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(Stroke. 2007;38:2826.)
© 2007 American Heart Association, Inc.

Original Contributions

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

Masunari Shibata, MD; Nobuyuki Yamasaki, MD; Tsuyoshi Miyakawa, PhD; Rajesh N. Kalaria, PhD, FRCPath; Youshi Fujita, MD; Ryo Ohtani, MD; Masafumi Ihara, MD; Ryosuke Takahashi, MD Hidekazu Tomimoto, MD

From the Department of Neurology (M.S., Y.F., R.O., M.I., R.T., H.T.), Graduate School of Medicine, and Horizontal Brain Research Organization (N.Y., T.M.), Kyoto University, Sakyo-ku, Kyoto, Japan; and the Institute for Health and Ageing (R.N.K.), University of Newcastle upon Tyne, Newcastle General Hospital, Newcastle-upon-Tyne, UK.

Correspondence to Hidekazu Tomimoto, MD, Department of Neurology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan. E-mail tomimoto{at}kuhp.kyoto-u.ac.jp

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 n=13; sham-operated n=11). The second group was for the working memory task of the 8-arm radial maze test (BCAS n=12; sham-operated n=10), and the third for the reference memory task of the 8-arm radial maze test (BCAS n=13; sham-operated n=11). Another batch of animals were examined for histological changes (BCAS n=11; sham-operated n=12).

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 (P<0.0001). 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.

Key Words: behavioral neurology • cerebral blood flow • hippocampus • leukoaraiosis • memory • vascular dementia • white matter disease