Chronic cerebral hypoperfusion elicits neuronal apoptosis and behavioral impairment.

Chronic reductions in cerebral blood flow associated with aging and progressive neurodegenerative disorders can precipitate cognitive failure. To assess whether chronic cerebrovascular insufficiency elicits neuronal apoptosis, apoptotic cell death in the hippocampus was quantitated in a rat model of permanent carotid occlusion. Bilateral carotid artery occlusion (2VO) was shown to induce apoptotic morphology and DNA strand breaks in hippocampal neurons 2 and 27 weeks after ligation. The rate of pyramidal cell apoptosis was higher at chronic (27 weeks) compared to sub-chronic (2 weeks) time points. 2VO-induced apoptosis resulted in a decrease in total pyramidal cell number at 27 weeks but not at earlier time points, indicating progressive neuronal loss. Working and reference memory errors in the radial arm maze were strongly correlated with the number of apoptotic neurons in CA1 but not CA3 pyramidal cell fields. These data provide the first indication that apoptotic loss of pyramidal neurons may play a role in memory impairment associated with clinical conditions of chronic cerebrovascular insufficiency.

Chronic reduction of cerebral blood flow in the adult rat: late-emerging CA1 cell loss and memory dysfunction.

Ten-month-old rats were subjected to permanent bilateral occlusion of both common carotid arteries (2-VO) to chronically but moderately reduce brain blood flow. 2-VO impaired Morris water maze acquisition as soon as 7 days post-surgery. 2-VO also caused a later-appearing impairment on the radial arm maze which did not reach significance until 63 days post-surgery. At 14 dats post-surgery there were no effects of 2-VO on hippocampal CA1 pyramidal cell number or density of glial fibrillary acidic protein (GFAP). Hippocampal choline acetyltransferase activity at 70 days was also unaffected by 2-VO. At 190 days post-surgery, however, the 2-VO rats showed loss of cells and increased GFAP density in CA1. The increased density of hippocampal GFAP correlated with radial arm maze but not Morris water maze impairment. It is suggested that 2-VO causes neuronal dysfunction which can be exacerbated by stress and thereby manifested on aversively motivated tasks such as the water maze. As well, CA1 neurons begin to degenerate after several weeks of the reduced energy availability caused by 2-VO and this impairs memory. Since reduced neuronal energy metabolism is associated with the progressive neurodegeneration that underlies disorders such as Alzheimer's, research should further explore the possibility that the effects of 2-VO may model age-related dementia.