Chronic mild stress exacerbates the effects of permanent bilateral common carotid artery occlusion on CA1 neurons

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.