Chen Yan, Ai Yi, Slevin John R, Maley Bruce E, Gash Don M
Department of Anatomy and Neurobiology, University of Kentucky Medical Center, 317 Whitney Hendrickson Building (MRISC), Lexington, KY 40536-0098, USA.
Exp Neurol. 2005 Nov;196(1):87-95. doi: 10.1016/j.expneurol.2005.07.010. Epub 2005 Aug 19.
Neurogenesis is an ongoing process in the hippocampus and olfactory bulb of adult mammals, regulated in part by trophic factors. While glial cell line-derived neurotrophic factor (GDNF) is being directly delivered into the nigrostriatal system of the brain for the treatment of Parkinson's disease in clinical trials, little is known about its effects on cell genesis in the brain. Here, we investigated the effects of GDNF on progenitor cell proliferation and differentiation in two GDNF-responsive areas, the hippocampus and substantia nigra. GDNF (18 microg/day) was infused in the striatum of 2-month-old Sprague-Dawley rats for 28 days. New cells were identified by the nuclear incorporation of 5-bromo-2-deoxyuridine (BrdU) and analyzed by light and electron microscopic immunostaining and quantitative morphometric techniques. GDNF significantly increased cell proliferation in the hippocampus by 78% and in the substantia nigra by 52%. There was no evidence of neurogenesis in the substantia nigra, with new cells displaying glial features and none of the 1549 BrdU-positive cells co-labeled for the dopamine neuronal marker tyrosine hydroxylase (TH). Rather, GDNF upregulated TH in existing neurons, consistent with the restorative actions of this tropic factor. The hippocampus is a site that supports adult neurogenesis and new cells generated here were closely associated with granule cells in the dentate gyrus. Some were double labeled for the neuronal marker NeuN; others had features of astrocytes, the principal source of new adult neurons in the hippocampus. The effects of GDNF on the hippocampus are potentially important in memory and learning processes.
神经发生是成年哺乳动物海马体和嗅球中一个持续进行的过程，部分受营养因子调控。虽然在临床试验中，胶质细胞源性神经营养因子（GDNF）正被直接注入大脑的黑质纹状体系统以治疗帕金森病，但对于其对大脑细胞生成的影响却知之甚少。在此，我们研究了GDNF对两个GDNF反应区域，即海马体和黑质中祖细胞增殖与分化的影响。将GDNF（18微克/天）注入2月龄Sprague-Dawley大鼠的纹状体中，持续28天。通过5-溴-2-脱氧尿苷（BrdU）的核掺入来识别新细胞，并通过光镜和电镜免疫染色以及定量形态计量学技术进行分析。GDNF使海马体中的细胞增殖显著增加了78%，使黑质中的细胞增殖显著增加了52%。黑质中没有神经发生的证据，新细胞呈现胶质细胞特征，1549个BrdU阳性细胞中没有一个与多巴胺神经元标记酪氨酸羟化酶（TH）共标记。相反，GDNF上调了现有神经元中的TH，这与这种营养因子的修复作用一致。海马体是支持成年神经发生的部位，这里产生的新细胞与齿状回中的颗粒细胞密切相关。一些细胞双标记了神经元标记NeuN；其他细胞具有星形胶质细胞的特征，星形胶质细胞是海马体中成年新神经元的主要来源。GDNF对海马体的影响在记忆和学习过程中可能具有重要意义。
