Nat Neurosci,2003,6(5):507-18.
[9]Shors T.J.,Miesegaes G.,Beylin A.,et al.Neurogenesis in the adult is involved in the formation of trace memories[J].Nature,2001,410(6826):372-6.
[10]van Praag H.,Schinder A.F.,Christie B.R.,et al.Functional neurogenesis in the adult hippocampus[J].Nature,2002,415(6875):1030-4.
[11]Iwai M.,Sato K.,Omori N.,et al.Three steps of neural stem cells development in gerbil dentate gyrus after transient ischemia[J].J Cereb Blood Flow Metab,2002,22(4):411-9.
[12]Matsumura N.,Yoshida N.,Ohta A.,et al.Neural precursor cells from adult mouse cerebral cortex differentiate into both neurons and oligodendrocytes[J].Cytotechnology,2003,43(1-3):19-25.
[13]Nunes M.C.,Roy N.S.,Keyoung H.M.,et al.Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain[J].Nat Med,2003,9(4):439-47.
[14]Laplagne D.A.,Esposito M.S.,Piatti V.C.,et al.Functional convergence of neurons generated in the developing and adult hippocarnpus[J].PLoS Biol,2006,4(12):e409.
[15]姬西团,章翔,费舟,et al.EG F'bFG F,NGF.RA对小鼠神经干细胞定向分化的调控[J].中华神经医学杂志,2005,4(006):556-559.
[16]Chen J.,Zacharek A.,Zhang C.,et al.Endothelial nitric oxide synthase regulates brain-derived neurotrophic factor expression and neurogenesis after stroke in mice[J].J Neurosci,2005,25(9):2366-75.
[17]王细林,曾庆杏,陈迎春.N-Methyl-D-Aspartate受体拮抗剂对脑缺血后成年大鼠神经干细胞 内源性激活的实验研究[J].中风与神经疾病杂志,2005,22(002):121-124.
[18]袁固艳,任铭新,张新.MK-801的浓度与局灶性脑缺血大鼠内源性神经干细胞增殖的关系[J].医学信息手术学分册,2006,19(2):51-54.
[19]Scharfman H.E.,Hen R.Neuroscience.Is more neurogenesis always better?[J].Science,2007,315(5810):336-8.
[20]陈迎春,曾庆杏,段申汉,et al.雌激素对大鼠脑缺血再灌注神经干细胞内源性激活的实验研究[J].卒中与神经疾病,2005,12(005):265-268.
[21]陆澄秋,钟乐,颜崇淮,et al.丰富环境对神经发生影响的研究进展[J].国际神经病学神经外科学杂志,2007,34(05):474-477.
[22]Raballo R.,Rhee J.,Lyn-Cook R.,et al.Basic fibroblast growth factor(Fgf2) is necessary for cell proliferation and neurogenesis in the developing cerebral cortex[J].J Neurosci,2000,20(13):5012-23.
[23]Tropepe V.,Sibilia M.,Ciruna B.G.,et al.Distinct neural stem cells proliferate in response to EGF and FGF in the developing mouse telencephalon[J].Dev Biol,1999,208(1):166-88.
[24]Kalyani A.,Hobson K.,Rao M.S.Neuroepithelial stem cells from the embryonic spinal cord:isolation,characterization,and clonal analysis[J].Dev Biol,1997,186(2):202-23.
[25]Gritti A.,Frolichsthal-Schoeller P.,Galli R.,et al.Epidermal and fibroblast growth factors behave as mitogenic regulators for a single multipotent stem cell-like population from the subventricular region of the adult mouse forebrain[J].J Neurosci,1999,19(9):3287-97.
[26]Haydar Y.F.,Wang F.,Schwartz M.L.,et al.Differential modulation of proliferation in the neocortical ventricular and subventricular zones[J].J Neurosci,2000,20(15):5764-74.
[27]李学坤,左萍萍.成体哺乳动物脑内的神经发生及其调节[J].中国康复理论与实践,2003,9(007):401-404.
[28]Morrison S.J.,Perez S.E.,Qiao Z.,et al.Transient Notch activation initiates an irreversible switch from neurogenesis to gliogenesis by neural crest stem cells[J].Cell,2000,101(5):499-510.
[29]Ohlsson A.L.,Johansson B.B.Environment influences functional outcome of cerebral infarction in rats[J].Stroke,1995,26(4):644-9.
[30]Song H.,Stevens C.E,Gage F.H.Astroglia induce neurogenesis from adult neural stem cells[J].Nature,2002,417(6884):39-44.
[31]Lauder J.M.Ontogeny of the serotonergic system in the rat:serotonin as a developmental signal[J].Ann N Y Acad Sci,1990,600(297-313;discussion 314.
[32]Kempermann G.,Kuhn H.G.,Gage F.H.Genetic influence on neurogenesis in the dentate gyrus of adult mice[J].Proc Natl Acad Sci U S A,1997,94(19):10409-14.
[33]Kornack D.R.,Rakic P.Continuation of neurogenesis in the hippocampus of the adult macaque monkey[J].Proe Natl Acad Sci U S A,1999,96(10):5768-73.
[34]Kuhn H.G.,Dickinson-Anson H.,Gage F.H.Neurogenesis in the dentate gyrus of the adult rat:age-related decrease of neuronal progenitor proliferation[J].J Neurosci,1996,16(6):2027-33.
[35]Yoshimura S.,Takagi Y.,Harada J.,et al.FGF-2 regulation of neurogenesis in adult hippocampus after brain injury[J].Proc Natl Acad Sci U S A,2001,98(10):5874-9.
[36]Jin K.,Zhu Y.,Sun Y.,et al.Vascular endothelial growth factor(VEGF) stimulates neurogenesis in vitro and in vivo[J].Proc Natl Acad Sci U S A,2002,99(18):11946-50.
[37]Aberg M.A.,Aberg N.D.,Hedbacker H.,et al.Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus[J].J Neurosci,2000,20(8):2896-903.
[38]Gross C.G.Brain,Vision,Memory:Tales in the History of Neuroscience[M].Cambridge,MA:MIT Press,1999.
[39]Miller D.B.,O'Callaghan J.P.Aging,stress and the hippocampus[J].Ageing Res Rev,2005,4(2):123-40.
[40]Cameron H.A.,McKay R.D.Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus[J].J Comp Neurol,2001,435(4):406-17.
[41]关新民.医学神经生物学[M].北京:人民卫生出版社,2002:360.
(42]肖献忠.病理生理学[M].全国高等学校医学规划教材,北京:高等教育出版社,2004.
[43]杨权.下丘脑-垂体-肾上腺皮质轴应激反应的中枢控制[J].生理科学进展,2000,31(03):222-226.
[44]McEwen B.S.Stress and hippocampal plasticity[J].Annu Rev Neurosci,1999,22(105-22.
[45]McEwen B.S.Effects of adverse experiences for brain structure and function[J].Biol Psychiatry,2000,48(8):721-31.
[46]Gould E.,Tanapat P.,Rydel T.,et al.Regulation of hippocampal neurogenesis in adulthood[J].Biol Psychiatry,2000,48(8):715-20.
[47]Panegyres P.K.The contribution of the study of neurodegenerative disorders to the understanding of human memory[J].QJM,2004,97(9):555-67.
[48]Herman J.P.,Cullinan W.E.,Morano M.I.,et al.Contribution of the ventral subiculum to inhibitory regulation of the hypothalamo-pituitary-adrenocortical axis[J].J Neuroendocrinol,1995,7(6):475-82.
[49]Jacobson L.,Sapolsky R.The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis[J].Endocr Rev,1991,12(2):118-34.
[50]McKittrick C.R.,Magarinos A.M.,Blanchard D.C.,et al.Chronic social stress reduces dendritic arbors in CA3 of hippocampus and decreases binding to serotonin transporter sites[J].Synapse,2000,36(2):85-94.
[51]连晓媛,张均田,包天桐.海马与下丘脑-垂体-肾上腺轴功能调节[J].国外医学.内分泌学分册,1998,18(04):169-172.
[52]Weidenfeld J.,Feldman S.Glucocorticoid feedback regulation of adrenocortical responses to neural stimuli:role of CRF-41 and corticosteroid type I and type Ⅱ receptors[J].Neuroendocrinology,1993,58(1):49-56.
[53]Brooke S.M.,de Haas-Johnson A.M,Kaplan J.R.,et al.Dexamethasone resistance among nonhuman primates associated with a selective decrease of glucocorticoid receptors in the hippocampus and a history of social instability[J].Neuroendocrinology,1994,60(2):134-40.
[54]Brown E.S.,D J.W.,Frol A.,et al.Hippocampal volume,spectroscopy,cognition,and mood in patients receiving corticosteroid therapy[J].Biol Psychiatry,2004,55(5):538-45.
[55]Wilner A.P.,de Varennes B? Gregoire P.A.,et al.Glucocorticoids and hippocampal atrophy after heart transplantation[J].Ann Thorac Surg,2002,73(6):1965-7.
[56]McEwen B.S.,Magarinos A.M.Stress effects on morphology and function of the hippocampus[J].Ann N Y Acad Sci,1997,821 (271-84.
[57]Sousa N.,Lukoyanov N.V.,Madeira M.D.,et al.Erratum to “Reorganization of the morphology of hippocampal neurites and synapses after stress-induced damage correlates with behavioral improvement”[J].Neuroscience,2000,101(2):483.
[58]Duman R.S.,Malberg J.,Thome J.Neural plasticity to stress and antidepressant treatment[J].Biol Psychiatry,1999,46(9):1181-91.
[59]Gould E.,Tanapat P.Stress and hippocampal neurogenesis[J].Biol Psychiatry,1999,46(11):1472-9.
[60]Kerr J.F.,Wyllie A.H.,Currie A.R.Apoptosis:a basic biological phenomenon with wide-ranging implications in tissue kinetics[J].Br J Cancer,1972,26(4):239-57.
[61]Lucassen P.J.,Vollmann-Honsdorf G.K.,Gleisberg M.,et al.Chronic psychosocial stress differentially affects apoptosis in hippocampal subregions and cortex of the adult tree shrew[J].Eur J Neurosci,2001,14(1):161-6.
[62]Lucassen P.J.,Muller M.B.,Holsboer F.,et al.Hippocampal apoptosis in major depression is a minor event and absent from subareas at risk for glucocorticoid overexposure[J].Am J Pathol,2001,158(2):453-68.
[63]Zhang L.,Kokkonen G.,Roth G.S.Identification of neuronal programmed cell death in situ in the striatum of normal adult rat brain and its relationship to neuronal death during aging[J].Brain Res,1995,677(1):177-9.
[64]Czeh B.,Welt T.,Fischer A.K.,et al.Chronic psychosocial stress and concomitant repetitive transcranial magnetic stimulation:effects on stress hormone levels and adult hippocampal neurogenesis[J].Biol Psychiatry,2002,52(11):1057-65.
[65]Pham K.,Nacher J.,Hof P.R.,et al.Repeated restraint stress suppresses neurogenesis and induces biphasic PSA-NCAM expression in the adult rat dentate gyrus[J].Eur J Neurosci,2003,17(4):879-86.
[66]Westenbroek C,Den Boer J.A.,Veenhuis M.,et al.Chronic stress and social housing differentially affect neurogenesis in male and female rats[J].Brain Res Bull,2004,64(4):303-8.
[67]Sapolsky R.M.The possibility of neurotoxicity in the hippocampus in major depression:a primer on neuron death[J].Biol Psychiatry,2000,48(8):755-65.
[68]Sapolsky R.M,Steinberg G.K.Gene therapy using viral vectors for acute neurologic insults[J].Neurology,1999,53(9):1922-31.
[69]Cameron H.A.,Woolley C.S.,Gould E.Adrenal steroid receptor immunoreactivity in cells born in the adult rat dentate gyrus[J].Brain Res,1993,611(2):342-6.
[70]Cameron H.A.,McEwen B.S.,Gould E.Regulation of adult neurogenesis by excitatory input and NMDA receptor activation in the dentate gyrus[J].J Neurosci,1995,15(6):4687-92.
[71]Reagan L.P.,McKittrick C.R.,McEwen B.S.Corticosterone and phenytoin reduce neuronal nitric oxide synthase messenger RNA expression in rat hippocampus[J].Neuroscience,1999,91(1):211-9.
[72]唐启盛．抑郁症[M]．北京：中国中医药出版社．2006．
[73]Moghaddam B.,Bolinao M.L.,Stein-Behrens B.,et al.Glucocorticoids mediate the stress-induced extracellular accumulation of glutamate[J].Brain Res,1994,655(1-2):251-4.
[74]Stein-Behrens B.A.,Elliott E.M.,Miller C.A.,et al.Glucocorticoids exacerbate kainic acid-induced extracellular accumulation of excitatory amino acids in the rat hippocampus[J].J Neurochem,1992,58(5):1730-5.
[75]Garthwaite J.,Charles S.L.,Chess-Williams R.Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain[J].Nature,1988,336(6197):385-8.
[76]Bolanos J.P.,Almeida A.Roles of nitric oxide in brain hypoxia-ischemia[J].Biochim Biophys Acta,1999,1411(2-3):415-36.
[77]Gursoy-Ozdemir Y.,Bolay H.,Saribas O.,et al.Role of endothelial nitric oxide generation and peroxynitrite formation in reperfusion injury after focal cerebral ischemia[J],Stroke,2000,31(8):1974-80;discussion 1981.
[78]Olivenza R.,Moro M.A.,Lizasoain I.,et al.Chronic stress induces the expression of inducible nitric oxide synthase in rat brain cortex[J].J Neurochem,2000,74(2):785-91.
[79]Stepien A.[The role of nitrogen oxide in migraine attack][J].Neurol Neurochir Pol,1999,33(2):435-44.
[80]Samdani A.R,Newcamp C,Resink A.,et al.Differential susceptibility to neurotoxicity mediated by neurotrophins and neuronal nitric oxide synthase[J].J Neurosci,1997,17(12):4633-41.
[81]Nacher J.,Rosell D.R.,Alonso-Llosa G.,et al.NMDA receptor antagonist treatment induces a long-lasting increase in the number of proliferating cells,PSA-NCAM-immunoreactive granule neurons and radial glia in the adult rat dentate gyrus[J].Eur J Neurosci,2001,13(3):512-20.
[82]Farah J.M.,Jr.,Rao T.S.,Mick S.J.,et al.N-methyl-D-aspartate treatment increases circulating adrenocorticotropin and luteinizing hormone in the rat[J].Endocrinology,1991,128(4):1875-80.
[83]Chautard T.,Boudouresque F.,Guillaume V.,et al.Effect of excitatory amino acid on the hypothalamo-pituitary-adrenal axis in the rat during the stress-hyporesponsive period[J].Neuroendocrinology,1993,57(1):70-8.
[84]Conner J.M.,Lauterborn J.C.,Yah Q.,et al.Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS:evidence for anterograde axonal transport[J].J Neurosci,1997,17(7):2295-313.
[85]Murua V.S.,Gomez R.A.,Andrea M.E.,et al.Shuttle-box deficits induced by chronic variable stress:reversal by imipramine administration[J].Pharmacol Biochem Behav,1991,38(I):125-30.
[86]Mertz K.,Koscheck T.,Schilling K.Brain-derived neurotrophic factor modulates dendritic morphology of cerebellar basket and stellate cells:an in vitro study[J].Neuroscience,2000,97(2):303-10.
[87]Brandoli C.,Sanna A.,De Bernardi M.A.,et al.Brain-derived neurotrophic factor and basic fibroblast growth factor downregulate NMDA receptor function in cerebellar granule cells[J].J Neurosci,1998,18(19):7953-61.
[88]Kokaia Z.,Othberg A.,Kokaia M.,et al.BDNF makes cultured dentate granule cells more resistant to hypoglycaemic damage[J].Neuroreport,1994,5(10):1241-4.
[89]Ueyama T.,Kawai Y.,Nemoto K.,et al.Immobilization stress reduced the expression of neurotrophins and their receptors in the rat brain[J].Neurosci Res,1997,28(2):103-10.
[90]Schaaf M.J.,De Kloet E.R.,Vreugdenhil E.Corticosterone effects on BDNF expression in the hippocampus.Implications for memory formation[J].Stress,2000,3(3):201-8.
[91]Nibuya M.,Takahashi M.,Russell D.S.,et al.Repeated stress increases catalytic TrkB mRNA in rat hippocampus[J].Neurosci Lett,1999,267(2):81-4.
[92]Tsukahara T.,Yonekawa Y.,Tanaka K.,et al.The role of brain-derived neurotrophic factor in transient forebrain ischemia in the rat brain[J].Neurosurgery,1994,34(2):323-31;discussion 331.
[93]吴志霞,姜乾金.近二十余年医学心理学应激模型发展[D].浙江省医学会心身医学分会成立大会暨2006年浙江省心身医学学术年会,2006.
[94]敖海清,徐志伟,严灿,et al.逍遥散对应激大鼠海马突触体内PKC活性及Ca^2+浓度的影响[J].山东中医杂志,2006,25(002):112-114.
[95]敖海清,徐志伟,严灿,et al.逍遥散对慢性应激大鼠海马突触体结构可塑性的影响[J].中成药,2006,28(005):697-700.
[96]徐志伟,敖海清,吴丽丽,et al.逍遥散对慢性心理应激损伤大鼠海马神经元的影响[J].中药药理与临床,2005,21(001),:5-9.
[97]敖海清,徐志伟,严灿,et al.柴胡疏肝散及逍遥散对慢性心理应激大鼠血清皮质酮及胃肠激素 的影响[J].中药新药与临床药理,2007,18(04):288-291.
[98]吴丽丽.运用肝主疏泄理论防治应激性抑郁症的基础研究[D].广州中医药大学,2006.
[99]严灿,徐志伟,李艳,et al.调肝、补肾、健脾方药对慢性心理应激大鼠单胺类神经递质影响的比较研究[J].中国中西医结合杂志,2002,22(12):925-928.
[100]严灿,吴丽丽,徐志伟,et al.加味四逆散对慢性束缚应激大鼠海马部分氨基酸含量的影响[J].中国病理生理杂志,2005,21(010):2032-2034.
[101]吴丽丽,严灿,丁胜元,et al.加味四逆散抗应激性抑郁效应及其海马NMDA受体通道机制的初步研究[J].国药理学通报,2007,23(011):1425-1431.
[102]严灿,徐忠伟,吴丽丽,et al.慢性心理应激大鼠下丘脑环核廿酸和不同脑区核团c-fos蛋白表达及加味四逆散的影响[J].中国行为医学科学,2005,14(003):196-198.
[103]吴丽丽,王文竹,严灿,et al.加味四逆散对慢性心理应激抑郁症大鼠海马损伤的保护作用[J].中医杂志,2008,49(004):353-355.
[104]李艳,严灿.反复心理应激大鼠血浆和下丘脑单胺神经递质的变化及加味四逆散的影响[J].中药药理与临床,2002,18(001):1-3.
[105]Benelli A.,Filaferro M.,Bertolini A.,et al.Influence of S-adenosyI-L-methionine on chronic mild stress-induced anhedonia in castrated rats[J].Br J Pharmacol,1999,127(3):645-54.
[106]Overmier J.B.,Seligman M.E.Effects of inescapable shock upon subsequent escape and avoidance responding[J].J Comp Physiol Psychol,1967,63(1):28-33.
[107]毛羽,安书成.应激抑郁症动物模型的神经机制及其评价[J].中华现代内科学杂志,2005,2(2):113-116.
[108]Willner P.,Towell A.,Sampson D.,et al.Reduction of sucrose preference by chronic unpredictable mild stress,and its restoration by a tricyclic antidepressant[J].Psychopharmacology(Berl),1987,93(3):358-64.
[109]Katz R.J.Animal models and human depressive disorders[J].Neurosci Biobehav Rev,1981,5(2):231-46.
[110]Papp M.,Willner R,Muscat R.An animal model of anhedonia:attenuation of sucrose consumption and place preference conditioning by chronic unpredictable mild stress[J].Psychopharmacology (Berl),1991,104(2):255-9.
[111]D'Aquila R S.,Newton J.,Willner P.Diurnal variation in the effect of chronic mild stress on sucrose intake and preference[J].Physiol Behav,1997,62(2):421-6.
[112]郑丽芳,明亮.抑郁症动物模型的研究与应用[J].安徽医药,2005,9(11):801-804.
[113]武丽,张丽萍.中医药对抑郁动物模型影响的研究现状[J].广西中医学院学报,2004,7(002):69-72.
[114]Fumagalli E,Molteni R.,Calabrese E,et al.Chronic fluoxetine administration inhibits extracellular signal-regulated kinase 1/2 phosphorylation in rat brain[J].J Neurochem,2005,93(6):1551-60.
[115]Porsolt R.D.,Le Pichon M.,Jalfre M.Depression:a new animal model sensitive to antidepressant treatments[J].Nature,1977,266(5604):730-2.
[116]李仲铭,徐成丽,朱广瑾.强迫游泳动物模型的研究进展[J].中国行为医学科学,2004,13(005):595-596.
[117]Lino-de-Oliveira C.,De Lima T.C.,de Padua Carobrez A.Structure of the rat behaviour in the forced swimming test[J].Behav Brain Res,2005,158(2):243-50.
[118]Vazquez-Palacios G.,Bonilla-Jaime H.,Velazquez-Moctezuma J.Antidepressant effects of nicotine and fluoxetine in an animal model of depression induced by neonatal treatment with clomipramine[J].Prog Neuropsychopharmacol Biol Psychiatry,2005,29(1):39-46.
[119]Willner P.Validation criteria for animal models of human mental disorders:learned helplessness as a paradigm case[J].Progress in neuro-psychopharmacology & biological psychiatry,1986,10(6):677-690.
[120]刘晓军,谭庆荣,王百忍,et al.氟西汀和阿米替林对大鼠强迫游泳中的行为结构及体质量的影响[J].中国行为医学科学,2006,15(005):420-422.
[121]诸葛启钏.大鼠脑立体定位图谱.北京:人民卫生出版社,2005.
[122]Henderson C.E.Role of neurotrophic factors in neuronal development[J].Curr Opin Neurobiol,1996,6(1):64-70.
[123]Kempermann G.,Kuhn H.G.,Gage F.H.Experience-induced neurogenesis in the senescent dentate gyrus[J].J Neurosci,1998,18(9):3206-12.
[124]Eisch A.J.,Barrot M.,Schad C.A.,et al.Opiates inhibit neurogenesis in the adult rat hippocampus[J].Proc Natl Acad Sci U S A,2000,97(13):7579-84.
[125]蔡文琴,李海标.发育神经生物学:生命科学专论[M].北京:科学出版社,1999.
[126]Ciaroni S.,Cecchini T.,Ferri P.,et al.Impairment of neural precursor proliferation increases survival of cell progeny in the adult rat dentate gyrus[J].Mech Ageing Dev,2002,123(10):1341-52.
[127]Barde Y.A.,Edgar D.,Thoenen H.Purification of a new neurotrophic factor from mammalian brain[J].The EMBO Journal,1982,I(5):549.
[128]Von Bartheld C.S.,Johnson J.E.Target-derived BDNF(brain-derived neurotrophic factor) is essential for the survival of developing neurons in the isthmo-optic nucleus[J].J Comp Neurol,2001,433(4):550-64.
[129]Deiksson N.P.,Aldskogius H.,Grant E Effects ofNGF,BDNF and NT-3 on the laminar distribution of transganglioncally transported cholerafemoid in the spinal cord dorsal horn following transaction of the sciatic nerve in the adult rat[J].Neurosci,1997,78(867-872.
[130]Huang E.J.,Reichardt L.F.Neurotrophins:roles in neuronal development and function[J].Annu Rev Neurosci,2001,24(1):677-736.
[131]Duman R.S.,Heninger G.R.,Nestler E.J.A molecular and cellular theory of depression[J].Arch Gen Psychiatry,1997,54(7):597-606.
[132]Smith M.A.,Makino S.,Kvetnansky R.,et al.Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus[J].J Neurosci,1995,15(3 Pt 1):1768-77.
[133]Russo-Neustadt A.,Ha T.,Ramirez R.,et al.Physical activity-antidepressant treatment combination:impact on brain-derived neurotrophic factor and behavior in an animal model[J].Behavioural brain research,2001,120(1 ):87-95.
[134]Anderson A.,Su J.,Cotman C.DNA damage and apoptosis in Alzheimer's disease:colocalization with c-Jun immunoreactivity,relationship to brain area,and effect of postmortem delay[J].Journal of Neuroscience,1996,16(5):1710-1719.
[135]李学礼,李艳娜,吕立夏,et al.BDNF对诱导分化的SH-SY5Y细胞G1期相关蛋自表达的影响[J].神经解剖学杂志,2006,22(001):71-76.
[136]Encinas M.,Iglesias M.,Liu Y.,et al.Sequential treatment of SH-SY5Y cells with retinoic acid and brain-derived neurotrophic factor gives rise to fully differentiated,neurotrophic factor-dependent,human neuron-like cells[J].Journal of neurochemistry,2000,75(3):991.
[137]Montminy M.,Bilezikjian L.Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene[J].Nature,1987,328(6126):175-178.
[138]Yamamoto K.,Gonzalez G.,Biggs W.,et al.Phosphorylation-induced binding and transcriptional efficacy of nuclear factor CREB[J],1988.
[139]陈秋萍,张励才,王曙,et al.慢性吗啡依赖和戒断对大鼠远位触液神经元环腺苷酸反应元件结合蛋自表达的影响[J].解剖学报,2008,39(006):800-803.
[140]Nakagawa S.,Kim J.E.,Lee R.,et al.Regulation of neurogenesis in adult mouse hippocampus by cAMP and the cAMP response element-binding protein[J].J Neurosci,2002,22(9):3673-82.
[141]卢峻,时宇静,费宇彤,et al.电针对抑郁症模型大鼠脑磷酸化cAMP反应元件结合蛋白表达的影响[J].中国中医基础医学杂志,2006,12(005):380-382.
[142]Tao X.,Finkbeiner S.,Arnold D.,et al.Ca Influx Regulates BDNF Transcription by a CREB Family Transcription Factor-Dependent Mechanism[J].Neuron,1998,20(4):709-726.
[143]Gottlicher M.,Heck S.,Herrlich P.Transcriptional cross-talk,the second mode of steroid hormone receptor action[J].J Mol Med,1998,76(7):480-9.
[144]Isokawa M.N-methyl-D-aspartic acid-induced and Ca-dependent neuronal swelling and its retardation by brain-derived neurotrophic factor in the epileptic hippoeampus[J].Neuroscience,2005,131(4):801-12.
[145]戴海斌.组胺及其受体对NMDA受体介导的神经元毒性作用机制研究[D].浙江大学.
[146]亓晓丽,姚树桥.应激与海马可塑性及其机制的研究进展[J].中国行为医学科学,2003,12(003):356-359.
[2]Lowenstein D.H.,Parent J.M.Brain,heal thyself[J].Science,1999,283(5405):1126-7.
[3]Altman J.Are new neurons formed in the brains of adult mammals?[J].Science,1962,135(1127-8.
[4]Airman J.,Das G.D.Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats[J].J Comp Neurol,1965,124(3):319-35.
[5]Reynolds B.A.,Weiss S.Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system[J].Science,1992,255(5052):1707-10.
[6]Eriksson P.S.,Perfilieva E.,Bjork-Eriksson T.,et al.Neurogenesis in the adult human hippocampus[J].Nat Med,1998,4(11 ):1313-7.
[7]范晓棠.Noggin与BMP4在大鼠中枢神经系统的发育学表达及与学习记忆的相关性研究[D].第三军医大学,2002.
[8]Carleton A.,Petreanu L.T.,Lansford R.,et al.Becoming a new neuron in the adult olfactory bulb[J[.Nat Neurosci,2003,6(5):507-18.
[9]Shors T.J.,Miesegaes G.,Beylin A.,et al.Neurogenesis in the adult is involved in the formation of trace memories[J].Nature,2001,410(6826):372-6.
[10]van Praag H.,Schinder A.F.,Christie B.R.,et al.Functional neurogenesis in the adult hippocampus[J].Nature,2002,415(6875):1030-4.
[11]Iwai M.,Sato K.,Omori N.,et al.Three steps of neural stem cells development in gerbil dentate gyrus after transient ischemia[J].J Cereb Blood Flow Metab,2002,22(4):411-9.
[12]Matsumura N.,Yoshida N.,Ohta A.,et al.Neural precursor cells from adult mouse cerebral cortex differentiate into both neurons and oligodendrocytes[J].Cytotechnology,2003,43(1-3):19-25.
[13]Nunes M.C.,Roy N.S.,Keyoung H.M.,et al.Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain[J].Nat Med,2003,9(4):439-47.
[14]Laplagne D.A.,Esposito M.S.,Piatti V.C.,et al.Functional convergence of neurons generated in the developing and adult hippocarnpus[J].PLoS Biol,2006,4(12):e409.
[15]姬西团,章翔,费舟,et al.EG F'bFG F,NGF.RA对小鼠神经干细胞定向分化的调控[J].中华神经医学杂志,2005,4(006):556-559.
[16]Chen J.,Zacharek A.,Zhang C.,et al.Endothelial nitric oxide synthase regulates brain-derived neurotrophic factor expression and neurogenesis after stroke in mice[J].J Neurosci,2005,25(9):2366-75.
[17]王细林,曾庆杏,陈迎春.N-Methyl-D-Aspartate受体拮抗剂对脑缺血后成年大鼠神经干细胞 内源性激活的实验研究[J].中风与神经疾病杂志,2005,22(002):121-124.
[18]袁固艳,任铭新,张新.MK-801的浓度与局灶性脑缺血大鼠内源性神经干细胞增殖的关系[J].医学信息手术学分册,2006,19(2):51-54.
[19]Scharfman H.E.,Hen R.Neuroscience.Is more neurogenesis always better?[J].Science,2007,315(5810):336-8.
[20]陈迎春,曾庆杏,段申汉,et al.雌激素对大鼠脑缺血再灌注神经干细胞内源性激活的实验研究[J].卒中与神经疾病,2005,12(005):265-268.
[21]陆澄秋,钟乐,颜崇淮,et al.丰富环境对神经发生影响的研究进展[J].国际神经病学神经外科学杂志,2007,34(05):474-477.
[22]Raballo R.,Rhee J.,Lyn-Cook R.,et al.Basic fibroblast growth factor(Fgf2) is necessary for cell proliferation and neurogenesis in the developing cerebral cortex[J].J Neurosci,2000,20(13):5012-23.
[23]Tropepe V.,Sibilia M.,Ciruna B.G.,et al.Distinct neural stem cells proliferate in response to EGF and FGF in the developing mouse telencephalon[J].Dev Biol,1999,208(1):166-88.
[24]Kalyani A.,Hobson K.,Rao M.S.Neuroepithelial stem cells from the embryonic spinal cord:isolation,characterization,and clonal analysis[J].Dev Biol,1997,186(2):202-23.
[25]Gritti A.,Frolichsthal-Schoeller P.,Galli R.,et al.Epidermal and fibroblast growth factors behave as mitogenic regulators for a single multipotent stem cell-like population from the subventricular region of the adult mouse forebrain[J].J Neurosci,1999,19(9):3287-97.
[26]Haydar Y.F.,Wang F.,Schwartz M.L.,et al.Differential modulation of proliferation in the neocortical ventricular and subventricular zones[J].J Neurosci,2000,20(15):5764-74.
[27]李学坤,左萍萍.成体哺乳动物脑内的神经发生及其调节[J].中国康复理论与实践,2003,9(007):401-404.
[28]Morrison S.J.,Perez S.E.,Qiao Z.,et al.Transient Notch activation initiates an irreversible switch from neurogenesis to gliogenesis by neural crest stem cells[J].Cell,2000,101(5):499-510.
[29]Ohlsson A.L.,Johansson B.B.Environment influences functional outcome of cerebral infarction in rats[J].Stroke,1995,26(4):644-9.
[30]Song H.,Stevens C.E,Gage F.H.Astroglia induce neurogenesis from adult neural stem cells[J].Nature,2002,417(6884):39-44.
[31]Lauder J.M.Ontogeny of the serotonergic system in the rat:serotonin as a developmental signal[J].Ann N Y Acad Sci,1990,600(297-313;discussion 314.
[32]Kempermann G.,Kuhn H.G.,Gage F.H.Genetic influence on neurogenesis in the dentate gyrus of adult mice[J].Proc Natl Acad Sci U S A,1997,94(19):10409-14.
[33]Kornack D.R.,Rakic P.Continuation of neurogenesis in the hippocampus of the adult macaque monkey[J].Proe Natl Acad Sci U S A,1999,96(10):5768-73.
[34]Kuhn H.G.,Dickinson-Anson H.,Gage F.H.Neurogenesis in the dentate gyrus of the adult rat:age-related decrease of neuronal progenitor proliferation[J].J Neurosci,1996,16(6):2027-33.
[35]Yoshimura S.,Takagi Y.,Harada J.,et al.FGF-2 regulation of neurogenesis in adult hippocampus after brain injury[J].Proc Natl Acad Sci U S A,2001,98(10):5874-9.
[36]Jin K.,Zhu Y.,Sun Y.,et al.Vascular endothelial growth factor(VEGF) stimulates neurogenesis in vitro and in vivo[J].Proc Natl Acad Sci U S A,2002,99(18):11946-50.
[37]Aberg M.A.,Aberg N.D.,Hedbacker H.,et al.Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus[J].J Neurosci,2000,20(8):2896-903.
[38]Gross C.G.Brain,Vision,Memory:Tales in the History of Neuroscience[M].Cambridge,MA:MIT Press,1999.
[39]Miller D.B.,O'Callaghan J.P.Aging,stress and the hippocampus[J].Ageing Res Rev,2005,4(2):123-40.
[40]Cameron H.A.,McKay R.D.Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus[J].J Comp Neurol,2001,435(4):406-17.
[41]关新民.医学神经生物学[M].北京:人民卫生出版社,2002:360.
(42]肖献忠.病理生理学[M].全国高等学校医学规划教材,北京:高等教育出版社,2004.
[43]杨权.下丘脑-垂体-肾上腺皮质轴应激反应的中枢控制[J].生理科学进展,2000,31(03):222-226.
[44]McEwen B.S.Stress and hippocampal plasticity[J].Annu Rev Neurosci,1999,22(105-22.
[45]McEwen B.S.Effects of adverse experiences for brain structure and function[J].Biol Psychiatry,2000,48(8):721-31.
[46]Gould E.,Tanapat P.,Rydel T.,et al.Regulation of hippocampal neurogenesis in adulthood[J].Biol Psychiatry,2000,48(8):715-20.
[47]Panegyres P.K.The contribution of the study of neurodegenerative disorders to the understanding of human memory[J].QJM,2004,97(9):555-67.
[48]Herman J.P.,Cullinan W.E.,Morano M.I.,et al.Contribution of the ventral subiculum to inhibitory regulation of the hypothalamo-pituitary-adrenocortical axis[J].J Neuroendocrinol,1995,7(6):475-82.
[49]Jacobson L.,Sapolsky R.The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis[J].Endocr Rev,1991,12(2):118-34.
[50]McKittrick C.R.,Magarinos A.M.,Blanchard D.C.,et al.Chronic social stress reduces dendritic arbors in CA3 of hippocampus and decreases binding to serotonin transporter sites[J].Synapse,2000,36(2):85-94.
[51]连晓媛,张均田,包天桐.海马与下丘脑-垂体-肾上腺轴功能调节[J].国外医学.内分泌学分册,1998,18(04):169-172.
[52]Weidenfeld J.,Feldman S.Glucocorticoid feedback regulation of adrenocortical responses to neural stimuli:role of CRF-41 and corticosteroid type I and type Ⅱ receptors[J].Neuroendocrinology,1993,58(1):49-56.
[53]Brooke S.M.,de Haas-Johnson A.M,Kaplan J.R.,et al.Dexamethasone resistance among nonhuman primates associated with a selective decrease of glucocorticoid receptors in the hippocampus and a history of social instability[J].Neuroendocrinology,1994,60(2):134-40.
[54]Brown E.S.,D J.W.,Frol A.,et al.Hippocampal volume,spectroscopy,cognition,and mood in patients receiving corticosteroid therapy[J].Biol Psychiatry,2004,55(5):538-45.
[55]Wilner A.P.,de Varennes B? Gregoire P.A.,et al.Glucocorticoids and hippocampal atrophy after heart transplantation[J].Ann Thorac Surg,2002,73(6):1965-7.
[56]McEwen B.S.,Magarinos A.M.Stress effects on morphology and function of the hippocampus[J].Ann N Y Acad Sci,1997,821 (271-84.
[57]Sousa N.,Lukoyanov N.V.,Madeira M.D.,et al.Erratum to “Reorganization of the morphology of hippocampal neurites and synapses after stress-induced damage correlates with behavioral improvement”[J].Neuroscience,2000,101(2):483.
[58]Duman R.S.,Malberg J.,Thome J.Neural plasticity to stress and antidepressant treatment[J].Biol Psychiatry,1999,46(9):1181-91.
[59]Gould E.,Tanapat P.Stress and hippocampal neurogenesis[J].Biol Psychiatry,1999,46(11):1472-9.
[60]Kerr J.F.,Wyllie A.H.,Currie A.R.Apoptosis:a basic biological phenomenon with wide-ranging implications in tissue kinetics[J].Br J Cancer,1972,26(4):239-57.
[61]Lucassen P.J.,Vollmann-Honsdorf G.K.,Gleisberg M.,et al.Chronic psychosocial stress differentially affects apoptosis in hippocampal subregions and cortex of the adult tree shrew[J].Eur J Neurosci,2001,14(1):161-6.
[62]Lucassen P.J.,Muller M.B.,Holsboer F.,et al.Hippocampal apoptosis in major depression is a minor event and absent from subareas at risk for glucocorticoid overexposure[J].Am J Pathol,2001,158(2):453-68.
[63]Zhang L.,Kokkonen G.,Roth G.S.Identification of neuronal programmed cell death in situ in the striatum of normal adult rat brain and its relationship to neuronal death during aging[J].Brain Res,1995,677(1):177-9.
[64]Czeh B.,Welt T.,Fischer A.K.,et al.Chronic psychosocial stress and concomitant repetitive transcranial magnetic stimulation:effects on stress hormone levels and adult hippocampal neurogenesis[J].Biol Psychiatry,2002,52(11):1057-65.
[65]Pham K.,Nacher J.,Hof P.R.,et al.Repeated restraint stress suppresses neurogenesis and induces biphasic PSA-NCAM expression in the adult rat dentate gyrus[J].Eur J Neurosci,2003,17(4):879-86.
[66]Westenbroek C,Den Boer J.A.,Veenhuis M.,et al.Chronic stress and social housing differentially affect neurogenesis in male and female rats[J].Brain Res Bull,2004,64(4):303-8.
[67]Sapolsky R.M.The possibility of neurotoxicity in the hippocampus in major depression:a primer on neuron death[J].Biol Psychiatry,2000,48(8):755-65.
[68]Sapolsky R.M,Steinberg G.K.Gene therapy using viral vectors for acute neurologic insults[J].Neurology,1999,53(9):1922-31.
[69]Cameron H.A.,Woolley C.S.,Gould E.Adrenal steroid receptor immunoreactivity in cells born in the adult rat dentate gyrus[J].Brain Res,1993,611(2):342-6.
[70]Cameron H.A.,McEwen B.S.,Gould E.Regulation of adult neurogenesis by excitatory input and NMDA receptor activation in the dentate gyrus[J].J Neurosci,1995,15(6):4687-92.
[71]Reagan L.P.,McKittrick C.R.,McEwen B.S.Corticosterone and phenytoin reduce neuronal nitric oxide synthase messenger RNA expression in rat hippocampus[J].Neuroscience,1999,91(1):211-9.
[72]唐启盛．抑郁症[M]．北京：中国中医药出版社．2006．
[73]Moghaddam B.,Bolinao M.L.,Stein-Behrens B.,et al.Glucocorticoids mediate the stress-induced extracellular accumulation of glutamate[J].Brain Res,1994,655(1-2):251-4.
[74]Stein-Behrens B.A.,Elliott E.M.,Miller C.A.,et al.Glucocorticoids exacerbate kainic acid-induced extracellular accumulation of excitatory amino acids in the rat hippocampus[J].J Neurochem,1992,58(5):1730-5.
[75]Garthwaite J.,Charles S.L.,Chess-Williams R.Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain[J].Nature,1988,336(6197):385-8.
[76]Bolanos J.P.,Almeida A.Roles of nitric oxide in brain hypoxia-ischemia[J].Biochim Biophys Acta,1999,1411(2-3):415-36.
[77]Gursoy-Ozdemir Y.,Bolay H.,Saribas O.,et al.Role of endothelial nitric oxide generation and peroxynitrite formation in reperfusion injury after focal cerebral ischemia[J],Stroke,2000,31(8):1974-80;discussion 1981.
[78]Olivenza R.,Moro M.A.,Lizasoain I.,et al.Chronic stress induces the expression of inducible nitric oxide synthase in rat brain cortex[J].J Neurochem,2000,74(2):785-91.
[79]Stepien A.[The role of nitrogen oxide in migraine attack][J].Neurol Neurochir Pol,1999,33(2):435-44.
[80]Samdani A.R,Newcamp C,Resink A.,et al.Differential susceptibility to neurotoxicity mediated by neurotrophins and neuronal nitric oxide synthase[J].J Neurosci,1997,17(12):4633-41.
[81]Nacher J.,Rosell D.R.,Alonso-Llosa G.,et al.NMDA receptor antagonist treatment induces a long-lasting increase in the number of proliferating cells,PSA-NCAM-immunoreactive granule neurons and radial glia in the adult rat dentate gyrus[J].Eur J Neurosci,2001,13(3):512-20.
[82]Farah J.M.,Jr.,Rao T.S.,Mick S.J.,et al.N-methyl-D-aspartate treatment increases circulating adrenocorticotropin and luteinizing hormone in the rat[J].Endocrinology,1991,128(4):1875-80.
[83]Chautard T.,Boudouresque F.,Guillaume V.,et al.Effect of excitatory amino acid on the hypothalamo-pituitary-adrenal axis in the rat during the stress-hyporesponsive period[J].Neuroendocrinology,1993,57(1):70-8.
[84]Conner J.M.,Lauterborn J.C.,Yah Q.,et al.Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS:evidence for anterograde axonal transport[J].J Neurosci,1997,17(7):2295-313.
[85]Murua V.S.,Gomez R.A.,Andrea M.E.,et al.Shuttle-box deficits induced by chronic variable stress:reversal by imipramine administration[J].Pharmacol Biochem Behav,1991,38(I):125-30.
[86]Mertz K.,Koscheck T.,Schilling K.Brain-derived neurotrophic factor modulates dendritic morphology of cerebellar basket and stellate cells:an in vitro study[J].Neuroscience,2000,97(2):303-10.
[87]Brandoli C.,Sanna A.,De Bernardi M.A.,et al.Brain-derived neurotrophic factor and basic fibroblast growth factor downregulate NMDA receptor function in cerebellar granule cells[J].J Neurosci,1998,18(19):7953-61.
[88]Kokaia Z.,Othberg A.,Kokaia M.,et al.BDNF makes cultured dentate granule cells more resistant to hypoglycaemic damage[J].Neuroreport,1994,5(10):1241-4.
[89]Ueyama T.,Kawai Y.,Nemoto K.,et al.Immobilization stress reduced the expression of neurotrophins and their receptors in the rat brain[J].Neurosci Res,1997,28(2):103-10.
[90]Schaaf M.J.,De Kloet E.R.,Vreugdenhil E.Corticosterone effects on BDNF expression in the hippocampus.Implications for memory formation[J].Stress,2000,3(3):201-8.
[91]Nibuya M.,Takahashi M.,Russell D.S.,et al.Repeated stress increases catalytic TrkB mRNA in rat hippocampus[J].Neurosci Lett,1999,267(2):81-4.
[92]Tsukahara T.,Yonekawa Y.,Tanaka K.,et al.The role of brain-derived neurotrophic factor in transient forebrain ischemia in the rat brain[J].Neurosurgery,1994,34(2):323-31;discussion 331.
[93]吴志霞,姜乾金.近二十余年医学心理学应激模型发展[D].浙江省医学会心身医学分会成立大会暨2006年浙江省心身医学学术年会,2006.
[94]敖海清,徐志伟,严灿,et al.逍遥散对应激大鼠海马突触体内PKC活性及Ca^2+浓度的影响[J].山东中医杂志,2006,25(002):112-114.
[95]敖海清,徐志伟,严灿,et al.逍遥散对慢性应激大鼠海马突触体结构可塑性的影响[J].中成药,2006,28(005):697-700.
[96]徐志伟,敖海清,吴丽丽,et al.逍遥散对慢性心理应激损伤大鼠海马神经元的影响[J].中药药理与临床,2005,21(001),:5-9.
[97]敖海清,徐志伟,严灿,et al.柴胡疏肝散及逍遥散对慢性心理应激大鼠血清皮质酮及胃肠激素 的影响[J].中药新药与临床药理,2007,18(04):288-291.
[98]吴丽丽.运用肝主疏泄理论防治应激性抑郁症的基础研究[D].广州中医药大学,2006.
[99]严灿,徐志伟,李艳,et al.调肝、补肾、健脾方药对慢性心理应激大鼠单胺类神经递质影响的比较研究[J].中国中西医结合杂志,2002,22(12):925-928.
[100]严灿,吴丽丽,徐志伟,et al.加味四逆散对慢性束缚应激大鼠海马部分氨基酸含量的影响[J].中国病理生理杂志,2005,21(010):2032-2034.
[101]吴丽丽,严灿,丁胜元,et al.加味四逆散抗应激性抑郁效应及其海马NMDA受体通道机制的初步研究[J].国药理学通报,2007,23(011):1425-1431.
[102]严灿,徐忠伟,吴丽丽,et al.慢性心理应激大鼠下丘脑环核廿酸和不同脑区核团c-fos蛋白表达及加味四逆散的影响[J].中国行为医学科学,2005,14(003):196-198.
[103]吴丽丽,王文竹,严灿,et al.加味四逆散对慢性心理应激抑郁症大鼠海马损伤的保护作用[J].中医杂志,2008,49(004):353-355.
[104]李艳,严灿.反复心理应激大鼠血浆和下丘脑单胺神经递质的变化及加味四逆散的影响[J].中药药理与临床,2002,18(001):1-3.
[105]Benelli A.,Filaferro M.,Bertolini A.,et al.Influence of S-adenosyI-L-methionine on chronic mild stress-induced anhedonia in castrated rats[J].Br J Pharmacol,1999,127(3):645-54.
[106]Overmier J.B.,Seligman M.E.Effects of inescapable shock upon subsequent escape and avoidance responding[J].J Comp Physiol Psychol,1967,63(1):28-33.
[107]毛羽,安书成.应激抑郁症动物模型的神经机制及其评价[J].中华现代内科学杂志,2005,2(2):113-116.
[108]Willner P.,Towell A.,Sampson D.,et al.Reduction of sucrose preference by chronic unpredictable mild stress,and its restoration by a tricyclic antidepressant[J].Psychopharmacology(Berl),1987,93(3):358-64.
[109]Katz R.J.Animal models and human depressive disorders[J].Neurosci Biobehav Rev,1981,5(2):231-46.
[110]Papp M.,Willner R,Muscat R.An animal model of anhedonia:attenuation of sucrose consumption and place preference conditioning by chronic unpredictable mild stress[J].Psychopharmacology (Berl),1991,104(2):255-9.
[111]D'Aquila R S.,Newton J.,Willner P.Diurnal variation in the effect of chronic mild stress on sucrose intake and preference[J].Physiol Behav,1997,62(2):421-6.
[112]郑丽芳,明亮.抑郁症动物模型的研究与应用[J].安徽医药,2005,9(11):801-804.
[113]武丽,张丽萍.中医药对抑郁动物模型影响的研究现状[J].广西中医学院学报,2004,7(002):69-72.
[114]Fumagalli E,Molteni R.,Calabrese E,et al.Chronic fluoxetine administration inhibits extracellular signal-regulated kinase 1/2 phosphorylation in rat brain[J].J Neurochem,2005,93(6):1551-60.
[115]Porsolt R.D.,Le Pichon M.,Jalfre M.Depression:a new animal model sensitive to antidepressant treatments[J].Nature,1977,266(5604):730-2.
[116]李仲铭,徐成丽,朱广瑾.强迫游泳动物模型的研究进展[J].中国行为医学科学,2004,13(005):595-596.
[117]Lino-de-Oliveira C.,De Lima T.C.,de Padua Carobrez A.Structure of the rat behaviour in the forced swimming test[J].Behav Brain Res,2005,158(2):243-50.
[118]Vazquez-Palacios G.,Bonilla-Jaime H.,Velazquez-Moctezuma J.Antidepressant effects of nicotine and fluoxetine in an animal model of depression induced by neonatal treatment with clomipramine[J].Prog Neuropsychopharmacol Biol Psychiatry,2005,29(1):39-46.
[119]Willner P.Validation criteria for animal models of human mental disorders:learned helplessness as a paradigm case[J].Progress in neuro-psychopharmacology & biological psychiatry,1986,10(6):677-690.
[120]刘晓军,谭庆荣,王百忍,et al.氟西汀和阿米替林对大鼠强迫游泳中的行为结构及体质量的影响[J].中国行为医学科学,2006,15(005):420-422.
[121]诸葛启钏.大鼠脑立体定位图谱.北京:人民卫生出版社,2005.
[122]Henderson C.E.Role of neurotrophic factors in neuronal development[J].Curr Opin Neurobiol,1996,6(1):64-70.
[123]Kempermann G.,Kuhn H.G.,Gage F.H.Experience-induced neurogenesis in the senescent dentate gyrus[J].J Neurosci,1998,18(9):3206-12.
[124]Eisch A.J.,Barrot M.,Schad C.A.,et al.Opiates inhibit neurogenesis in the adult rat hippocampus[J].Proc Natl Acad Sci U S A,2000,97(13):7579-84.
[125]蔡文琴,李海标.发育神经生物学:生命科学专论[M].北京:科学出版社,1999.
[126]Ciaroni S.,Cecchini T.,Ferri P.,et al.Impairment of neural precursor proliferation increases survival of cell progeny in the adult rat dentate gyrus[J].Mech Ageing Dev,2002,123(10):1341-52.
[127]Barde Y.A.,Edgar D.,Thoenen H.Purification of a new neurotrophic factor from mammalian brain[J].The EMBO Journal,1982,I(5):549.
[128]Von Bartheld C.S.,Johnson J.E.Target-derived BDNF(brain-derived neurotrophic factor) is essential for the survival of developing neurons in the isthmo-optic nucleus[J].J Comp Neurol,2001,433(4):550-64.
[129]Deiksson N.P.,Aldskogius H.,Grant E Effects ofNGF,BDNF and NT-3 on the laminar distribution of transganglioncally transported cholerafemoid in the spinal cord dorsal horn following transaction of the sciatic nerve in the adult rat[J].Neurosci,1997,78(867-872.
[130]Huang E.J.,Reichardt L.F.Neurotrophins:roles in neuronal development and function[J].Annu Rev Neurosci,2001,24(1):677-736.
[131]Duman R.S.,Heninger G.R.,Nestler E.J.A molecular and cellular theory of depression[J].Arch Gen Psychiatry,1997,54(7):597-606.
[132]Smith M.A.,Makino S.,Kvetnansky R.,et al.Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus[J].J Neurosci,1995,15(3 Pt 1):1768-77.
[133]Russo-Neustadt A.,Ha T.,Ramirez R.,et al.Physical activity-antidepressant treatment combination:impact on brain-derived neurotrophic factor and behavior in an animal model[J].Behavioural brain research,2001,120(1 ):87-95.
[134]Anderson A.,Su J.,Cotman C.DNA damage and apoptosis in Alzheimer's disease:colocalization with c-Jun immunoreactivity,relationship to brain area,and effect of postmortem delay[J].Journal of Neuroscience,1996,16(5):1710-1719.
[135]李学礼,李艳娜,吕立夏,et al.BDNF对诱导分化的SH-SY5Y细胞G1期相关蛋自表达的影响[J].神经解剖学杂志,2006,22(001):71-76.
[136]Encinas M.,Iglesias M.,Liu Y.,et al.Sequential treatment of SH-SY5Y cells with retinoic acid and brain-derived neurotrophic factor gives rise to fully differentiated,neurotrophic factor-dependent,human neuron-like cells[J].Journal of neurochemistry,2000,75(3):991.
[137]Montminy M.,Bilezikjian L.Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene[J].Nature,1987,328(6126):175-178.
[138]Yamamoto K.,Gonzalez G.,Biggs W.,et al.Phosphorylation-induced binding and transcriptional efficacy of nuclear factor CREB[J],1988.
[139]陈秋萍,张励才,王曙,et al.慢性吗啡依赖和戒断对大鼠远位触液神经元环腺苷酸反应元件结合蛋自表达的影响[J].解剖学报,2008,39(006):800-803.
[140]Nakagawa S.,Kim J.E.,Lee R.,et al.Regulation of neurogenesis in adult mouse hippocampus by cAMP and the cAMP response element-binding protein[J].J Neurosci,2002,22(9):3673-82.
[141]卢峻,时宇静,费宇彤,et al.电针对抑郁症模型大鼠脑磷酸化cAMP反应元件结合蛋白表达的影响[J].中国中医基础医学杂志,2006,12(005):380-382.
[142]Tao X.,Finkbeiner S.,Arnold D.,et al.Ca Influx Regulates BDNF Transcription by a CREB Family Transcription Factor-Dependent Mechanism[J].Neuron,1998,20(4):709-726.
[143]Gottlicher M.,Heck S.,Herrlich P.Transcriptional cross-talk,the second mode of steroid hormone receptor action[J].J Mol Med,1998,76(7):480-9.
[144]Isokawa M.N-methyl-D-aspartic acid-induced and Ca-dependent neuronal swelling and its retardation by brain-derived neurotrophic factor in the epileptic hippoeampus[J].Neuroscience,2005,131(4):801-12.
[145]戴海斌.组胺及其受体对NMDA受体介导的神经元毒性作用机制研究[D].浙江大学.
[146]亓晓丽,姚树桥.应激与海马可塑性及其机制的研究进展[J].中国行为医学科学,2003,12(003):356-359.