A Mouse Model Characterizing Features of Vascular Dementia With Hippocampal Atrophy

Abstract

Background and Purpose-We have previously described effects of chronic cerebral hypoperfusion in mice with bilateral common carotid artery stenosis (BCAS) using microcoils for 30 days. These mice specifically exhibit working memory deficits attributable to frontal-subcortical circuit damage without apparent gray matter changes, indicating similarities with subcortical ischemic vascular dementia. However, as subcortical ischemic vascular dementia progresses over time, the longer-term effects that characterize the mouse model are not known. Methods-Comprehensive behavioral test batteries and histological examinations were performed in mice subjected to BCAS for up to 8 months. Laser speckle flowmetry and 18 F-fluorodeoxyglucose positron emission tomography were performed to assess cerebral blood flow and metabolism at several time points. Results-At 2 hours after BCAS, cerebral blood flow in the cerebral cortex temporarily decreased to as much as 60% to 70% of the control value but gradually recovered to Ͼ80% at 1 to 3 months. At 5 to 6 months after BCAS, reference and working memory were impaired as demonstrated by the Barnes and radial arm maze tests, respectively. Furthermore,

Elevated levels of plasma homocysteine, deficiencies in dietary folic acid and uracil–DNA glycosylase impair learning in a mouse model of vascular cognitive impairment

“…Another possible explanation for the discrepancy could be that FADD and/or hypoperfusion is influencing other aspects of behavior not related to spatial memory, such as motivation, attention, mobility, or anxiety in the Ung−/−.We found that there was decreased anxiety in the hypoperfused Ung−/− mice when compared to shams. Indeed, decreased anxiety has been reported following hypoperfusion by other groups [36,58], though, it has been suggested that hypoperfusion may simply be increasing activity levels, rather than anxiety, by another group that observed hypoperfused mice made more entries into both the open and closed arms of the elevated plus maze [59]. We did not observe differences in activity between groups during any of the tests.…”

“…At any rate, deficits in the MWM were not surprising during this study, as performance in this task is dependent on hippocampal function. The hippocampus has consistently been described as being affected by hypoperfusion [36,58]. Furthermore, folic acid deficiency results in hippocampal neurodegeneration [33,60].…”

“…Recently, an animal model of vascular cognitive impairment was described in mice [35], this model involves wrapping microcoils around the common carotid arteries in mice to induce a state of chronic hypoperfusion in the brain. Long-term effects of chronic hypoperfusion result in impairments in spatial working memory, as well as white matter damage, activated microglia and astrogila [36,37]. The purpose of this study is to examine whether elevated levels of plasma homocysteine through folic acid deficiency affect the progression of neurodegeneration via chronic hypoperfusion.…”

Nonhypotensive Dose of Telmisartan Attenuates Cognitive Impairment Partially Due to Peroxisome Proliferator-Activated Receptor-γ Activation in Mice With Chronic Cerebral Hypoperfusion

“…Thus, telmisartan may have restored frontal-subcortical circuitry function, which is also associated with spatial working memory. 8,14 However, hippocampal changes appear at 3 months post-BCAS 15 ; it would therefore be of interest to extend the observation period to investigate effect of telmisartan on the gray matter in a future study.…”

The heart-brain connection: mechanistic insights and models

“…The BCAS model is a model of chronic cerebral hypoperfusion induced by placement of microcoils around both carotid arteries [21]. In this model a reduced CBF, activation of microglia and astroglia, white matter lesions, grey matter changes, hippocampal atrophy and micro-infarcts have been described [21][22][23][24][25]. TAC, the ligation of the aortic arch between the carotids, is a mouse model of chronic heart failure leading to a reduced ejection fraction [26,27].…”