Lhx8在海马胆碱能神经再生中所起作用的初步研究
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摘要
LIM同源盒基因8（LIM homeobox8, Lhx8）与胚胎基底前脑胆碱能神经元的发育有关，但Lhx8在中枢胆碱能神经再生及海马齿状回胆碱能神经再生过程中所起的作用尚未见到报道，本研究主要探讨Lhx8在海马胆碱能神经再生中所起的作用。
一．目的：
体外培养大鼠海马源性放射状胶质细胞（Radial glia cells, RGCs），观察并检测海马提取液在RGCs增殖和向胆碱能神经元分化过程中所发挥的效用；构建Lhx8过表达载体并经慢病毒包装，转染至体外培养的RGCs，同时注入大鼠海马齿状回中，对Lhx8在海马胆碱能神经再生过程中所起的作用进行初步的探讨。
二．方法：
（1）切割大鼠右侧穹窿海马伞并且制备正常侧及切割侧海马提取液；
（2）体外培养海马源性RGCs，在培养液中加入正常侧及切割侧海马提取液，观察海马提取液对RGCs增殖和向神经元分化方面的作用；
（3）联合应用海马提取液及NGF共同促进海马RGCs向胆碱能神经元分化，观察Lhx8在ChAT阳性的神经元中的表达和定位；
（4）克隆Lhx8cDNA序列，构建pLenti6.3-Lhx8-IRES2-EGFP表达载体并经慢病毒包装，将收集的慢病毒Lenti6.3-Lhx8转染RGCs，观察RGCs向胆碱能神经元分化的情况，检测Lhx8和ChAT的基因及蛋白的表达变化；
（5）将慢病毒Lenti6.3-Lhx8注入正常侧及切割穹窿海马伞侧大鼠海马齿状回中，观察正常侧及切割侧海马齿状回中ChAT阳性的胆碱能神经元的表达和定位，检测Lhx8和ChAT的基因及蛋白的表达变化。
三．结果：
（1） RGCs具有典型的双突起形态学特征，同时可表达胶质相关标记物BLBP、GFAP、Vimentin，并且这些胶质相关标记物能与干细胞相关标记物Nestin进行双标，此外RGCs还能够分化为神经元、星形胶质细胞以及少突胶质细胞；
（2）切割穹窿海马伞侧的海马提取液能够明显促进RGCs的增殖和向神经元分化；切割侧海马提取液联合NGF能够促进RGCs向ChAT阳性的胆碱能神经元分化，这些ChAT阳性的胆碱能神经元能够表达Lhx8；
（3） RGCs转染慢病毒Lenti6.3-Lhx8后，分化为MAP2阳性神经元的总体数目没有明显增加，但是能够提高ChAT阳性细胞在MAP2阳性神经元中所占的比例，Lhx8和ChAT的基因及蛋白的表达量也明显增高，说明转染慢病毒Lenti6.3-Lhx8后，能够促进RGCs向胆碱能神经元分化；
（4）在正常海马齿状回中注入慢病毒Lenti6.3-Lhx8后，能够明显提高齿状回内ChAT/Lhx8阳性的胆碱能神经元数量；切割穹窿海马伞并联合慢病毒注射后，发现齿状回内ChAT/Lhx8阳性的胆碱能神经元的数量增加更为明显，Lhx8和ChAT的基因及蛋白的表达量也明显增高，说明切割穹窿海马伞并且联合应用Lenti6.3-Lhx8慢病毒可以明显地促进海马内的胆碱能神经再生水平。
四．结论：
（1）体外培养的海马源性RGCs具有典型的双突起形态学特征，这些细胞能够同时表达胶质细胞相关标记物和干细胞相关标记物。体外应用切割穹窿海马伞侧海马提取液能够较好的模拟切割穹窿海马伞后的海马再生微环境。在RGCs扩增培养阶段切割侧海马提取液能明显地促进RGCs增殖，而在RGCs分化阶段切割侧海马提取液也能够促进RGCs更多地向神经元分化；
（2）慢病毒Lenti6.3-Lhx8能够促进体外培养的海马源性RGCs向胆碱能神经元分化，但对RGCs分化产生的神经元总体数量没有影响。Lhx8作为LIM同源盒基因家族成员，仅在神经元胆碱能表型确立方面起到作用，而不能促进体外培养的海马源性RGCs更多地向神经元分化；
（3）慢病毒Lenti6.3-Lhx8注入海马齿状回后，齿状回ChAT阳性胆碱能神经元的数量与正常海马比较明显增多。在切割穹窿海马伞侧的海马齿状回中注入慢病毒Lenti6.3-Lhx8后，发现ChAT阳性的神经元数量增加更为明显，说明LIM同源盒基因家族成员Lhx8在切割穹窿海马伞后的海马胆碱能神经再生过程中发挥了重要作用。
Lhx8（LIM homeobox8）is associated with the development of embryo basalcholinergic neurons, however the function of Lhx8on cholinergic neural regeneration incentral nervous system and hippocampal dentate gyrus is still unclear, this research willstudy the function of Lhx8on hippocampal cholinergic neural regeneration.
Objective:
Radial glia cells （RGCs） derived from rat hippocampus was cultured in vitro, weinvestigated and detected the effects of normal and transected hippocampal extracts in theproliferation and differentiation of RGCs, and then we studied the function of Lhx8onhippocampal cholinergic neural regeneration.
Methods:
（1） The rats’ hippocampal right fimbria-fornix was transected and the normal andtransected hippocampal extracts were prepared successfully;
（2） The RGCs was cultured in vitro, normal and transected hippocampal extractswas added into the culture mediums, then investigated the function of hippocampalextracts in the proliferation and differentiation of RGCs;
（3） Using hippocapal extracts and NGF to promote the cholinergic differentiationof RGCs, then investigate the expression and location of Lhx8in ChAT positive cells;
（4） Cloning of Lhx8cDNA sequence, the expression recombinant plasmidpLenti6.3-Lhx8-IRES2-EGFP was constructed successfully and packaged by lentivirus, thecollected lentivirus Lenti6.3-Lhx8were transfected into RGCs, then investigated thecholinergic differentiation of RGCs and the dynamic gene and protein expression of Lhx8and ChAT;
（5） The lentivirus Lenti6.3-Lhx8were injected into the normal and fimbria-fornixtransected hippocampal dentate gyrus, then investigated the expression and location of theChAT positive cholinergic neurons in normal and transected hippocampal dentate gyrusand the dynamic gene and protein expression of Lhx8and ChAT.
Results:
（1）RGCs presented typical double processes morphological feature, they expressedastroglial markers BLBP, GFAP, Vimentin, and these astroglial markers co-expressed withstem cells marker Nestin, and these RGCs could differentiate into neurons, astrocytes andoligodendrocytes;
（2） The transected hippocampal extracts could promote the proliferation andneuronal differentiation of RGCs; the transected hippocampal extracts combined with NGFcould promote the RGCs differentiation into cholinergic neurons, and these cholinergicneurons could co-express with Lhx8;
（3） Lenti6.3-Lhx8was transfected into RGCs, the number of differentiated MAP2positive neurons was not increased, but the proportion of ChAT positive cells to MAP2cells was increased, and the gene and protein expression of Lhx8and ChAT were increasedsignificantly, it indicated that transfection of Lenti6.3-Lhx8could promote the cholinergicneurons differentiation;
（4） The Lenti6.3-Lhx8were injected into normal hippocampal dentate gyrus, thenumber of ChAT/Lhx8positive cholinergic neurons were increased; the hippocampalfimbria-fornix transection combined with Lenti6.3-Lhx8injection of dentate gyrus, thenumber of ChAT/Lhx8positive cholinergic neurons were increased significantly, the geneand protein expression of Lhx8and ChAT were also increased, it indicated that thehippocampal fimbria-fornix transection combined with Lenti6.3-Lhx8injection couldpromote the level of cholinergic neural regeneration in hippocampus.
Conclusions:
（1） The RGCs presented typical double processes morphological feature in vitro,these cells co-expressed astroglial markers with stem cells marker. The fimbria-fornixtransected hippocampal extracts could mimic the hippocampal neural regeneration niche invitro. On the proliferation stage the transected hippocampal extracts could promote theproliferation of RGCs, on the differentiation stage the transected hippocampal extracts alsocould promote the RGCs differentiation into neurons;
（2） Lentivirus Lenti6.3-Lhx8could promote the hippocampal RGCs differentiationinto cholinergic neurons, but had no effect on the total number of neurons. As a familymember of LIM homeobox genes, Lhx8was only associated with the establishment of cholinergic phenotype, but Lhx8could not promote hippocampal RGCs differentiation intomore neurons in vitro;
（3） Lentivirus Lenti6.3-Lhx8were injected into the hippocampal dentate gyrus, theChAT positive cholinergic neurons was increased, Lenti6.3-Lhx8were injected into thefimbria-fornix transected hippocampal dentate gyrus, the number of ChAT positivecholinergic neurons was significantly increased, it indicated that LIM homeobox geneLhx8played an important role in the hippocampal cholinergic neural regeneration afterfimbria-fornix transection.
一．目的：
体外培养大鼠海马源性放射状胶质细胞（Radial glia cells, RGCs），观察并检测海马提取液在RGCs增殖和向胆碱能神经元分化过程中所发挥的效用；构建Lhx8过表达载体并经慢病毒包装，转染至体外培养的RGCs，同时注入大鼠海马齿状回中，对Lhx8在海马胆碱能神经再生过程中所起的作用进行初步的探讨。
二．方法：
（1）切割大鼠右侧穹窿海马伞并且制备正常侧及切割侧海马提取液；
（2）体外培养海马源性RGCs，在培养液中加入正常侧及切割侧海马提取液，观察海马提取液对RGCs增殖和向神经元分化方面的作用；
（3）联合应用海马提取液及NGF共同促进海马RGCs向胆碱能神经元分化，观察Lhx8在ChAT阳性的神经元中的表达和定位；
（4）克隆Lhx8cDNA序列，构建pLenti6.3-Lhx8-IRES2-EGFP表达载体并经慢病毒包装，将收集的慢病毒Lenti6.3-Lhx8转染RGCs，观察RGCs向胆碱能神经元分化的情况，检测Lhx8和ChAT的基因及蛋白的表达变化；
（5）将慢病毒Lenti6.3-Lhx8注入正常侧及切割穹窿海马伞侧大鼠海马齿状回中，观察正常侧及切割侧海马齿状回中ChAT阳性的胆碱能神经元的表达和定位，检测Lhx8和ChAT的基因及蛋白的表达变化。
三．结果：
（1） RGCs具有典型的双突起形态学特征，同时可表达胶质相关标记物BLBP、GFAP、Vimentin，并且这些胶质相关标记物能与干细胞相关标记物Nestin进行双标，此外RGCs还能够分化为神经元、星形胶质细胞以及少突胶质细胞；
（2）切割穹窿海马伞侧的海马提取液能够明显促进RGCs的增殖和向神经元分化；切割侧海马提取液联合NGF能够促进RGCs向ChAT阳性的胆碱能神经元分化，这些ChAT阳性的胆碱能神经元能够表达Lhx8；
（3） RGCs转染慢病毒Lenti6.3-Lhx8后，分化为MAP2阳性神经元的总体数目没有明显增加，但是能够提高ChAT阳性细胞在MAP2阳性神经元中所占的比例，Lhx8和ChAT的基因及蛋白的表达量也明显增高，说明转染慢病毒Lenti6.3-Lhx8后，能够促进RGCs向胆碱能神经元分化；
（4）在正常海马齿状回中注入慢病毒Lenti6.3-Lhx8后，能够明显提高齿状回内ChAT/Lhx8阳性的胆碱能神经元数量；切割穹窿海马伞并联合慢病毒注射后，发现齿状回内ChAT/Lhx8阳性的胆碱能神经元的数量增加更为明显，Lhx8和ChAT的基因及蛋白的表达量也明显增高，说明切割穹窿海马伞并且联合应用Lenti6.3-Lhx8慢病毒可以明显地促进海马内的胆碱能神经再生水平。
四．结论：
（1）体外培养的海马源性RGCs具有典型的双突起形态学特征，这些细胞能够同时表达胶质细胞相关标记物和干细胞相关标记物。体外应用切割穹窿海马伞侧海马提取液能够较好的模拟切割穹窿海马伞后的海马再生微环境。在RGCs扩增培养阶段切割侧海马提取液能明显地促进RGCs增殖，而在RGCs分化阶段切割侧海马提取液也能够促进RGCs更多地向神经元分化；
（2）慢病毒Lenti6.3-Lhx8能够促进体外培养的海马源性RGCs向胆碱能神经元分化，但对RGCs分化产生的神经元总体数量没有影响。Lhx8作为LIM同源盒基因家族成员，仅在神经元胆碱能表型确立方面起到作用，而不能促进体外培养的海马源性RGCs更多地向神经元分化；
（3）慢病毒Lenti6.3-Lhx8注入海马齿状回后，齿状回ChAT阳性胆碱能神经元的数量与正常海马比较明显增多。在切割穹窿海马伞侧的海马齿状回中注入慢病毒Lenti6.3-Lhx8后，发现ChAT阳性的神经元数量增加更为明显，说明LIM同源盒基因家族成员Lhx8在切割穹窿海马伞后的海马胆碱能神经再生过程中发挥了重要作用。
Lhx8（LIM homeobox8）is associated with the development of embryo basalcholinergic neurons, however the function of Lhx8on cholinergic neural regeneration incentral nervous system and hippocampal dentate gyrus is still unclear, this research willstudy the function of Lhx8on hippocampal cholinergic neural regeneration.
Objective:
Radial glia cells （RGCs） derived from rat hippocampus was cultured in vitro, weinvestigated and detected the effects of normal and transected hippocampal extracts in theproliferation and differentiation of RGCs, and then we studied the function of Lhx8onhippocampal cholinergic neural regeneration.
Methods:
（1） The rats’ hippocampal right fimbria-fornix was transected and the normal andtransected hippocampal extracts were prepared successfully;
（2） The RGCs was cultured in vitro, normal and transected hippocampal extractswas added into the culture mediums, then investigated the function of hippocampalextracts in the proliferation and differentiation of RGCs;
（3） Using hippocapal extracts and NGF to promote the cholinergic differentiationof RGCs, then investigate the expression and location of Lhx8in ChAT positive cells;
（4） Cloning of Lhx8cDNA sequence, the expression recombinant plasmidpLenti6.3-Lhx8-IRES2-EGFP was constructed successfully and packaged by lentivirus, thecollected lentivirus Lenti6.3-Lhx8were transfected into RGCs, then investigated thecholinergic differentiation of RGCs and the dynamic gene and protein expression of Lhx8and ChAT;
（5） The lentivirus Lenti6.3-Lhx8were injected into the normal and fimbria-fornixtransected hippocampal dentate gyrus, then investigated the expression and location of theChAT positive cholinergic neurons in normal and transected hippocampal dentate gyrusand the dynamic gene and protein expression of Lhx8and ChAT.
Results:
（1）RGCs presented typical double processes morphological feature, they expressedastroglial markers BLBP, GFAP, Vimentin, and these astroglial markers co-expressed withstem cells marker Nestin, and these RGCs could differentiate into neurons, astrocytes andoligodendrocytes;
（2） The transected hippocampal extracts could promote the proliferation andneuronal differentiation of RGCs; the transected hippocampal extracts combined with NGFcould promote the RGCs differentiation into cholinergic neurons, and these cholinergicneurons could co-express with Lhx8;
（3） Lenti6.3-Lhx8was transfected into RGCs, the number of differentiated MAP2positive neurons was not increased, but the proportion of ChAT positive cells to MAP2cells was increased, and the gene and protein expression of Lhx8and ChAT were increasedsignificantly, it indicated that transfection of Lenti6.3-Lhx8could promote the cholinergicneurons differentiation;
（4） The Lenti6.3-Lhx8were injected into normal hippocampal dentate gyrus, thenumber of ChAT/Lhx8positive cholinergic neurons were increased; the hippocampalfimbria-fornix transection combined with Lenti6.3-Lhx8injection of dentate gyrus, thenumber of ChAT/Lhx8positive cholinergic neurons were increased significantly, the geneand protein expression of Lhx8and ChAT were also increased, it indicated that thehippocampal fimbria-fornix transection combined with Lenti6.3-Lhx8injection couldpromote the level of cholinergic neural regeneration in hippocampus.
Conclusions:
（1） The RGCs presented typical double processes morphological feature in vitro,these cells co-expressed astroglial markers with stem cells marker. The fimbria-fornixtransected hippocampal extracts could mimic the hippocampal neural regeneration niche invitro. On the proliferation stage the transected hippocampal extracts could promote theproliferation of RGCs, on the differentiation stage the transected hippocampal extracts alsocould promote the RGCs differentiation into neurons;
（2） Lentivirus Lenti6.3-Lhx8could promote the hippocampal RGCs differentiationinto cholinergic neurons, but had no effect on the total number of neurons. As a familymember of LIM homeobox genes, Lhx8was only associated with the establishment of cholinergic phenotype, but Lhx8could not promote hippocampal RGCs differentiation intomore neurons in vitro;
（3） Lentivirus Lenti6.3-Lhx8were injected into the hippocampal dentate gyrus, theChAT positive cholinergic neurons was increased, Lenti6.3-Lhx8were injected into thefimbria-fornix transected hippocampal dentate gyrus, the number of ChAT positivecholinergic neurons was significantly increased, it indicated that LIM homeobox geneLhx8played an important role in the hippocampal cholinergic neural regeneration afterfimbria-fornix transection.
引文
1. Wang SH, Morris RG. Hippocampal-neocortical interactions in memory formation,consolidation, and reconsolidation. Annu Rev Psychol,2010;61:49-79, C1-4.
2. Akhondzadeh S. Hippocampal synaptic plasticity and cognition. J Clin Pharm Ther,1999;24（4）:241-248.
3. Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells ofthe adult mammalian central nervous system. Science,1992;255（5052）:1707-1710.
4. Richards LJ, Kilpatrick TJ, Bartlett PF. De novo generation of neuronal cells from theadult mouse brain. Proc Natl Acad Sci U S A,1992;89（18）:8591-8595.
5. Ourednik V, Ourednik J, Flax JD, et al. Segregation of human neural stem cells in thedeveloping primate forebrain. Science,2001;293（5536）:1820-1824.
6. Palmer TD, Takahashi J, Gage FH. The adult rat hippocampus contains primordialneural stem cells. Mol Cell Neurosci,1997;8（6）:389-404.
7. Galli R, Gritti A, Bonfanti L, Vescovi AL. Neural stem cells: an overview. Circ Res,2003;92（6）:598-608.
8. Dutton R, Bartlett PF. Precursor cells in the subventricular zone of the adult mouseare actively inhibited from differentiating into neurons. Dev Neurosci,2000;22（1-2）:96-105.
9. Ma DK, Bonaguidi MA, Ming GL, Song H. Adult neural stem cells in the mammaliancentral nervous system. Cell Res,2009;19（6）:672-682.
10. Jordan JD, Ma DK, Ming GL, Song H. Cellular niches for endogenous neural stemcells in the adult brain. CNS Neurol Disord Drug Targets,2007;6（5）:336-341.
11. Taupin P. Adult neural stem cells, neurogenic niches, and cellular therapy. Stem CellRev,2006;2（3）:213-219.
12. Alvarez-Buylla A, Kohwi M, Nguyen TM, Merkle FT. The heterogeneity of adultneural stem cells and the emerging complexity of their niche. Cold Spring Harb SympQuant Biol,2008;73:357-365.
13. Nishino H, Hida H, Takei N, et al. Mesencephalic neural stem （progenitor） cellsdevelop to dopaminergic neurons more strongly in dopamine-depleted striatum thanin intact striatum. Exp Neurol,2000;164（1）:209-214.
14. Fricker RA, Carpenter MK, Winkler C, et al. Site-specific migration and neuronaldifferentiation of human neural progenitor cells after transplantation in the adult ratbrain. J Neurosci,1999;19（14）:5990-6005.
15. Brewer GJ. Regeneration and proliferation of embryonic and adult rat hippocampalneurons in culture. Exp Neurol,1999;159（1）:237-347.
16. Vicario-Abejon C, Collin C, Tsoulfas P, et al. Hippocampal stem cells differentiateinto excitatory and inhibitory neurons. Eur J Neurosci,2000;12（2）:677-688.
17. Ling ZD, Potter ED, Lipton JW, et al. Differentiation of mesencephalic progenitorcells into dopaminergic neurons by cytokines. Exp Neurol,1998;149（2）:411-423.
18. Flandin P, Zhao Y, Vogt D, et al. Lhx6and Lhx8coordinately induce neuronalexpression of Shh that controls the generation of interneuron progenitors. Neuron,2011;70（5）:939-950.
19. Zhao Y, Marin O, Hermesz E, et al. The LIM-homeobox gene Lhx8is required for thedevelopment of many cholinergic neurons in the mouse forebrain. Proc Natl Acad SciU S A,2003;100（15）:9005-9010.
20. Manabe T, Tatsumi K, Inoue M, et al. L3/Lhx8is a pivotal factor for cholinergicdifferentiation of murine embryonic stem cells. Cell Death Differ,2007;14（6）:1080-1085.
21. Tan XF, Jin GH, Tian ML, et al. The co-transduction of Nurr1and Brn4genes inducesthe differentiation of neural stem cells into dopaminergic neurons. Cell Biol Int,2011;35（12）:1217-1223.
22. Zhang X, Jin G, Wang L, et al. Brn-4is upregulated in the deafferented hippocampusand promotes neuronal differentiation of neural progenitors in vitro. Hippocampus,2009;19（2）:176-186.
23. Shi J, Jin G, Zhu H, et al. The role of Brn-4in the regulation of neural stem celldifferentiation into neurons. Neurosci Res,2010;67（1）:8-17.
24. Seri B, Garcia-Verdugo JM, Collado-Morente L, et al. Cell types, lineage, andarchitecture of the germinal zone in the adult dentate gyrus. J Comp Neurol,2004;478（4）:359-378.
25. Seri B, Garcia-Verdugo JM, McEwen BS, et al. Astrocytes give rise to new neurons inthe adult mammalian hippocampus. J Neurosci,2001;21（18）:7153-7160.
26. Fukuda S, Kato F, Tozuka Y, et al. Two distinct subpopulations of nestin-positive cellsin adult mouse dentate gyrus. J Neurosci,2003;23（28）:9357-9366.
27. Liu Y, Namba T, Liu J, et al. Glial fibrillary acidic protein-expressing neuralprogenitors give rise to immature neurons via early intermediate progenitorsexpressing both glial fibrillary acidic protein and neuronal markers in the adulthippocampus. Neuroscience,2010;166（1）:241-251.
28. Kronenberg G, Reuter K, Steiner B, et al. Subpopulations of proliferating cells of theadult hippocampus respond differently to physiologic neurogenic stimuli. J CompNeurol,2003;467（4）:455-463.
29. Kempermann G, Gage FH. Neurogenesis in the adult hippocampus. Novartis FoundSymp,2000;231:220-35; discussion235-241,302-306.
30. Kempermann G, Jessberger S, Steiner B, et al. Milestones of neuronal development inthe adult hippocampus. Trends Neurosci,2004;27（8）:447-452.
31. Bonaguidi MA, Wheeler MA, Shapiro JS, et al. In vivo clonal analysis revealsself-renewing and multipotent adult neural stem cell characteristics. Cell,2011;145（7）:1142-1155.
32. Conti L, Pollard SM, Gorba T, et al. Niche-independent symmetrical self-renewal of amammalian tissue stem cell. PLoS Biol,2005;3（9）:e283.
33. Glaser T, Brustle O. Retinoic acid induction of ES-cell-derived neurons: the radialglia connection. Trends Neurosci,2005;28（8）:397-400.
34. Glaser T, Pollard SM, Smith A, et al. Tripotential differentiation of adherentlyexpandable neural stem （NS） cells. PLoS One2007;2（3）:e298.
35. Li H, Jin G, Qin J, et al. Characterization and identification of Sox2+radial glia cellsderived from rat embryonic cerebral cortex. Histochem Cell Biol,2011;136（5）:515-526.
36. Li H, Jin G, Qin J, et al. Identification of neonatal rat hippocampal radial glia cells invitro. Neurosci Lett,2011;490（3）:209-214.
37. Zou L, Jin G, Zhang X, et al. Proliferation, migration, and neuronal differentiation ofthe endogenous neural progenitors in hippocampus after fimbria fornix transection.Int J Neurosci,2010;120（3）:192-200.
38. Zhang X, Jin G, Tian M, Qin J, Huang Z. The denervated hippocampus providesproper microenvironment for the survival and differentiation of neural progenitors.Neurosci Lett,2007;414（2）:115-120.
39. Simmons DK, Pang K, Martindale MQ. Lim homeobox genes in the CtenophoreMnemiopsis leidyi: the evolution of neural cell type specification. Evodevo,2012;3（1）:2.
40. Srivastava M, Larroux C, Lu DR, et al. Early evolution of the LIM homeobox genefamily. BMC Biol,2010;8:4.
41. Holland PW, Takahashi T. The evolution of homeobox genes: Implications for thestudy of brain development. Brain Res Bull,2005;66（4-6）:484-490.
42. Schonemann MD, Ryan AK, Erkman L, et al. POU domain factors in neuraldevelopment. Adv Exp Med Biol,1998;449:39-53.
43. Latchman DS. POU family transcription factors in the nervous system. J Cell Physiol,1999;179（2）:126-33.
44. Josephson R, Muller T, Pickel J, et al. POU transcription factors control expression ofCNS stem cell-specific genes. Development,1998;125（16）:3087-3100.
45. Kitanaka J, Takemura M, Matsumoto K, et al. Structure and chromosomal localizationof a murine LIM/homeobox gene, Lhx8. Genomics,1998;49（2）:307-309.
46. Shibaguchi T, Kato J, Abe M, et al. Expression and role of Lhx8in murine toothdevelopment. Arch Histol Cytol,2003;66（1）:95-108.
47. Zhang Y, Mori T, Takaki H, et al. Comparison of the expression patterns of twoLIM-homeodomain genes, Lhx6and L3/Lhx8, in the developing palate. OrthodCraniofac Res,2002;5（2）:65-70.
48. Zhao Y, Guo YJ, Tomac AC, et al. Isolated cleft palate in mice with a targetedmutation of the LIM homeobox gene lhx8. Proc Natl Acad Sci U S A,1999;96（26）:15002-15006.
49. Pangas SA, Choi Y, Ballow DJ, et al. Oogenesis requires germ cell-specifictranscriptional regulators Sohlh1and Lhx8. Proc Natl Acad Sci U S A,2006;103（21）:8090-8095.
50. Mori T, Yuxing Z, Takaki H, et al. The LIM homeobox gene, L3/Lhx8, is necessaryfor proper development of basal forebrain cholinergic neurons. Eur J Neurosci,2004;19（12）:3129-3141.
51. Manabe T, Tatsumi K, Inoue M, et al. Knockdown of the L3/Lhx8gene suppressescholinergic differentiation of murine embryonic stem cell-derived spheres. Int J DevNeurosci,2008;26（2）:249-252.
1. Ihrie RA, Alvarez-Buylla A. Cells in the astroglial lineage are neural stem cells. CellTissue Res,2008;331（1）:179-91.
2. Kriegstein AR, Gotz M. Radial glia diversity: a matter of cell fate. Glia,2003;43（1）:37-43.
3. Malatesta P, Appolloni I, Calzolari F. Radial glia and neural stem cells. Cell TissueRes,2008;331（1）:165-78.
4. Morrens J, Van Den Broeck W, Kempermann G. Glial cells in adult neurogenesis. Glia,2012;60（2）:159-74.
5. Li H, Jin G, Qin J, et al. Characterization and identification of Sox2+radial glia cellsderived from rat embryonic cerebral cortex. Histochem Cell Biol,2011;136（5）:515-26.
6. Zhang X, Jin G, Li W, et al. Ectopic neurogenesis in the forebrain cholinergicsystem-related areas of a rat dementia model. Stem Cells Dev,2011;20（9）:1627-38.
7. Zou L, Jin G, Zhang X, et al. Proliferation, migration, and neuronal differentiation ofthe endogenous neural progenitors in hippocampus after fimbria fornix transection.Int J Neurosci,2010;120（3）:192-200.
8. Zhang X, Jin G, Tian M, Qin J, et al. The denervated hippocampus provides propermicroenvironment for the survival and differentiation of neural progenitors. NeurosciLett,2007;414（2）:115-20.
9. Shi J, Jin G, Zhu H, et al. The role of Brn-4in the regulation of neural stem celldifferentiation into neurons. Neurosci Res,2010;67（1）:8-17.
10. Zhao H, Jin G, Tian M, Li H, et al. Extract of deafferented hippocampus promotes invitro radial glial cell differentiation into neurons. Neurosci Lett,2011;498（1）:93-8.
11. Seri B, Garcia-Verdugo JM, McEwen BS, et al. Astrocytes give rise to new neurons inthe adult mammalian hippocampus. J Neurosci,2001;21（18）:7153-60.
12. Fukuda S, Kato F, Tozuka Y, et al. Two distinct subpopulations of nestin-positive cellsin adult mouse dentate gyrus. J Neurosci,2003;23（28）:9357-66.
13. Seri B, Garcia-Verdugo JM, Collado-Morente L, et al. Cell types, lineage, andarchitecture of the germinal zone in the adult dentate gyrus. J Comp Neurol,2004;478（4）:359-78.
14. Suh H, Consiglio A, Ray J, et al. In vivo fate analysis reveals the multipotent andself-renewal capacities of Sox2+neural stem cells in the adult hippocampus. CellStem Cell,2007;1（5）:515-28.
15. Liu Y, Namba T, Liu J, et al. Glial fibrillary acidic protein-expressing neuralprogenitors give rise to immature neurons via early intermediate progenitorsexpressing both glial fibrillary acidic protein and neuronal markers in the adulthippocampus. Neuroscience,2010;166（1）:241-51.
16. Kempermann G, Jessberger S, et al. Milestones of neuronal development in the adulthippocampus. Trends Neurosci,2004;27（8）:447-52.
17. Bonaguidi MA, Wheeler MA, Shapiro JS, et al. In vivo clonal analysis revealsself-renewing and multipotent adult neural stem cell characteristics. Cell,2011;145（7）:1142-55.
18. Li H, Jin G, Qin J, et al. Identification of neonatal rat hippocampal radial glia cells invitro. Neurosci Lett,2011;490（3）:209-14.
19. Conti L, Pollard SM, Gorba T, et al. Niche-independent symmetrical self-renewal of amammalian tissue stem cell. PLoS Biol,2005;3（9）:e283.
20. Glaser T, Pollard SM, Smith A, Brustle O. Tripotential differentiation of adherentlyexpandable neural stem （NS） cells. PLoS One,2007;2（3）:e298.
21. Pollard SM, Conti L, Sun Y, et al. Adherent neural stem （NS） cells from fetal andadult forebrain. Cereb Cortex,2006;16Suppl1:i112-20.
22. Kronenberg G, Reuter K, Steiner B, et al. Subpopulations of proliferating cells of theadult hippocampus respond differently to physiologic neurogenic stimuli. J CompNeurol,2003;467（4）:455-63.
1. Zhao Y, Marin O, Hermesz E, et al. The LIM-homeobox gene Lhx8is required for thedevelopment of many cholinergic neurons in the mouse forebrain. Proc Natl Acad SciU S, A2003;100（15）:9005-9010.
2. Mori T, Yuxing Z, Takaki H, et al. The LIM homeobox gene, L3/Lhx8, is necessaryfor proper development of basal forebrain cholinergic neurons. Eur J Neurosci,2004;19（12）:3129-3141.
3. Manabe T, Tatsumi K, Inoue M, et al. L3/Lhx8is a pivotal factor for cholinergicdifferentiation of murine embryonic stem cells. Cell Death Differ,2007;14（6）:1080-1085.
4. Manabe T, Tatsumi K, Inoue M, et al. Knockdown of the L3/Lhx8gene suppressescholinergic differentiation of murine embryonic stem cell-derived spheres. Int J DevNeurosci,2008;26（2）:249-252.
5. Pfaffl MW. A new mathematical model for relative quantification in real-timeRT-PCR. Nucleic Acids Res,2001;29（9）:e45.
6. Simmons DK, Pang K, Martindale MQ. Lim homeobox genes in the CtenophoreMnemiopsis leidyi: the evolution of neural cell type specification. Evodevo,2012;3（1）:2.
7. Srivastava M, Larroux C, Lu DR, et al. Early evolution of the LIM homeobox genefamily. BMC Biol,2010;8:4.
8. Wang JQ, Hou L, Yi N,et al. Molecular analysis and its expression of a pou homeoboxprotein gene during development and in response to salinity stress from brine shrimp,Artemia sinica. Comp Biochem Physiol A Mol Integr Physiol,2012;161（1）:36-43.
9. Schonemann MD, Ryan AK, Erkman L, et al. POU domain factors in neuraldevelopment. Adv Exp Med Biol,1998;449:39-53.
10. Kitanaka J, Takemura M, Matsumoto K, et al. Structure and chromosomal localizationof a murine LIM/homeobox gene, Lhx8. Genomics,1998;49（2）:307-309.
11. Shibaguchi T, Kato J, Abe M, et al. Expression and role of Lhx8in murine toothdevelopment. Arch Histol Cytol,2003;66（1）:95-108.
12. Zhang Y, Mori T, Takaki H, et al. Comparison of the expression patterns of twoLIM-homeodomain genes, Lhx6and L3/Lhx8, in the developing palate. OrthodCraniofac Res,2002;5（2）:65-70.
13. Zhao Y, Guo YJ, Tomac AC, et al. Isolated cleft palate in mice with a targetedmutation of the LIM homeobox gene lhx8. Proc Natl Acad Sci U S A,1999;96（26）:15002-15006.
14. Pangas SA, Choi Y, Ballow DJ, et al. Oogenesis requires germ cell-specifictranscriptional regulators Sohlh1and Lhx8. Proc Natl Acad Sci U S A,2006;103（21）:8090-8095.
15. Jagarlamudi K, Rajkovic A. Oogenesis: Transcriptional regulators and mouse models.Mol Cell Endocrinol,2011.
16. Zhang X, Jin G, Tian M, et al. The denervated hippocampus provides propermicroenvironment for the survival and differentiation of neural progenitors. NeurosciLett,2007;414（2）:115-120.
17. Zou L, Jin G, Zhang X, et al. Proliferation, migration, and neuronal differentiation ofthe endogenous neural progenitors in hippocampus after fimbria fornix transection.Int J Neurosci,2010;120（3）:192-200.
18. Liu Y, Namba T, Liu J, et al. Glial fibrillary acidic protein-expressing neuralprogenitors give rise to immature neurons via early intermediate progenitorsexpressing both glial fibrillary acidic protein and neuronal markers in the adulthippocampus. Neuroscience,2010;166（1）:241-251.
19. Brunne B, Zhao S, Derouiche A, et al. Origin, maturation, and astroglialtransformation of secondary radial glial cells in the developing dentate gyrus. Glia,2010;58（13）:1553-1569.
20. Suh H, Consiglio A, Ray J, et al. In vivo fate analysis reveals the multipotent andself-renewal capacities of Sox2+neural stem cells in the adult hippocampus. CellStem Cell,2007;1（5）:515-528.
21. Kronenberg G, Reuter K, Steiner B, et al. Subpopulations of proliferating cells of theadult hippocampus respond differently to physiologic neurogenic stimuli. J CompNeurol,2003;467（4）:455-463.
1. Zou L, Jin G, Zhang X, et al. Proliferation, migration, and neuronal differentiation ofthe endogenous neural progenitors in hippocampus after fimbria fornix transection.Int J Neurosci,2010;120（3）:192-200.
2. Zhang X, Jin G, Tian M, et al. The denervated hippocampus provides propermicroenvironment for the survival and differentiation of neural progenitors. NeurosciLett,2007;414（2）:115-120.
3. Zhao H, Jin G, Tian M, et al. Extract of deafferented hippocampus promotes in vitroradial glial cell differentiation into neurons. Neurosci Lett,2011;498（1）:93-98.
4. Kitanaka J, Takemura M, Matsumoto K, et al. Structure and chromosomal localizationof a murine LIM/homeobox gene, Lhx8. Genomics,1998;49（2）:307-309.
5. Manabe T, Tatsumi K, Inoue M, et al. L3/Lhx8is a pivotal factor for cholinergicdifferentiation of murine embryonic stem cells. Cell Death Differ,2007;14（6）:1080-1085.
6. Manabe T, Tatsumi K, Inoue M, et al. Knockdown of the L3/Lhx8gene suppressescholinergic differentiation of murine embryonic stem cell-derived spheres. Int J DevNeurosci,2008;26（2）:249-252.
7. Manabe T, Tatsumi K, Inoue M, et al. L3/Lhx8is involved in the determination ofcholinergic or GABAergic cell fate. J Neurochem,2005;94（3）:723-730.
8. Pfaffl MW. A new mathematical model for relative quantification in real-timeRT-PCR. Nucleic Acids Res,2001;29（9）:e45.
9. Bruel-Jungerman E, Rampon C, Laroche S. Adult hippocampal neurogenesis,synaptic plasticity and memory: facts and hypotheses. Rev Neurosci,2007;18（2）:93-114.
10. DeCarolis NA, Eisch AJ. Hippocampal neurogenesis as a target for the treatment ofmental illness: a critical evaluation. Neuropharmacology,2010;58（6）:884-893.
11. Gould E, McEwen BS, Tanapat P, et al. Neurogenesis in the dentate gyrus of the adulttree shrew is regulated by psychosocial stress and NMDA receptor activation. JNeurosci,1997;17（7）:2492-2498.
12. Fricker RA, Carpenter MK, Winkler C, et al. Site-specific migration and neuronaldifferentiation of human neural progenitor cells after transplantation in the adult ratbrain. J Neurosci,1999;19（14）:5990-6005.
13. Seri B, Garcia-Verdugo JM, McEwen BS, Alvarez-Buylla A. Astrocytes give rise tonew neurons in the adult mammalian hippocampus. J Neurosci,2001;21（18）:7153-7160.
14. Liu Y, Namba T, Liu J, et al. Glial fibrillary acidic protein-expressing neuralprogenitors give rise to immature neurons via early intermediate progenitorsexpressing both glial fibrillary acidic protein and neuronal markers in the adulthippocampus. Neuroscience,2010;166（1）:241-251.
15. Seri B, Garcia-Verdugo JM, Collado-Morente L, McEwen BS, Alvarez-Buylla A. Celltypes, lineage, and architecture of the germinal zone in the adult dentate gyrus. JComp Neurol,2004;478（4）:359-378.
16. Simmons DK, Pang K, Martindale MQ. Lim homeobox genes in the CtenophoreMnemiopsis leidyi: the evolution of neural cell type specification. Evodevo,2012;3（1）:2.
17. Srivastava M, Larroux C, Lu DR, et al. Early evolution of the LIM homeobox genefamily. BMC Biol,2010;8:4.
18. Hung TM, Hu RH, Ho CM, et al. Downregulation of alpha-fetoprotein expression byLHX4: a critical role in hepatocarcinogenesis. Carcinogenesis,2011;32（12）:1815-1823.
19. Colvin SC, Mullen RD, Pfaeffle RW, et al. LHX3and LHX4transcription factors inpituitary development and disease. Pediatr Endocrinol Rev,2009;6Suppl2:283-90.
20. Bertrand N, Dahmane N. Sonic hedgehog signaling in forebrain development and itsinteractions with pathways that modify its effects. Trends Cell Biol,2006;16（11）:597-605.
21. Sheng HZ, Bertuzzi S, Chiang C, et al. Expression of murine Lhx5suggests a role inspecifying the forebrain. Dev Dyn,1997;208（2）:266-277.
22. Mori T, Yuxing Z, Takaki H, et al. The LIM homeobox gene, L3/Lhx8, is necessaryfor proper development of basal forebrain cholinergic neurons. Eur J Neurosci,2004;19（12）:3129-3141.
1. Doetsch F. A niche for adult neural stem cells. Curr Opin Genet Dev,2003;13（5）:543-550.
2. Kempermann G, Gage FH. Neurogenesis in the adult hippocampus. Novartis Found,Symp2000;231:220-235; discussion235-41,302-306.
3. Kazanis I, Lathia J, Moss L, et al. The neural stem cell, microenvironment.2008.
4. Balu DT, Lucki I. Adult hippocampal neurogenesis: regulation, functional implications,and contribution to disease pathology. Neurosci Biobehav Rev,2009;33（3）:232-352.
5. Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells ofthe adult mammalian central nervous system. Science,1992;255（5052）:1707-1710.
6. Richards LJ, Kilpatrick TJ, Bartlett PF. De novo generation of neuronal cells from theadult mouse brain. Proc Natl Acad Sci U S A,1992;89（18）:8591-8595.
7. Taupin P, Gage FH. Adult neurogenesis and neural stem cells of the central nervoussystem in mammals. J Neurosci Res,2002;69（6）:745-749.
8. Seaberg RM, van der Kooy D. Adult rodent neurogenic regions: the ventricularsubependyma contains neural stem cells, but the dentate gyrus contains restrictedprogenitors. J Neurosci,2002;22（5）:1784-1793.
9. Bull ND, Bartlett PF. The adult mouse hippocampal progenitor is neurogenic but not astem cell. J Neurosci,2005;25（47）:10815-10821.
10. Shors TJ, Townsend DA, Zhao M, et al. Neurogenesis may relate to some but not alltypes of hippocampal-dependent learning. Hippocampus,2002;12（5）:578-584.
11. Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adultneurogenesis. Cell,2008;132（4）:645-660.
12. Warner-Schmidt JL, Duman RS. Hippocampal neurogenesis: opposing effects ofstress and antidepressant treatment. Hippocampus,2006;16（3）:239-249.
13. Dranovsky A, Hen R. Hippocampal neurogenesis: regulation by stress andantidepressants. Biol Psychiatry,2006;59（12）:1136-1143.
14. Parent JM, Murphy GG. Mechanisms and functional significance of aberrantseizure-induced hippocampal neurogenesis. Epilepsia,2008;49Suppl5:19-25.
15. Parent JM, Elliott RC, Pleasure SJ, et al. Aberrant seizure-induced neurogenesis inexperimental temporal lobe epilepsy. Ann Neurol,2006;59（1）:81-91.
16. Kallur T, Farr TD, Bohm-Sturm P, et al. Spatio-temporal dynamics, differentiation andviability of human neural stem cells after implantation into neonatal rat brain. Eur JNeurosci,2011;34（3）:382-393.
17. Shear DA, Tate CC, Tate MC, et al. Stem cell survival and functional outcome aftertraumatic brain injury is dependent on transplant timing and location. Restor NeurolNeurosci,2011;29（4）:215-225.
18. Lois C, Garcia-Verdugo JM, Alvarez-Buylla A. Chain migration of neuronalprecursors. Science,1996;271（5251）:978-981.
19. Zou L, Jin G, Zhang X, et al. Proliferation, migration, and neuronal differentiation ofthe endogenous neural progenitors in hippocampus after fimbria fornix transection.Int J Neurosci,2010;120（3）:192-200.
20. Ostenfeld T, Svendsen CN. Requirement for neurogenesis to proceed through thedivision of neuronal progenitors following differentiation of epidermal growth factorand fibroblast growth factor-2-responsive human neural stem cells. Stem Cells,2004;22（5）:798-811.
21. Duan SR, Wang HH, Qi JP, et al. Influences of bFGF and EGF on the proliferationand differentiation of endogenous neural stem cells after cerebral infarction in human.Zhonghua Yi Xue Za Zhi,2008;88（47）:3337-3341.
22. Mudo G, Bonomo A, Di Liberto V, et al. The FGF-2/FGFRs neurotrophic systempromotes neurogenesis in the adult brain. J Neural Transm,2009;116（8）:995-1005.
23. Bauer S, Patterson PH. Leukemia inhibitory factor promotes neural stem cellself-renewal in the adult brain. J Neurosci,2006;26（46）:12089-12099.
24. Gonzalez-Perez O, Jauregui-Huerta F, Galvez-Contreras AY. Immune system modulatesthe function of adult neural stem cells. Curr Immunol Rev,2010;6（3）:167-173.
25. Arsenijevic Y, Weiss S, Schneider B, et al. Insulin-like growth factor-I is necessary forneural stem cell proliferation and demonstrates distinct actions of epidermal growthfactor and fibroblast growth factor-2. J Neurosci,2001;21（18）:7194-7202.
26. Muller S, Chakrapani BP, Schwegler H, et al. Neurogenesis in the dentate gyrusdepends on ciliary neurotrophic factor and signal transducer and activator oftranscription3signaling. Stem Cells,2009;27（2）:431-441.
27. Zhang X, Jin G, Tian M, et al. The denervated hippocampus provides propermicroenvironment for the survival and differentiation of neural progenitors. NeurosciLett,2007;414（2）:115-120.
28. Sidman RL, Li J, Stewart GR, et al. Injection of mouse and human neural stem cellsinto neonatal Niemann-Pick A model mice. Brain Res,2007;1140:195-204.
29. Seri B, Garcia-Verdugo JM, McEwen BS, et al. Astrocytes give rise to new neurons inthe adult mammalian hippocampus. J Neurosci,2001;21（18）:7153-7160.
30. Fukuda S, Kato F, Tozuka Y, et al. Two distinct subpopulations of nestin-positive cellsin adult mouse dentate gyrus. J Neurosci,2003;23（28）:9357-9366.
31. Seri B, Garcia-Verdugo JM, Collado-Morente L, et al. Cell types, lineage, andarchitecture of the germinal zone in the adult dentate gyrus. J Comp Neurol,2004;478（4）:359-378.
32. Suh H, Consiglio A, Ray J, et al. In vivo fate analysis reveals the multipotent andself-renewal capacities of Sox2+neural stem cells in the adult hippocampus. Cell StemCell,2007;1（5）:515-528.
33. Liu Y, Namba T, Liu J, et al. Glial fibrillary acidic protein-expressing neuralprogenitors give rise to immature neurons via early intermediate progenitors expressingboth glial fibrillary acidic protein and neuronal markers in the adult hippocampus.Neuroscience,2010;166（1）:241-51.
34. Kronenberg G, Reuter K, Steiner B, et al. Subpopulations of proliferating cells of theadult hippocampus respond differently to physiologic neurogenic stimuli. J CompNeurol,2003;467（4）:455-463.
35. Kempermann G, Jessberger S, Steiner B, et al. Milestones of neuronal development inthe adult hippocampus. Trends Neurosci,2004;27（8）:447-452.
36. Simmons DK, Pang K, Martindale MQ. Lim homeobox genes in the CtenophoreMnemiopsis leidyi: the evolution of neural cell type specification. Evodevo,2012;3（1）:2.
37. Srivastava M, Larroux C, Lu DR, et al. Early evolution of the LIM homeobox genefamily. BMC Biol,2010;8:4.
38. Hung TM, Hu RH, Ho CM, et al. Downregulation of alpha-fetoprotein expression byLHX4: a critical role in hepatocarcinogenesis. Carcinogenesis,2011;32（12）:1815-1823.
39. Colvin SC, Mullen RD, Pfaeffle RW, et al. LHX3and LHX4transcription factors inpituitary development and disease. Pediatr Endocrinol Rev,2009;6Suppl2:283-290.
40. Bertrand N, Dahmane N. Sonic hedgehog signaling in forebrain development and itsinteractions with pathways that modify its effects. Trends Cell Biol,2006;16（11）:597-605.
41. Miquelajauregui A, Varela-Echavarria A, Ceci ML, et al. LIM-homeobox gene Lhx5is required for normal development of Cajal-Retzius cells. J Neurosci,2010;30（31）:10551-10562.
42. Sheng HZ, Bertuzzi S, Chiang C, et al. Expression of murine Lhx5suggests a role inspecifying the forebrain. Dev Dyn,1997;208（2）:266-277.
43. Filippov V, Kronenberg G, Pivneva T, et al. Subpopulation of nestin-expressingprogenitor cells in the adult murine hippocampus shows electrophysiological andmorphological characteristics of astrocytes. Mol Cell Neurosci,2003;23（3）:373-382.
44. Manabe T, Tatsumi K, Inoue M, et al. L3/Lhx8is a pivotal factor for cholinergicdifferentiation of murine embryonic stem cells. Cell Death Differ,2007;14（6）:1080-1085.
45. Manabe T, Tatsumi K, Inoue M, et al. Knockdown of the L3/Lhx8gene suppressescholinergic differentiation of murine embryonic stem cell-derived spheres. Int J DevNeurosci,2008;26（2）:249-252.
46. Manabe T, Tatsumi K, Inoue M, et al. L3/Lhx8is involved in the determination ofcholinergic or GABAergic cell fate. J Neurochem,2005;94（3）:723-730.
47. Schonemann MD, Ryan AK, Erkman L, et al. POU domain factors in neuraldevelopment. Adv Exp Med Biol,1998;449:39-53.
48. Latchman DS. POU family transcription factors in the nervous system. J Cell Physiol,1999;179（2）:126-133.
49. Ingraham HA, Albert VR, Chen RP, et al. A family of POU-domain and Pit-1tissue-specific transcription factors in pituitary and neuroendocrine development.Annu Rev Physiol,1990;52:773-791.
50. Josephson R, Muller T, Pickel J, et al. POU transcription factors control expression ofCNS stem cell-specific genes. Development,1998;125（16）:3087-3100.
51. Tan XF, Qin JB, Jin GH, et al. Effects of Brn-4on the neuronal differentiation ofneural stem cells derived from rat midbrain. Cell Biol Int,2010;34（9）:877-882.
52. Shi J, Jin G, Zhu H, et al. The role of Brn-4in the regulation of neural stem celldifferentiation into neurons. Neurosci Res,2010;67（1）:8-17.
53. Zhang X, Jin G, Wang L, et al. Brn-4is upregulated in the deafferented hippocampusand promotes neuronal differentiation of neural progenitors in vitro. Hippocampus,2009;19（2）:176-186.
54. Wu R, Jurek M, Sundarababu S, et al. The POU gene Brn-5is induced by neuregulinand is restricted to myelinating Schwann cells. Mol Cell Neurosci,2001;17（4）:683-695.
55. Shah N, Sukumar S. The Hox genes and their roles in oncogenesis. Nat Rev Cancer,2010;10（5）:361-371.
56. Thompson JA, Ziman M. Pax genes during neural development and their potentialrole in neuroregeneration. Prog Neurobiol,2011;95（3）:334-351.
57. Asami M, Pilz GA, Ninkovic J, et al. The role of Pax6in regulating the orientationand mode of cell division of progenitors in the mouse cerebral cortex. Development,2011;138（23）:5067-5078.
58. Zhao M, Li D, Shimazu K, et al. Fibroblast growth factor receptor-1is required forlong-term potentiation, memory consolidation, and neurogenesis. Biol Psychiatry,2007;62（5）:381-390.
59. Kuhn HG, Winkler J, Kempermann G, et al. Epidermal growth factor and fibroblastgrowth factor-2have different effects on neural progenitors in the adult rat brain. JNeurosci,1997;17（15）:5820-5829.
60. Aberg MA, Aberg ND, Hedbacker H, et al. Peripheral infusion of IGF-I selectivelyinduces neurogenesis in the adult rat hippocampus. J Neurosci,2000;20（8）:2896-2903.
61. Aberg MA, Aberg ND, Palmer TD, et al. IGF-I has a direct proliferative effect inadult hippocampal progenitor cells. Mol Cell Neurosci,2003;24（1）:23-40.
62. Trejo JL, Llorens-Martin MV, Torres-Aleman I. The effects of exercise on spatiallearning and anxiety-like behavior are mediated by an IGF-I-dependent mechanismrelated to hippocampal neurogenesis. Mol Cell Neurosci,2008;37（2）:402-411.
63. Schanzer A, Wachs FP, Wilhelm D, et al. Direct stimulation of adult neural stem cellsin vitro and neurogenesis in vivo by vascular endothelial growth factor. Brain Pathol,2004;14（3）:237-248.
64. Fabel K, Tam B, Kaufer D, et al. VEGF is necessary for exercise-induced adulthippocampal neurogenesis. Eur J Neurosci,2003;18（10）:2803-2812.
65. Manca A, Capsoni S, Di Luzio A, et al. Nerve growth factor regulates axial rotationduring early stages of chick embryo development. Proc Natl Acad Sci U S A,2012;109（6）:2009-2014.
66. Nagata T, Shinagawa S, Nukariya K, et al. Association between Nerve Growth FactorGene Polymorphism and Executive Dysfunction in Japanese Patients withEarly-Stage Alzheimer's Disease and Amnestic Mild Cognitive Impairment. DementGeriatr Cogn Disord,2012;32（6）:379-386.
67. Hayashi K, Ozaki N, Kawakita K, et al. Involvement of NGF in the rat model ofpersistent muscle pain associated with taut band. J Pain,2011;12（10）:1059-1068.
68. Scharfman H, Goodman J, Macleod A, et al. Increased neurogenesis and the ectopicgranule cells after intrahippocampal BDNF infusion in adult rats. Exp Neurol,2005;192（2）:348-356.
69. Lee J, Duan W, Mattson MP. Evidence that brain-derived neurotrophic factor isrequired for basal neurogenesis and mediates, in part, the enhancement ofneurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem,2002;82（6）:1367-1375.
70. Frielingsdorf H, Simpson DR, Thal LJ, et al. Nerve growth factor promotes survivalof new neurons in the adult hippocampus. Neurobiol Dis,2007;26（1）:47-55.
71. Shimode H, Ueki A, Morita Y. Nerve growth factor attenuates hippocampalcholinergic deficits and operant learning impairment in rats with entorhinal cortexlesions. Behav Pharmacol,2003;14（3）:179-190.
72. Shimazu K, Zhao M, Sakata K, et al. NT-3facilitates hippocampal plasticity andlearning and memory by regulating neurogenesis. Learn Mem,2006;13（3）:307-315.
73. Emsley JG, Hagg T. Endogenous and exogenous ciliary neurotrophic factor enhancesforebrain neurogenesis in adult mice. Exp Neurol,2003;183（2）:298-310.
74. Vereyken EJ, Bajova H, Chow S, et al. Chronic interleukin-6alters the level ofsynaptic proteins in hippocampus in culture and in vivo. Eur J Neurosci,2007;25（12）:3605-3616.
75. Stanley EM, Wilson MA, Fadel JR. Hippocampal neurotransmitter efflux duringone-trial novel object recognition in rats. Neurosci Lett,2012;511（1）:38-42.
76. Gould E, Cameron HA, McEwen BS. Blockade of NMDA receptors increases celldeath and birth in the developing rat dentate gyrus. J Comp Neurol,1994;340（4）:551-565.
77. Cameron HA, Tanapat P, Gould E. Adrenal steroids and N-methyl-D-aspartatereceptor activation regulate neurogenesis in the dentate gyrus of adult rats through acommon pathway. Neuroscience,1998;82（2）:349-354.
78. Bursztajn S, Falls WA, Berman SA, et al. Cell proliferation in the brains of NMDARNR1transgenic mice. Brain Res,2007;1172:10-20.
79. Jessberger S, Zhao C, Toni N, et al. Seizure-associated, aberrant neurogenesis in adultrats characterized with retrovirus-mediated cell labeling. J Neurosci,2007;27（35）:9400-9407.
80. Bai F, Bergeron M, Nelson DL. Chronic AMPA receptor potentiator （LY451646）treatment increases cell proliferation in adult rat hippocampus. Neuropharmacology,2003;44（8）:1013-1021.
81. Ge S, Goh EL, Sailor KA, et al. GABA regulates synaptic integration of newlygenerated neurons in the adult brain. Nature,2006;439（7076）:589-593.
82. Earnheart JC, Schweizer C, Crestani F, et al. GABAergic control of adulthippocampal neurogenesis in relation to behavior indicative of trait anxiety anddepression states. J Neurosci,2007;27（14）:3845-3854.
83. Tozuka Y, Fukuda S, Namba T, et al. GABAergic excitation promotes neuronaldifferentiation in adult hippocampal progenitor cells. Neuron,2005;47（6）:803-815.
84. Dominguez-Escriba L, Hernandez-Rabaza V, Soriano-Navarro M, et al. Chroniccocaine exposure impairs progenitor proliferation but spares survival and maturationof neural precursors in adult rat dentate gyrus. Eur J Neurosci,2006;24（2）:586-594.
85. Hoglinger GU, Rizk P, Muriel MP, et al. Dopamine depletion impairs precursor cellproliferation in Parkinson disease. Nat Neurosci,2004;7（7）:726-735.
86. Cooper-Kuhn CM, Winkler J, Kuhn HG. Decreased neurogenesis after cholinergicforebrain lesion in the adult rat. J Neurosci Res,2004;77（2）:155-165.
87. Kaneko N, Okano H, Sawamoto K. Role of the cholinergic system in regulatingsurvival of newborn neurons in the adult mouse dentate gyrus and olfactory bulb.Genes Cells,2006;11（10）:1145-1159.
88. Kotani S, Yamauchi T, Teramoto T, et al. Donepezil, an acetylcholinesterase inhibitor,enhances adult hippocampal neurogenesis. Chem Biol Interact,2008;175（1-3）:227-230.
89. Kotani S, Yamauchi T, Teramoto T, et al. Pharmacological evidence of cholinergicinvolvement in adult hippocampal neurogenesis in rats. Neuroscience,2006;142（2）:505-514.
90. Kulkarni VA, Jha S, Vaidya VA. Depletion of norepinephrine decreases the proliferation,but does not influence the survival and differentiation, of granule cell progenitors in theadult rat hippocampus. Eur J Neurosci,2002;16（10）:2008-2012.
91. Banasr M, Hery M, Brezun JM, et al. Serotonin mediates oestrogen stimulation of cellproliferation in the adult dentate gyrus. Eur J Neurosci,2001;14（9）:1417-1424.
92. Banasr M, Hery M, Printemps R, et al. Serotonin-induced increases in adult cellproliferation and neurogenesis are mediated through different and common5-HT receptorsubtypes in the dentate gyrus and the subventricular zone. Neuropsychopharmacology,2004;29（3）:450-460.
93. Reif A, Schmitt A, Fritzen S, et al. Differential effect of endothelial nitric oxide synthase（NOS-III）on the regulation of adult neurogenesis and behaviour. Eur J Neurosci,2004;20（4）:885-895.
94. Fritzen S, Schmitt A, Koth K, et al. Neuronal nitric oxide synthase （NOS-I） knockoutincreases the survival rate of neural cells in the hippocampus independently of BDNF. MolCell Neurosci,2007;35（2）:261-271.
95. Calza L, Fernandez M, Giuliani A, et al. Stem cells and nervous tissue repair: from invitro to in vivo. Prog Brain Res,2004;146:75-91.
96. Wu QY, Li J, Feng ZT, et al. Bone marrow stromal cells of transgenic mice canimprove the cognitive ability of an Alzheimer's disease rat model. Neurosci Lett,2007;417（3）:281-285.
97. Park D, Lee HJ, Joo SS, et al. Human neural stem cells over-expressing cholineacetyltransferase restore cognition in rat model of cognitive dysfunction. Exp Neurol,2012;234（2）:521-526.
98. Park D, Joo SS, Kim TK, et al. Human Neural Stem Cells Overexpressing CholineAcetyltransferase Restore Cognitive Function of Kainic Acid-Induced Learning andMemory Deficit Animals. Cell Transplant,2012,21（1）:365-371.
99. Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders.Biol Psychiatry2006;59（12）:1116-1127.
100. Ueyama T, Kawai Y, Nemoto K, et al. Immobilization stress reduced the expression ofneurotrophins and their receptors in the rat brain. Neurosci Res,1997;28（2）:103-110.
101. Heine VM, Zareno J, Maslam S, et al. Chronic stress in the adult dentate gyrusreduces cell proliferation near the vasculature and VEGF and Flk-1protein expression.Eur J Neurosci,2005;21（5）:1304-1314.
102. Schulz S, Zaiss A, Brunner R, et al. Conversion problems concerning automatedmapping from ICD-10to ICD-9. Methods Inf Med,1998;37（3）:254-259.
103. Howell OW, Doyle K, Goodman JH, et al. Neuropeptide Y stimulates neuronalprecursor proliferation in the post-natal and adult dentate gyrus. J Neurochem,2005;93（3）:560-570.
104. Howell OW, Silva S, Scharfman HE, et al. Neuropeptide Y is important for basal andseizure-induced precursor cell proliferation in the hippocampus. Neurobiol Dis,2007;26（1）:174-188.
105. Lie DC, Colamarino SA, Song HJ, et al. Wnt signalling regulates adult hippocampalneurogenesis. Nature,2005;437（7063）:1370-1375.
106. Breunig JJ, Silbereis J, Vaccarino FM, et al. Notch regulates cell fate and dendritemorphology of newborn neurons in the postnatal dentate gyrus. Proc Natl Acad Sci US A,2007;104（51）:20558-20563.
107. Xiao MJ, Han Z, Shao B, et al. Notch signaling and neurogenesis in normal and strokebrain. Int J Physiol Pathophysiol Pharmacol,2009;1（2）:192-202.
108. Lai K, Kaspar BK, Gage FH, et al. Sonic hedgehog regulates adult neural progenitorproliferation in vitro and in vivo. Nat Neurosci,2003;6（1）:21-27.
109. Banerjee SB, Rajendran R, Dias BG, et al. Recruitment of the Sonic hedgehogsignalling cascade in electroconvulsive seizure-mediated regulation of adult rathippocampal neurogenesis. Eur J Neurosci,2005;22（7）:1570-1580.
110. Fan XT, Xu HW, Cai WQ, et al. Antisense Noggin oligodeoxynucleotideadministration decreases cell proliferation in the dentate gyrus of adult rats. NeurosciLett,2004;366（1）:107-111.
111. Aguado T, Monory K, Palazuelos J, et al. The endocannabinoid system drives neuralprogenitor proliferation. FASEB J,2005;19（12）:1704-1706.
112. Koehl M, Meerlo P, Gonzales D, et al. Exercise-induced promotion of hippocampal cellproliferation requires beta-endorphin. FASEB J,2008;22（7）:2253-2262.
113. Spritzer MD, Galea LA. Testosterone and dihydrotestosterone, but not estradiol,enhance survival of new hippocampal neurons in adult male rats. Dev Neurobiol,2007;67（10）:1321-1333.
114. Brannvall K, Bogdanovic N, Korhonen L, et al.19-Nortestosterone influences neuralstem cell proliferation and neurogenesis in the rat brain. Eur J Neurosci,2005;21（4）:871-878.
2. Akhondzadeh S. Hippocampal synaptic plasticity and cognition. J Clin Pharm Ther,1999;24（4）:241-248.
3. Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells ofthe adult mammalian central nervous system. Science,1992;255（5052）:1707-1710.
4. Richards LJ, Kilpatrick TJ, Bartlett PF. De novo generation of neuronal cells from theadult mouse brain. Proc Natl Acad Sci U S A,1992;89（18）:8591-8595.
5. Ourednik V, Ourednik J, Flax JD, et al. Segregation of human neural stem cells in thedeveloping primate forebrain. Science,2001;293（5536）:1820-1824.
6. Palmer TD, Takahashi J, Gage FH. The adult rat hippocampus contains primordialneural stem cells. Mol Cell Neurosci,1997;8（6）:389-404.
7. Galli R, Gritti A, Bonfanti L, Vescovi AL. Neural stem cells: an overview. Circ Res,2003;92（6）:598-608.
8. Dutton R, Bartlett PF. Precursor cells in the subventricular zone of the adult mouseare actively inhibited from differentiating into neurons. Dev Neurosci,2000;22（1-2）:96-105.
9. Ma DK, Bonaguidi MA, Ming GL, Song H. Adult neural stem cells in the mammaliancentral nervous system. Cell Res,2009;19（6）:672-682.
10. Jordan JD, Ma DK, Ming GL, Song H. Cellular niches for endogenous neural stemcells in the adult brain. CNS Neurol Disord Drug Targets,2007;6（5）:336-341.
11. Taupin P. Adult neural stem cells, neurogenic niches, and cellular therapy. Stem CellRev,2006;2（3）:213-219.
12. Alvarez-Buylla A, Kohwi M, Nguyen TM, Merkle FT. The heterogeneity of adultneural stem cells and the emerging complexity of their niche. Cold Spring Harb SympQuant Biol,2008;73:357-365.
13. Nishino H, Hida H, Takei N, et al. Mesencephalic neural stem （progenitor） cellsdevelop to dopaminergic neurons more strongly in dopamine-depleted striatum thanin intact striatum. Exp Neurol,2000;164（1）:209-214.
14. Fricker RA, Carpenter MK, Winkler C, et al. Site-specific migration and neuronaldifferentiation of human neural progenitor cells after transplantation in the adult ratbrain. J Neurosci,1999;19（14）:5990-6005.
15. Brewer GJ. Regeneration and proliferation of embryonic and adult rat hippocampalneurons in culture. Exp Neurol,1999;159（1）:237-347.
16. Vicario-Abejon C, Collin C, Tsoulfas P, et al. Hippocampal stem cells differentiateinto excitatory and inhibitory neurons. Eur J Neurosci,2000;12（2）:677-688.
17. Ling ZD, Potter ED, Lipton JW, et al. Differentiation of mesencephalic progenitorcells into dopaminergic neurons by cytokines. Exp Neurol,1998;149（2）:411-423.
18. Flandin P, Zhao Y, Vogt D, et al. Lhx6and Lhx8coordinately induce neuronalexpression of Shh that controls the generation of interneuron progenitors. Neuron,2011;70（5）:939-950.
19. Zhao Y, Marin O, Hermesz E, et al. The LIM-homeobox gene Lhx8is required for thedevelopment of many cholinergic neurons in the mouse forebrain. Proc Natl Acad SciU S A,2003;100（15）:9005-9010.
20. Manabe T, Tatsumi K, Inoue M, et al. L3/Lhx8is a pivotal factor for cholinergicdifferentiation of murine embryonic stem cells. Cell Death Differ,2007;14（6）:1080-1085.
21. Tan XF, Jin GH, Tian ML, et al. The co-transduction of Nurr1and Brn4genes inducesthe differentiation of neural stem cells into dopaminergic neurons. Cell Biol Int,2011;35（12）:1217-1223.
22. Zhang X, Jin G, Wang L, et al. Brn-4is upregulated in the deafferented hippocampusand promotes neuronal differentiation of neural progenitors in vitro. Hippocampus,2009;19（2）:176-186.
23. Shi J, Jin G, Zhu H, et al. The role of Brn-4in the regulation of neural stem celldifferentiation into neurons. Neurosci Res,2010;67（1）:8-17.
24. Seri B, Garcia-Verdugo JM, Collado-Morente L, et al. Cell types, lineage, andarchitecture of the germinal zone in the adult dentate gyrus. J Comp Neurol,2004;478（4）:359-378.
25. Seri B, Garcia-Verdugo JM, McEwen BS, et al. Astrocytes give rise to new neurons inthe adult mammalian hippocampus. J Neurosci,2001;21（18）:7153-7160.
26. Fukuda S, Kato F, Tozuka Y, et al. Two distinct subpopulations of nestin-positive cellsin adult mouse dentate gyrus. J Neurosci,2003;23（28）:9357-9366.
27. Liu Y, Namba T, Liu J, et al. Glial fibrillary acidic protein-expressing neuralprogenitors give rise to immature neurons via early intermediate progenitorsexpressing both glial fibrillary acidic protein and neuronal markers in the adulthippocampus. Neuroscience,2010;166（1）:241-251.
28. Kronenberg G, Reuter K, Steiner B, et al. Subpopulations of proliferating cells of theadult hippocampus respond differently to physiologic neurogenic stimuli. J CompNeurol,2003;467（4）:455-463.
29. Kempermann G, Gage FH. Neurogenesis in the adult hippocampus. Novartis FoundSymp,2000;231:220-35; discussion235-241,302-306.
30. Kempermann G, Jessberger S, Steiner B, et al. Milestones of neuronal development inthe adult hippocampus. Trends Neurosci,2004;27（8）:447-452.
31. Bonaguidi MA, Wheeler MA, Shapiro JS, et al. In vivo clonal analysis revealsself-renewing and multipotent adult neural stem cell characteristics. Cell,2011;145（7）:1142-1155.
32. Conti L, Pollard SM, Gorba T, et al. Niche-independent symmetrical self-renewal of amammalian tissue stem cell. PLoS Biol,2005;3（9）:e283.
33. Glaser T, Brustle O. Retinoic acid induction of ES-cell-derived neurons: the radialglia connection. Trends Neurosci,2005;28（8）:397-400.
34. Glaser T, Pollard SM, Smith A, et al. Tripotential differentiation of adherentlyexpandable neural stem （NS） cells. PLoS One2007;2（3）:e298.
35. Li H, Jin G, Qin J, et al. Characterization and identification of Sox2+radial glia cellsderived from rat embryonic cerebral cortex. Histochem Cell Biol,2011;136（5）:515-526.
36. Li H, Jin G, Qin J, et al. Identification of neonatal rat hippocampal radial glia cells invitro. Neurosci Lett,2011;490（3）:209-214.
37. Zou L, Jin G, Zhang X, et al. Proliferation, migration, and neuronal differentiation ofthe endogenous neural progenitors in hippocampus after fimbria fornix transection.Int J Neurosci,2010;120（3）:192-200.
38. Zhang X, Jin G, Tian M, Qin J, Huang Z. The denervated hippocampus providesproper microenvironment for the survival and differentiation of neural progenitors.Neurosci Lett,2007;414（2）:115-120.
39. Simmons DK, Pang K, Martindale MQ. Lim homeobox genes in the CtenophoreMnemiopsis leidyi: the evolution of neural cell type specification. Evodevo,2012;3（1）:2.
40. Srivastava M, Larroux C, Lu DR, et al. Early evolution of the LIM homeobox genefamily. BMC Biol,2010;8:4.
41. Holland PW, Takahashi T. The evolution of homeobox genes: Implications for thestudy of brain development. Brain Res Bull,2005;66（4-6）:484-490.
42. Schonemann MD, Ryan AK, Erkman L, et al. POU domain factors in neuraldevelopment. Adv Exp Med Biol,1998;449:39-53.
43. Latchman DS. POU family transcription factors in the nervous system. J Cell Physiol,1999;179（2）:126-33.
44. Josephson R, Muller T, Pickel J, et al. POU transcription factors control expression ofCNS stem cell-specific genes. Development,1998;125（16）:3087-3100.
45. Kitanaka J, Takemura M, Matsumoto K, et al. Structure and chromosomal localizationof a murine LIM/homeobox gene, Lhx8. Genomics,1998;49（2）:307-309.
46. Shibaguchi T, Kato J, Abe M, et al. Expression and role of Lhx8in murine toothdevelopment. Arch Histol Cytol,2003;66（1）:95-108.
47. Zhang Y, Mori T, Takaki H, et al. Comparison of the expression patterns of twoLIM-homeodomain genes, Lhx6and L3/Lhx8, in the developing palate. OrthodCraniofac Res,2002;5（2）:65-70.
48. Zhao Y, Guo YJ, Tomac AC, et al. Isolated cleft palate in mice with a targetedmutation of the LIM homeobox gene lhx8. Proc Natl Acad Sci U S A,1999;96（26）:15002-15006.
49. Pangas SA, Choi Y, Ballow DJ, et al. Oogenesis requires germ cell-specifictranscriptional regulators Sohlh1and Lhx8. Proc Natl Acad Sci U S A,2006;103（21）:8090-8095.
50. Mori T, Yuxing Z, Takaki H, et al. The LIM homeobox gene, L3/Lhx8, is necessaryfor proper development of basal forebrain cholinergic neurons. Eur J Neurosci,2004;19（12）:3129-3141.
51. Manabe T, Tatsumi K, Inoue M, et al. Knockdown of the L3/Lhx8gene suppressescholinergic differentiation of murine embryonic stem cell-derived spheres. Int J DevNeurosci,2008;26（2）:249-252.
1. Ihrie RA, Alvarez-Buylla A. Cells in the astroglial lineage are neural stem cells. CellTissue Res,2008;331（1）:179-91.
2. Kriegstein AR, Gotz M. Radial glia diversity: a matter of cell fate. Glia,2003;43（1）:37-43.
3. Malatesta P, Appolloni I, Calzolari F. Radial glia and neural stem cells. Cell TissueRes,2008;331（1）:165-78.
4. Morrens J, Van Den Broeck W, Kempermann G. Glial cells in adult neurogenesis. Glia,2012;60（2）:159-74.
5. Li H, Jin G, Qin J, et al. Characterization and identification of Sox2+radial glia cellsderived from rat embryonic cerebral cortex. Histochem Cell Biol,2011;136（5）:515-26.
6. Zhang X, Jin G, Li W, et al. Ectopic neurogenesis in the forebrain cholinergicsystem-related areas of a rat dementia model. Stem Cells Dev,2011;20（9）:1627-38.
7. Zou L, Jin G, Zhang X, et al. Proliferation, migration, and neuronal differentiation ofthe endogenous neural progenitors in hippocampus after fimbria fornix transection.Int J Neurosci,2010;120（3）:192-200.
8. Zhang X, Jin G, Tian M, Qin J, et al. The denervated hippocampus provides propermicroenvironment for the survival and differentiation of neural progenitors. NeurosciLett,2007;414（2）:115-20.
9. Shi J, Jin G, Zhu H, et al. The role of Brn-4in the regulation of neural stem celldifferentiation into neurons. Neurosci Res,2010;67（1）:8-17.
10. Zhao H, Jin G, Tian M, Li H, et al. Extract of deafferented hippocampus promotes invitro radial glial cell differentiation into neurons. Neurosci Lett,2011;498（1）:93-8.
11. Seri B, Garcia-Verdugo JM, McEwen BS, et al. Astrocytes give rise to new neurons inthe adult mammalian hippocampus. J Neurosci,2001;21（18）:7153-60.
12. Fukuda S, Kato F, Tozuka Y, et al. Two distinct subpopulations of nestin-positive cellsin adult mouse dentate gyrus. J Neurosci,2003;23（28）:9357-66.
13. Seri B, Garcia-Verdugo JM, Collado-Morente L, et al. Cell types, lineage, andarchitecture of the germinal zone in the adult dentate gyrus. J Comp Neurol,2004;478（4）:359-78.
14. Suh H, Consiglio A, Ray J, et al. In vivo fate analysis reveals the multipotent andself-renewal capacities of Sox2+neural stem cells in the adult hippocampus. CellStem Cell,2007;1（5）:515-28.
15. Liu Y, Namba T, Liu J, et al. Glial fibrillary acidic protein-expressing neuralprogenitors give rise to immature neurons via early intermediate progenitorsexpressing both glial fibrillary acidic protein and neuronal markers in the adulthippocampus. Neuroscience,2010;166（1）:241-51.
16. Kempermann G, Jessberger S, et al. Milestones of neuronal development in the adulthippocampus. Trends Neurosci,2004;27（8）:447-52.
17. Bonaguidi MA, Wheeler MA, Shapiro JS, et al. In vivo clonal analysis revealsself-renewing and multipotent adult neural stem cell characteristics. Cell,2011;145（7）:1142-55.
18. Li H, Jin G, Qin J, et al. Identification of neonatal rat hippocampal radial glia cells invitro. Neurosci Lett,2011;490（3）:209-14.
19. Conti L, Pollard SM, Gorba T, et al. Niche-independent symmetrical self-renewal of amammalian tissue stem cell. PLoS Biol,2005;3（9）:e283.
20. Glaser T, Pollard SM, Smith A, Brustle O. Tripotential differentiation of adherentlyexpandable neural stem （NS） cells. PLoS One,2007;2（3）:e298.
21. Pollard SM, Conti L, Sun Y, et al. Adherent neural stem （NS） cells from fetal andadult forebrain. Cereb Cortex,2006;16Suppl1:i112-20.
22. Kronenberg G, Reuter K, Steiner B, et al. Subpopulations of proliferating cells of theadult hippocampus respond differently to physiologic neurogenic stimuli. J CompNeurol,2003;467（4）:455-63.
1. Zhao Y, Marin O, Hermesz E, et al. The LIM-homeobox gene Lhx8is required for thedevelopment of many cholinergic neurons in the mouse forebrain. Proc Natl Acad SciU S, A2003;100（15）:9005-9010.
2. Mori T, Yuxing Z, Takaki H, et al. The LIM homeobox gene, L3/Lhx8, is necessaryfor proper development of basal forebrain cholinergic neurons. Eur J Neurosci,2004;19（12）:3129-3141.
3. Manabe T, Tatsumi K, Inoue M, et al. L3/Lhx8is a pivotal factor for cholinergicdifferentiation of murine embryonic stem cells. Cell Death Differ,2007;14（6）:1080-1085.
4. Manabe T, Tatsumi K, Inoue M, et al. Knockdown of the L3/Lhx8gene suppressescholinergic differentiation of murine embryonic stem cell-derived spheres. Int J DevNeurosci,2008;26（2）:249-252.
5. Pfaffl MW. A new mathematical model for relative quantification in real-timeRT-PCR. Nucleic Acids Res,2001;29（9）:e45.
6. Simmons DK, Pang K, Martindale MQ. Lim homeobox genes in the CtenophoreMnemiopsis leidyi: the evolution of neural cell type specification. Evodevo,2012;3（1）:2.
7. Srivastava M, Larroux C, Lu DR, et al. Early evolution of the LIM homeobox genefamily. BMC Biol,2010;8:4.
8. Wang JQ, Hou L, Yi N,et al. Molecular analysis and its expression of a pou homeoboxprotein gene during development and in response to salinity stress from brine shrimp,Artemia sinica. Comp Biochem Physiol A Mol Integr Physiol,2012;161（1）:36-43.
9. Schonemann MD, Ryan AK, Erkman L, et al. POU domain factors in neuraldevelopment. Adv Exp Med Biol,1998;449:39-53.
10. Kitanaka J, Takemura M, Matsumoto K, et al. Structure and chromosomal localizationof a murine LIM/homeobox gene, Lhx8. Genomics,1998;49（2）:307-309.
11. Shibaguchi T, Kato J, Abe M, et al. Expression and role of Lhx8in murine toothdevelopment. Arch Histol Cytol,2003;66（1）:95-108.
12. Zhang Y, Mori T, Takaki H, et al. Comparison of the expression patterns of twoLIM-homeodomain genes, Lhx6and L3/Lhx8, in the developing palate. OrthodCraniofac Res,2002;5（2）:65-70.
13. Zhao Y, Guo YJ, Tomac AC, et al. Isolated cleft palate in mice with a targetedmutation of the LIM homeobox gene lhx8. Proc Natl Acad Sci U S A,1999;96（26）:15002-15006.
14. Pangas SA, Choi Y, Ballow DJ, et al. Oogenesis requires germ cell-specifictranscriptional regulators Sohlh1and Lhx8. Proc Natl Acad Sci U S A,2006;103（21）:8090-8095.
15. Jagarlamudi K, Rajkovic A. Oogenesis: Transcriptional regulators and mouse models.Mol Cell Endocrinol,2011.
16. Zhang X, Jin G, Tian M, et al. The denervated hippocampus provides propermicroenvironment for the survival and differentiation of neural progenitors. NeurosciLett,2007;414（2）:115-120.
17. Zou L, Jin G, Zhang X, et al. Proliferation, migration, and neuronal differentiation ofthe endogenous neural progenitors in hippocampus after fimbria fornix transection.Int J Neurosci,2010;120（3）:192-200.
18. Liu Y, Namba T, Liu J, et al. Glial fibrillary acidic protein-expressing neuralprogenitors give rise to immature neurons via early intermediate progenitorsexpressing both glial fibrillary acidic protein and neuronal markers in the adulthippocampus. Neuroscience,2010;166（1）:241-251.
19. Brunne B, Zhao S, Derouiche A, et al. Origin, maturation, and astroglialtransformation of secondary radial glial cells in the developing dentate gyrus. Glia,2010;58（13）:1553-1569.
20. Suh H, Consiglio A, Ray J, et al. In vivo fate analysis reveals the multipotent andself-renewal capacities of Sox2+neural stem cells in the adult hippocampus. CellStem Cell,2007;1（5）:515-528.
21. Kronenberg G, Reuter K, Steiner B, et al. Subpopulations of proliferating cells of theadult hippocampus respond differently to physiologic neurogenic stimuli. J CompNeurol,2003;467（4）:455-463.
1. Zou L, Jin G, Zhang X, et al. Proliferation, migration, and neuronal differentiation ofthe endogenous neural progenitors in hippocampus after fimbria fornix transection.Int J Neurosci,2010;120（3）:192-200.
2. Zhang X, Jin G, Tian M, et al. The denervated hippocampus provides propermicroenvironment for the survival and differentiation of neural progenitors. NeurosciLett,2007;414（2）:115-120.
3. Zhao H, Jin G, Tian M, et al. Extract of deafferented hippocampus promotes in vitroradial glial cell differentiation into neurons. Neurosci Lett,2011;498（1）:93-98.
4. Kitanaka J, Takemura M, Matsumoto K, et al. Structure and chromosomal localizationof a murine LIM/homeobox gene, Lhx8. Genomics,1998;49（2）:307-309.
5. Manabe T, Tatsumi K, Inoue M, et al. L3/Lhx8is a pivotal factor for cholinergicdifferentiation of murine embryonic stem cells. Cell Death Differ,2007;14（6）:1080-1085.
6. Manabe T, Tatsumi K, Inoue M, et al. Knockdown of the L3/Lhx8gene suppressescholinergic differentiation of murine embryonic stem cell-derived spheres. Int J DevNeurosci,2008;26（2）:249-252.
7. Manabe T, Tatsumi K, Inoue M, et al. L3/Lhx8is involved in the determination ofcholinergic or GABAergic cell fate. J Neurochem,2005;94（3）:723-730.
8. Pfaffl MW. A new mathematical model for relative quantification in real-timeRT-PCR. Nucleic Acids Res,2001;29（9）:e45.
9. Bruel-Jungerman E, Rampon C, Laroche S. Adult hippocampal neurogenesis,synaptic plasticity and memory: facts and hypotheses. Rev Neurosci,2007;18（2）:93-114.
10. DeCarolis NA, Eisch AJ. Hippocampal neurogenesis as a target for the treatment ofmental illness: a critical evaluation. Neuropharmacology,2010;58（6）:884-893.
11. Gould E, McEwen BS, Tanapat P, et al. Neurogenesis in the dentate gyrus of the adulttree shrew is regulated by psychosocial stress and NMDA receptor activation. JNeurosci,1997;17（7）:2492-2498.
12. Fricker RA, Carpenter MK, Winkler C, et al. Site-specific migration and neuronaldifferentiation of human neural progenitor cells after transplantation in the adult ratbrain. J Neurosci,1999;19（14）:5990-6005.
13. Seri B, Garcia-Verdugo JM, McEwen BS, Alvarez-Buylla A. Astrocytes give rise tonew neurons in the adult mammalian hippocampus. J Neurosci,2001;21（18）:7153-7160.
14. Liu Y, Namba T, Liu J, et al. Glial fibrillary acidic protein-expressing neuralprogenitors give rise to immature neurons via early intermediate progenitorsexpressing both glial fibrillary acidic protein and neuronal markers in the adulthippocampus. Neuroscience,2010;166（1）:241-251.
15. Seri B, Garcia-Verdugo JM, Collado-Morente L, McEwen BS, Alvarez-Buylla A. Celltypes, lineage, and architecture of the germinal zone in the adult dentate gyrus. JComp Neurol,2004;478（4）:359-378.
16. Simmons DK, Pang K, Martindale MQ. Lim homeobox genes in the CtenophoreMnemiopsis leidyi: the evolution of neural cell type specification. Evodevo,2012;3（1）:2.
17. Srivastava M, Larroux C, Lu DR, et al. Early evolution of the LIM homeobox genefamily. BMC Biol,2010;8:4.
18. Hung TM, Hu RH, Ho CM, et al. Downregulation of alpha-fetoprotein expression byLHX4: a critical role in hepatocarcinogenesis. Carcinogenesis,2011;32（12）:1815-1823.
19. Colvin SC, Mullen RD, Pfaeffle RW, et al. LHX3and LHX4transcription factors inpituitary development and disease. Pediatr Endocrinol Rev,2009;6Suppl2:283-90.
20. Bertrand N, Dahmane N. Sonic hedgehog signaling in forebrain development and itsinteractions with pathways that modify its effects. Trends Cell Biol,2006;16（11）:597-605.
21. Sheng HZ, Bertuzzi S, Chiang C, et al. Expression of murine Lhx5suggests a role inspecifying the forebrain. Dev Dyn,1997;208（2）:266-277.
22. Mori T, Yuxing Z, Takaki H, et al. The LIM homeobox gene, L3/Lhx8, is necessaryfor proper development of basal forebrain cholinergic neurons. Eur J Neurosci,2004;19（12）:3129-3141.
1. Doetsch F. A niche for adult neural stem cells. Curr Opin Genet Dev,2003;13（5）:543-550.
2. Kempermann G, Gage FH. Neurogenesis in the adult hippocampus. Novartis Found,Symp2000;231:220-235; discussion235-41,302-306.
3. Kazanis I, Lathia J, Moss L, et al. The neural stem cell, microenvironment.2008.
4. Balu DT, Lucki I. Adult hippocampal neurogenesis: regulation, functional implications,and contribution to disease pathology. Neurosci Biobehav Rev,2009;33（3）:232-352.
5. Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells ofthe adult mammalian central nervous system. Science,1992;255（5052）:1707-1710.
6. Richards LJ, Kilpatrick TJ, Bartlett PF. De novo generation of neuronal cells from theadult mouse brain. Proc Natl Acad Sci U S A,1992;89（18）:8591-8595.
7. Taupin P, Gage FH. Adult neurogenesis and neural stem cells of the central nervoussystem in mammals. J Neurosci Res,2002;69（6）:745-749.
8. Seaberg RM, van der Kooy D. Adult rodent neurogenic regions: the ventricularsubependyma contains neural stem cells, but the dentate gyrus contains restrictedprogenitors. J Neurosci,2002;22（5）:1784-1793.
9. Bull ND, Bartlett PF. The adult mouse hippocampal progenitor is neurogenic but not astem cell. J Neurosci,2005;25（47）:10815-10821.
10. Shors TJ, Townsend DA, Zhao M, et al. Neurogenesis may relate to some but not alltypes of hippocampal-dependent learning. Hippocampus,2002;12（5）:578-584.
11. Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adultneurogenesis. Cell,2008;132（4）:645-660.
12. Warner-Schmidt JL, Duman RS. Hippocampal neurogenesis: opposing effects ofstress and antidepressant treatment. Hippocampus,2006;16（3）:239-249.
13. Dranovsky A, Hen R. Hippocampal neurogenesis: regulation by stress andantidepressants. Biol Psychiatry,2006;59（12）:1136-1143.
14. Parent JM, Murphy GG. Mechanisms and functional significance of aberrantseizure-induced hippocampal neurogenesis. Epilepsia,2008;49Suppl5:19-25.
15. Parent JM, Elliott RC, Pleasure SJ, et al. Aberrant seizure-induced neurogenesis inexperimental temporal lobe epilepsy. Ann Neurol,2006;59（1）:81-91.
16. Kallur T, Farr TD, Bohm-Sturm P, et al. Spatio-temporal dynamics, differentiation andviability of human neural stem cells after implantation into neonatal rat brain. Eur JNeurosci,2011;34（3）:382-393.
17. Shear DA, Tate CC, Tate MC, et al. Stem cell survival and functional outcome aftertraumatic brain injury is dependent on transplant timing and location. Restor NeurolNeurosci,2011;29（4）:215-225.
18. Lois C, Garcia-Verdugo JM, Alvarez-Buylla A. Chain migration of neuronalprecursors. Science,1996;271（5251）:978-981.
19. Zou L, Jin G, Zhang X, et al. Proliferation, migration, and neuronal differentiation ofthe endogenous neural progenitors in hippocampus after fimbria fornix transection.Int J Neurosci,2010;120（3）:192-200.
20. Ostenfeld T, Svendsen CN. Requirement for neurogenesis to proceed through thedivision of neuronal progenitors following differentiation of epidermal growth factorand fibroblast growth factor-2-responsive human neural stem cells. Stem Cells,2004;22（5）:798-811.
21. Duan SR, Wang HH, Qi JP, et al. Influences of bFGF and EGF on the proliferationand differentiation of endogenous neural stem cells after cerebral infarction in human.Zhonghua Yi Xue Za Zhi,2008;88（47）:3337-3341.
22. Mudo G, Bonomo A, Di Liberto V, et al. The FGF-2/FGFRs neurotrophic systempromotes neurogenesis in the adult brain. J Neural Transm,2009;116（8）:995-1005.
23. Bauer S, Patterson PH. Leukemia inhibitory factor promotes neural stem cellself-renewal in the adult brain. J Neurosci,2006;26（46）:12089-12099.
24. Gonzalez-Perez O, Jauregui-Huerta F, Galvez-Contreras AY. Immune system modulatesthe function of adult neural stem cells. Curr Immunol Rev,2010;6（3）:167-173.
25. Arsenijevic Y, Weiss S, Schneider B, et al. Insulin-like growth factor-I is necessary forneural stem cell proliferation and demonstrates distinct actions of epidermal growthfactor and fibroblast growth factor-2. J Neurosci,2001;21（18）:7194-7202.
26. Muller S, Chakrapani BP, Schwegler H, et al. Neurogenesis in the dentate gyrusdepends on ciliary neurotrophic factor and signal transducer and activator oftranscription3signaling. Stem Cells,2009;27（2）:431-441.
27. Zhang X, Jin G, Tian M, et al. The denervated hippocampus provides propermicroenvironment for the survival and differentiation of neural progenitors. NeurosciLett,2007;414（2）:115-120.
28. Sidman RL, Li J, Stewart GR, et al. Injection of mouse and human neural stem cellsinto neonatal Niemann-Pick A model mice. Brain Res,2007;1140:195-204.
29. Seri B, Garcia-Verdugo JM, McEwen BS, et al. Astrocytes give rise to new neurons inthe adult mammalian hippocampus. J Neurosci,2001;21（18）:7153-7160.
30. Fukuda S, Kato F, Tozuka Y, et al. Two distinct subpopulations of nestin-positive cellsin adult mouse dentate gyrus. J Neurosci,2003;23（28）:9357-9366.
31. Seri B, Garcia-Verdugo JM, Collado-Morente L, et al. Cell types, lineage, andarchitecture of the germinal zone in the adult dentate gyrus. J Comp Neurol,2004;478（4）:359-378.
32. Suh H, Consiglio A, Ray J, et al. In vivo fate analysis reveals the multipotent andself-renewal capacities of Sox2+neural stem cells in the adult hippocampus. Cell StemCell,2007;1（5）:515-528.
33. Liu Y, Namba T, Liu J, et al. Glial fibrillary acidic protein-expressing neuralprogenitors give rise to immature neurons via early intermediate progenitors expressingboth glial fibrillary acidic protein and neuronal markers in the adult hippocampus.Neuroscience,2010;166（1）:241-51.
34. Kronenberg G, Reuter K, Steiner B, et al. Subpopulations of proliferating cells of theadult hippocampus respond differently to physiologic neurogenic stimuli. J CompNeurol,2003;467（4）:455-463.
35. Kempermann G, Jessberger S, Steiner B, et al. Milestones of neuronal development inthe adult hippocampus. Trends Neurosci,2004;27（8）:447-452.
36. Simmons DK, Pang K, Martindale MQ. Lim homeobox genes in the CtenophoreMnemiopsis leidyi: the evolution of neural cell type specification. Evodevo,2012;3（1）:2.
37. Srivastava M, Larroux C, Lu DR, et al. Early evolution of the LIM homeobox genefamily. BMC Biol,2010;8:4.
38. Hung TM, Hu RH, Ho CM, et al. Downregulation of alpha-fetoprotein expression byLHX4: a critical role in hepatocarcinogenesis. Carcinogenesis,2011;32（12）:1815-1823.
39. Colvin SC, Mullen RD, Pfaeffle RW, et al. LHX3and LHX4transcription factors inpituitary development and disease. Pediatr Endocrinol Rev,2009;6Suppl2:283-290.
40. Bertrand N, Dahmane N. Sonic hedgehog signaling in forebrain development and itsinteractions with pathways that modify its effects. Trends Cell Biol,2006;16（11）:597-605.
41. Miquelajauregui A, Varela-Echavarria A, Ceci ML, et al. LIM-homeobox gene Lhx5is required for normal development of Cajal-Retzius cells. J Neurosci,2010;30（31）:10551-10562.
42. Sheng HZ, Bertuzzi S, Chiang C, et al. Expression of murine Lhx5suggests a role inspecifying the forebrain. Dev Dyn,1997;208（2）:266-277.
43. Filippov V, Kronenberg G, Pivneva T, et al. Subpopulation of nestin-expressingprogenitor cells in the adult murine hippocampus shows electrophysiological andmorphological characteristics of astrocytes. Mol Cell Neurosci,2003;23（3）:373-382.
44. Manabe T, Tatsumi K, Inoue M, et al. L3/Lhx8is a pivotal factor for cholinergicdifferentiation of murine embryonic stem cells. Cell Death Differ,2007;14（6）:1080-1085.
45. Manabe T, Tatsumi K, Inoue M, et al. Knockdown of the L3/Lhx8gene suppressescholinergic differentiation of murine embryonic stem cell-derived spheres. Int J DevNeurosci,2008;26（2）:249-252.
46. Manabe T, Tatsumi K, Inoue M, et al. L3/Lhx8is involved in the determination ofcholinergic or GABAergic cell fate. J Neurochem,2005;94（3）:723-730.
47. Schonemann MD, Ryan AK, Erkman L, et al. POU domain factors in neuraldevelopment. Adv Exp Med Biol,1998;449:39-53.
48. Latchman DS. POU family transcription factors in the nervous system. J Cell Physiol,1999;179（2）:126-133.
49. Ingraham HA, Albert VR, Chen RP, et al. A family of POU-domain and Pit-1tissue-specific transcription factors in pituitary and neuroendocrine development.Annu Rev Physiol,1990;52:773-791.
50. Josephson R, Muller T, Pickel J, et al. POU transcription factors control expression ofCNS stem cell-specific genes. Development,1998;125（16）:3087-3100.
51. Tan XF, Qin JB, Jin GH, et al. Effects of Brn-4on the neuronal differentiation ofneural stem cells derived from rat midbrain. Cell Biol Int,2010;34（9）:877-882.
52. Shi J, Jin G, Zhu H, et al. The role of Brn-4in the regulation of neural stem celldifferentiation into neurons. Neurosci Res,2010;67（1）:8-17.
53. Zhang X, Jin G, Wang L, et al. Brn-4is upregulated in the deafferented hippocampusand promotes neuronal differentiation of neural progenitors in vitro. Hippocampus,2009;19（2）:176-186.
54. Wu R, Jurek M, Sundarababu S, et al. The POU gene Brn-5is induced by neuregulinand is restricted to myelinating Schwann cells. Mol Cell Neurosci,2001;17（4）:683-695.
55. Shah N, Sukumar S. The Hox genes and their roles in oncogenesis. Nat Rev Cancer,2010;10（5）:361-371.
56. Thompson JA, Ziman M. Pax genes during neural development and their potentialrole in neuroregeneration. Prog Neurobiol,2011;95（3）:334-351.
57. Asami M, Pilz GA, Ninkovic J, et al. The role of Pax6in regulating the orientationand mode of cell division of progenitors in the mouse cerebral cortex. Development,2011;138（23）:5067-5078.
58. Zhao M, Li D, Shimazu K, et al. Fibroblast growth factor receptor-1is required forlong-term potentiation, memory consolidation, and neurogenesis. Biol Psychiatry,2007;62（5）:381-390.
59. Kuhn HG, Winkler J, Kempermann G, et al. Epidermal growth factor and fibroblastgrowth factor-2have different effects on neural progenitors in the adult rat brain. JNeurosci,1997;17（15）:5820-5829.
60. Aberg MA, Aberg ND, Hedbacker H, et al. Peripheral infusion of IGF-I selectivelyinduces neurogenesis in the adult rat hippocampus. J Neurosci,2000;20（8）:2896-2903.
61. Aberg MA, Aberg ND, Palmer TD, et al. IGF-I has a direct proliferative effect inadult hippocampal progenitor cells. Mol Cell Neurosci,2003;24（1）:23-40.
62. Trejo JL, Llorens-Martin MV, Torres-Aleman I. The effects of exercise on spatiallearning and anxiety-like behavior are mediated by an IGF-I-dependent mechanismrelated to hippocampal neurogenesis. Mol Cell Neurosci,2008;37（2）:402-411.
63. Schanzer A, Wachs FP, Wilhelm D, et al. Direct stimulation of adult neural stem cellsin vitro and neurogenesis in vivo by vascular endothelial growth factor. Brain Pathol,2004;14（3）:237-248.
64. Fabel K, Tam B, Kaufer D, et al. VEGF is necessary for exercise-induced adulthippocampal neurogenesis. Eur J Neurosci,2003;18（10）:2803-2812.
65. Manca A, Capsoni S, Di Luzio A, et al. Nerve growth factor regulates axial rotationduring early stages of chick embryo development. Proc Natl Acad Sci U S A,2012;109（6）:2009-2014.
66. Nagata T, Shinagawa S, Nukariya K, et al. Association between Nerve Growth FactorGene Polymorphism and Executive Dysfunction in Japanese Patients withEarly-Stage Alzheimer's Disease and Amnestic Mild Cognitive Impairment. DementGeriatr Cogn Disord,2012;32（6）:379-386.
67. Hayashi K, Ozaki N, Kawakita K, et al. Involvement of NGF in the rat model ofpersistent muscle pain associated with taut band. J Pain,2011;12（10）:1059-1068.
68. Scharfman H, Goodman J, Macleod A, et al. Increased neurogenesis and the ectopicgranule cells after intrahippocampal BDNF infusion in adult rats. Exp Neurol,2005;192（2）:348-356.
69. Lee J, Duan W, Mattson MP. Evidence that brain-derived neurotrophic factor isrequired for basal neurogenesis and mediates, in part, the enhancement ofneurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem,2002;82（6）:1367-1375.
70. Frielingsdorf H, Simpson DR, Thal LJ, et al. Nerve growth factor promotes survivalof new neurons in the adult hippocampus. Neurobiol Dis,2007;26（1）:47-55.
71. Shimode H, Ueki A, Morita Y. Nerve growth factor attenuates hippocampalcholinergic deficits and operant learning impairment in rats with entorhinal cortexlesions. Behav Pharmacol,2003;14（3）:179-190.
72. Shimazu K, Zhao M, Sakata K, et al. NT-3facilitates hippocampal plasticity andlearning and memory by regulating neurogenesis. Learn Mem,2006;13（3）:307-315.
73. Emsley JG, Hagg T. Endogenous and exogenous ciliary neurotrophic factor enhancesforebrain neurogenesis in adult mice. Exp Neurol,2003;183（2）:298-310.
74. Vereyken EJ, Bajova H, Chow S, et al. Chronic interleukin-6alters the level ofsynaptic proteins in hippocampus in culture and in vivo. Eur J Neurosci,2007;25（12）:3605-3616.
75. Stanley EM, Wilson MA, Fadel JR. Hippocampal neurotransmitter efflux duringone-trial novel object recognition in rats. Neurosci Lett,2012;511（1）:38-42.
76. Gould E, Cameron HA, McEwen BS. Blockade of NMDA receptors increases celldeath and birth in the developing rat dentate gyrus. J Comp Neurol,1994;340（4）:551-565.
77. Cameron HA, Tanapat P, Gould E. Adrenal steroids and N-methyl-D-aspartatereceptor activation regulate neurogenesis in the dentate gyrus of adult rats through acommon pathway. Neuroscience,1998;82（2）:349-354.
78. Bursztajn S, Falls WA, Berman SA, et al. Cell proliferation in the brains of NMDARNR1transgenic mice. Brain Res,2007;1172:10-20.
79. Jessberger S, Zhao C, Toni N, et al. Seizure-associated, aberrant neurogenesis in adultrats characterized with retrovirus-mediated cell labeling. J Neurosci,2007;27（35）:9400-9407.
80. Bai F, Bergeron M, Nelson DL. Chronic AMPA receptor potentiator （LY451646）treatment increases cell proliferation in adult rat hippocampus. Neuropharmacology,2003;44（8）:1013-1021.
81. Ge S, Goh EL, Sailor KA, et al. GABA regulates synaptic integration of newlygenerated neurons in the adult brain. Nature,2006;439（7076）:589-593.
82. Earnheart JC, Schweizer C, Crestani F, et al. GABAergic control of adulthippocampal neurogenesis in relation to behavior indicative of trait anxiety anddepression states. J Neurosci,2007;27（14）:3845-3854.
83. Tozuka Y, Fukuda S, Namba T, et al. GABAergic excitation promotes neuronaldifferentiation in adult hippocampal progenitor cells. Neuron,2005;47（6）:803-815.
84. Dominguez-Escriba L, Hernandez-Rabaza V, Soriano-Navarro M, et al. Chroniccocaine exposure impairs progenitor proliferation but spares survival and maturationof neural precursors in adult rat dentate gyrus. Eur J Neurosci,2006;24（2）:586-594.
85. Hoglinger GU, Rizk P, Muriel MP, et al. Dopamine depletion impairs precursor cellproliferation in Parkinson disease. Nat Neurosci,2004;7（7）:726-735.
86. Cooper-Kuhn CM, Winkler J, Kuhn HG. Decreased neurogenesis after cholinergicforebrain lesion in the adult rat. J Neurosci Res,2004;77（2）:155-165.
87. Kaneko N, Okano H, Sawamoto K. Role of the cholinergic system in regulatingsurvival of newborn neurons in the adult mouse dentate gyrus and olfactory bulb.Genes Cells,2006;11（10）:1145-1159.
88. Kotani S, Yamauchi T, Teramoto T, et al. Donepezil, an acetylcholinesterase inhibitor,enhances adult hippocampal neurogenesis. Chem Biol Interact,2008;175（1-3）:227-230.
89. Kotani S, Yamauchi T, Teramoto T, et al. Pharmacological evidence of cholinergicinvolvement in adult hippocampal neurogenesis in rats. Neuroscience,2006;142（2）:505-514.
90. Kulkarni VA, Jha S, Vaidya VA. Depletion of norepinephrine decreases the proliferation,but does not influence the survival and differentiation, of granule cell progenitors in theadult rat hippocampus. Eur J Neurosci,2002;16（10）:2008-2012.
91. Banasr M, Hery M, Brezun JM, et al. Serotonin mediates oestrogen stimulation of cellproliferation in the adult dentate gyrus. Eur J Neurosci,2001;14（9）:1417-1424.
92. Banasr M, Hery M, Printemps R, et al. Serotonin-induced increases in adult cellproliferation and neurogenesis are mediated through different and common5-HT receptorsubtypes in the dentate gyrus and the subventricular zone. Neuropsychopharmacology,2004;29（3）:450-460.
93. Reif A, Schmitt A, Fritzen S, et al. Differential effect of endothelial nitric oxide synthase（NOS-III）on the regulation of adult neurogenesis and behaviour. Eur J Neurosci,2004;20（4）:885-895.
94. Fritzen S, Schmitt A, Koth K, et al. Neuronal nitric oxide synthase （NOS-I） knockoutincreases the survival rate of neural cells in the hippocampus independently of BDNF. MolCell Neurosci,2007;35（2）:261-271.
95. Calza L, Fernandez M, Giuliani A, et al. Stem cells and nervous tissue repair: from invitro to in vivo. Prog Brain Res,2004;146:75-91.
96. Wu QY, Li J, Feng ZT, et al. Bone marrow stromal cells of transgenic mice canimprove the cognitive ability of an Alzheimer's disease rat model. Neurosci Lett,2007;417（3）:281-285.
97. Park D, Lee HJ, Joo SS, et al. Human neural stem cells over-expressing cholineacetyltransferase restore cognition in rat model of cognitive dysfunction. Exp Neurol,2012;234（2）:521-526.
98. Park D, Joo SS, Kim TK, et al. Human Neural Stem Cells Overexpressing CholineAcetyltransferase Restore Cognitive Function of Kainic Acid-Induced Learning andMemory Deficit Animals. Cell Transplant,2012,21（1）:365-371.
99. Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders.Biol Psychiatry2006;59（12）:1116-1127.
100. Ueyama T, Kawai Y, Nemoto K, et al. Immobilization stress reduced the expression ofneurotrophins and their receptors in the rat brain. Neurosci Res,1997;28（2）:103-110.
101. Heine VM, Zareno J, Maslam S, et al. Chronic stress in the adult dentate gyrusreduces cell proliferation near the vasculature and VEGF and Flk-1protein expression.Eur J Neurosci,2005;21（5）:1304-1314.
102. Schulz S, Zaiss A, Brunner R, et al. Conversion problems concerning automatedmapping from ICD-10to ICD-9. Methods Inf Med,1998;37（3）:254-259.
103. Howell OW, Doyle K, Goodman JH, et al. Neuropeptide Y stimulates neuronalprecursor proliferation in the post-natal and adult dentate gyrus. J Neurochem,2005;93（3）:560-570.
104. Howell OW, Silva S, Scharfman HE, et al. Neuropeptide Y is important for basal andseizure-induced precursor cell proliferation in the hippocampus. Neurobiol Dis,2007;26（1）:174-188.
105. Lie DC, Colamarino SA, Song HJ, et al. Wnt signalling regulates adult hippocampalneurogenesis. Nature,2005;437（7063）:1370-1375.
106. Breunig JJ, Silbereis J, Vaccarino FM, et al. Notch regulates cell fate and dendritemorphology of newborn neurons in the postnatal dentate gyrus. Proc Natl Acad Sci US A,2007;104（51）:20558-20563.
107. Xiao MJ, Han Z, Shao B, et al. Notch signaling and neurogenesis in normal and strokebrain. Int J Physiol Pathophysiol Pharmacol,2009;1（2）:192-202.
108. Lai K, Kaspar BK, Gage FH, et al. Sonic hedgehog regulates adult neural progenitorproliferation in vitro and in vivo. Nat Neurosci,2003;6（1）:21-27.
109. Banerjee SB, Rajendran R, Dias BG, et al. Recruitment of the Sonic hedgehogsignalling cascade in electroconvulsive seizure-mediated regulation of adult rathippocampal neurogenesis. Eur J Neurosci,2005;22（7）:1570-1580.
110. Fan XT, Xu HW, Cai WQ, et al. Antisense Noggin oligodeoxynucleotideadministration decreases cell proliferation in the dentate gyrus of adult rats. NeurosciLett,2004;366（1）:107-111.
111. Aguado T, Monory K, Palazuelos J, et al. The endocannabinoid system drives neuralprogenitor proliferation. FASEB J,2005;19（12）:1704-1706.
112. Koehl M, Meerlo P, Gonzales D, et al. Exercise-induced promotion of hippocampal cellproliferation requires beta-endorphin. FASEB J,2008;22（7）:2253-2262.
113. Spritzer MD, Galea LA. Testosterone and dihydrotestosterone, but not estradiol,enhance survival of new hippocampal neurons in adult male rats. Dev Neurobiol,2007;67（10）:1321-1333.
114. Brannvall K, Bogdanovic N, Korhonen L, et al.19-Nortestosterone influences neuralstem cell proliferation and neurogenesis in the rat brain. Eur J Neurosci,2005;21（4）:871-878.