Neurohistological and behavioral changes following the four-vessel occlusion/internal carotid artery model of chronic cerebral hypoperfusion: Comparison between normotensive and spontaneously hypertensive rats

• Young, normotensive rats are cognitively asymptomatic to permanent 4-VO/ICA.
• Chronic hypertension aggravates the histological and cognitive outcomes of 4-VO/ICA.
• Such effects of hypertension paralleled that of aging.
• Hypertension may deteriorate brain adaptive responses to mild, chronic hypoperfusion.

Chronic cerebral hypoperfusion (CCH) may be a prodromal feature of aging-related dementias, and chronic hypertension is a major risk factor. We used a permanent, four-vessel occlusion/internal carotid artery (4-VO/ICA) model to evaluate the cognitive and neurohistological outcomes of CCH in both young and middle-aged rats. Young rats are asymptomatic after permanent 4-VO/ICA, and we tested the hypothesis that chronic hypertension aggravates the outcomes of CCH. Young normotensive rats (NTRs) and young spontaneously hypertensive rats (SHRs) were first subjected to 4-VO/ICA and then examined for hippocampal and cortical neurodegeneration 7, 15, and 30 days later. In a second experiment, both NTRs and SHRs were then trained in a modified, non-food-rewarded aversive radial maze (AvRM) task until acquiring asymptotic performance and then subjected to 4-VO/ICA. Thirty days later, they were assessed for memory retention of the previously acquired cognition. In a third, post hoc experiment, middle-aged NTRs were trained in the AvRM, subjected to 4-VO/ICA, and tested for memory retention 30 days later. Compared with NTRs, both SHRs and middle-aged NRTs had severe hippocampal and cortical damage, but they did not differ from each other, regardless of the chronicity of 4-VO/ICA. In contrast, NTRs were behaviorally asymptomatic, and retrograde memory performance was persistently impaired in SHRs. This amnesic effect in the SHR group was very similar to the middle-aged NTR group. These findings suggest that chronic hypertension deteriorates the capacity of the brain to adaptively respond to CCH. This influence of hypertension may parallel the effect of aging.