Ritchie Lesley J, De Butte Maxine, Pappas Bruce A
Institute of Neuroscience, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario, Canada K1S 5B6.
Brain Res. 2004 Jul 16;1014(1-2):228-35. doi: 10.1016/j.brainres.2004.04.036.
The effect of chronic mild stress (CMStress) was examined in an animal model of chronic cerebral hypoperfusion. Eight-month-old male Sprague-Dawley rats underwent permanent bilateral occlusion of the carotid arteries (2VO) or sham surgery. At 7 days postsurgery, animals from these groups were randomly assigned to undergo CMStress consisting of relatively mild stressor exposure 6 days a week for 6 weeks or a no-stress regimen. They were perfused 24 h thereafter and stereology was used to estimate the total number of hippocampal CA1 and CA3 pyramidal cells. Glial fibrillary acid protein (GFAP) immunoreactivity in the hippocampus was also measured. Degenerating neurons were quantified with the Fluoro-Jade B staining technique. CMStress significantly potentiated CA1 cell loss in 2VO rats (17% loss), compared to a 7% loss of CA1 cells in nonstressed 2VO rats. CMStress had no effect on CA3 cell number. CMStress also caused a significant reduction in GFAP-immunoreactive astrocyte density in CA1, CA3, and the hilus of both sham and 2VO rats. Fluoro-Jade staining was absent, indicating that cell loss probably occurred in the early stage of combined 2VO and CMStress. It was concluded that CMStress exacerbates the consequences of chronic cerebral hypoperfusion on CA1 probably by reducing astrocytes, thereby increasing extracellular glutamate and/or diminishing free radical defense systems. These findings have particular relevance to understanding the contribution of chronic stress to Alzheimer's disease, which, in its premorbid stage, is characterized by cerebral hypoperfusion, and, in its clinical stage, is characterized by CA1 cell loss.
在慢性脑灌注不足的动物模型中研究了慢性轻度应激（CMStress）的影响。8个月大的雄性Sprague-Dawley大鼠接受永久性双侧颈动脉闭塞（2VO）或假手术。术后7天，将这些组的动物随机分配接受CMStress，即每周6天暴露于相对轻度的应激源，持续6周，或接受无应激方案。此后24小时对它们进行灌注，并使用体视学方法估计海马CA1和CA3锥体细胞的总数。还测量了海马中胶质纤维酸性蛋白（GFAP）的免疫反应性。用Fluoro-Jade B染色技术对退化神经元进行定量。与未应激的2VO大鼠中7%的CA1细胞损失相比，CMStress显著增强了2VO大鼠中CA1细胞的损失（损失17%）。CMStress对CA3细胞数量没有影响。CMStress还导致假手术和2VO大鼠的CA1、CA3以及海马门区中GFAP免疫反应性星形胶质细胞密度显著降低。未发现Fluoro-Jade染色，表明细胞损失可能发生在2VO和CMStress联合作用的早期阶段。得出的结论是，CMStress可能通过减少星形胶质细胞，从而增加细胞外谷氨酸和/或减少自由基防御系统，加剧慢性脑灌注不足对CA1的影响。这些发现对于理解慢性应激对阿尔茨海默病的作用具有特别重要的意义，阿尔茨海默病在病前阶段以脑灌注不足为特征，在临床阶段以CA1细胞损失为特征。
