Intensity of chronic cerebral hypoperfusion determines white/gray matter injury and cognitive/motor dysfunction in mice
Article first published online: 24 OCT 2008
Copyright © 2008 Wiley-Liss, Inc.
Journal of Neuroscience Research
Volume 87, Issue 5, pages 1270–1281, April 2009
How to Cite
Miki, K., Ishibashi, S., Sun, L., Xu, H., Ohashi, W., Kuroiwa, T. and Mizusawa, H. (2009), Intensity of chronic cerebral hypoperfusion determines white/gray matter injury and cognitive/motor dysfunction in mice. J. Neurosci. Res., 87: 1270–1281. doi: 10.1002/jnr.21925
- Issue published online: 23 FEB 2009
- Article first published online: 24 OCT 2008
- Manuscript Accepted: 4 SEP 2008
- Manuscript Revised: 16 AUG 2008
- Manuscript Received: 5 APR 2008
- cerebral blood flow;
- cognitive impairment;
- white matter
We sought to establish a mouse model of subcortical ischemic vascular dementia (SIVD) that develops predominant white matter (WM) injury and cognitive dysfunction induced by chronic cerebral hypoperfusion. Adult C57Bl/6 male (n = 48) mice were subjected to bilateral common carotid artery stenosis with external microcoils (inner diameters: 0.16 mm, left; 0.18 mm, right). Mice were categorized according to left-side cerebral blood flow (CBF) value on day 6 into those with severe cerebral hypoperfusion (SCH; n = 16, < 30% of preoperative CBF baseline value) or moderate cerebral hypoperfusion (MCH; n = 21, 30–50% of preoperative value). Another 15 mice were sham operated. Neurological dysfunction was evaluated by Morris water maze, rotating rod, and open field tests. Histopathological examination was performed on day 35 after surgery. MCH animals showed persistent hyperlocomotion with reduced anxiety and spatial reference memory dysfunction. Rarefaction and small necrotic lesions were predominantly confined to the WM, with reactive astrocytosis, microglial infiltration, axonal loss, and myelin disruption, and these changes were dominant on the left side. SCH animals had persistent hyperlocomotion and motor dysfunction, and their ischemic lesions extended from the WM to the hippocampus and cortex. In MCH animals, myelin basic protein and neurofilament fiber densities in the WM were correlated with the time spent in the correct area in the water maze probe trials. Our MCH mouse model with the development of several types of neurological dysfunction with high reproducibility would be useful for investigating the pathomechanisms of WM injury in human SIVD. © 2008 Wiley-Liss, Inc.