Chronic ischemia: memory impairment and neural pathology in the rat.

Abstract

Recent findings, such as the presence of diseased cortical microvasculature in Alzheimer’s dementia (DAT)Z and the reduced cerebral blood flow in those at risk for DAT: suggest that brain hypoperfusion may be pathogenic in the etiology of this disease. To assess this possibility in an animal model of cerebral hypoperfusion, we permanently ligated both common carotid arteries in the early middle-aged (-10 months old) Sprague Dawley rats? In Wistar rats, this procedure (2-VO) chronically (and perhaps permanently) reduces cortical and hippocampal blood flow by approximately 30%.’ Using this model, we do not observe the behavioral and neuropathologic sequelae that are characteristic after transient ischemia in the rat. Surgery is performed with the rats under barbiturate plus ketamine anesthesia. Ketamine may prevent the immediate neurodegenerative consequences of the relatively severe reduction in blood flow resulting from the carotid ligation procedure in the early postligation period. 2-VO progressively impairs the ability of the rats to perform the Morris water maze. This task requires that the rat escape to a submerged platform in a circular pool of water. The rats use extra-maze cues to guide their navigation to the platformcontaining area. As shown in FIGURE 1(upper panel), the Morris maze impairment appears as early as 7 days post surgery and persists over time despite repeated training. It is unlikely that this early-appearing deficit reflects impaired learning or memory mechanisms. A more plausible explanation is that the spatial ability of the rats is compromised by 2-VO and that this deficit is exacerbated by the moderately stressful water maze task. In support of this hypothesis, we have shown that 2-VO rats demonstrate a greater plasma corticosterone elevation to water immersion than do sham-operated animals: As well, presurgical training attenuates the deficit, indicating that if the animals are allowed to adapt to the stress of water immersion prior to 2-VO surgery, they are capable of normal performance. It should be noted that spatial disorientation and “getting lost” are characteristics of DAT and are also anxiogenic and thus self-fueling. In rats that have been pre-trained to perform the radial arm maze task, 2-VO causes a strikingly late-emerging increase in errors. Rats will effectively forage for food located on the arms of this maze, shunning arms that are never baited with food (unbaited-arm entries, a measure of long-term, habit memory) and avoiding