Selective Impairment of Working Memory in a Mouse Model of Chronic Cerebral Hypoperfusion

Abstract

Background and Purpose-We recently designed a mouse model of chronic cerebral hypoperfusion, in which the cerebral white matter is damaged without significant gray matter lesions. The behavioral characteristics of these mice were studied using a test battery for neurological and cognitive functions. Methods-Adult C57Bl/6 male mice were subjected to either sham-operation or bilateral common carotid artery stenosis (BCAS) using microcoils with an internal diameter of 0.18 mm. At 30 days after BCAS, 70 animals were divided into 3 groups and subjected to behavioral test batteries. The first group underwent comprehensive behavioral test, including the neurological screen, prepulse inhibition, hot plate, open field, light/dark transition, Porsolt forced swim and contextual and cued fear conditioning (BCAS nϭ13; sham-operated nϭ11). The second group was for the working memory task of the 8-arm radial maze test (BCAS nϭ12; sham-operated nϭ10), and the third for the reference memory task of the 8-arm radial maze test (BCAS nϭ13; sham-operated nϭ11). Another batch of animals were examined for histological changes (BCAS nϭ11; sham-operated nϭ12). Results-The white matter including the corpus callosum was consistently found to be rarefied without clear ischemic lesions in the hippocampus. No apparent differences were observed in the comprehensive test batteries between the control and BCAS mice. However, in the working memory tasks tested with the 8-arm radial maze, the BCAS mice made significantly more errors than the control mice (PϽ0.0001). Again, there were no detectable differences in the reference memory tasks between the groups. Conclusions-At 30 days after BCAS, working memory deficits as well as white matter changes were apparent in the mice.Working memory deficit was attributable to damage of the frontal-subcortical circuits, suggesting the BCAS model is useful to evaluate the substrates of subcortical vascular dementia.

Gradual Carotid Artery Stenosis in Mice Closely Replicates Hypoperfusive Vascular Dementia in Humans

“…The OT can be vulnerable to CCA stenosis and occlusion in rodents, and the rat bilateral CCA occlusion model exhibits severe degeneration and atrophy of the OT 17. It is possible that the visual system impairment could compromise the motor and cognitive function test such as rotatod test, Y‐maze test, and Morris water maze test, because visual cues contribute to discrimination even in the rat bilateral CCA occlusion model 10. In the GCAS model, WM rarefaction in the OT is significantly less developed than that in the CC and ACo; thus, it appears that the visual system is preserved, as is the case with the BCAS model 9, 10.…”

“…It is possible that the visual system impairment could compromise the motor and cognitive function test such as rotatod test, Y‐maze test, and Morris water maze test, because visual cues contribute to discrimination even in the rat bilateral CCA occlusion model 10. In the GCAS model, WM rarefaction in the OT is significantly less developed than that in the CC and ACo; thus, it appears that the visual system is preserved, as is the case with the BCAS model 9, 10. Demyelination in the CC was accompanied by significant proliferation of GFAP‐positive astrocytes and Iba1‐positive microglia in GCAS mice compared with sham‐surgery mice.…”

“…The BCAS model exhibits characteristic features of human hypoperfusive VCI, such as WM rarefaction and gliosis, and working memory impairment. However, this model has an inherent limitation in that cerebral blood flow (CBF) drops sharply immediately after BCAS surgery and then gradually recovers over 1 month, thus failing to reliably replicate “chronic” cerebral hypoperfusion apparent in VCI 9, 10. The contribution of the preceding acute phase to the neuropathological and behavioral consequences is therefore an ongoing concern.…”

Subcortical ischemic vascular disease: Roles of oligodendrocyte function in experimental models of subcortical white-matter injury

“…In fact, the 8-arm radial maze, water maze, and Y-maze tests show that the mice with prolonged cerebral hypoperfusion exhibit significant impairments in learning ability. [30][31][32] One potential drawback of this model is the acute decrease in cerebral blood flow by the micro-coil placement, which may not be so consistent with the phenomena in clinic (this point is also applied to the rat model of bilateral common carotid artery occlusion).…”

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].…”