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The smallest stroke: occlusion of one penetrating vessel leads to infarction and a cognitive deficit

Abstract

Microinfarctions are present in the aged and injured human brain. Their clinical relevance is controversial, with postulated sequelae ranging from cognitive sparing to vascular dementia. To address the consequences of microinfarcts, we used controlled optical methods to create occlusions of individual penetrating arterioles or venules in rat cortex. Single microinfarcts, targeted to encompass all or part of a cortical column, impaired performance in a macrovibrissa-based behavioral task. Furthermore, the targeting of multiple vessels resulted in tissue damage that coalesced across cortex, even though the intervening penetrating vessels were acutely patent. Post-occlusion administration of memantine, a glutamate receptor antagonist that reduces cognitive decline in Alzheimer's disease, ameliorated tissue damage and perceptual deficits. Collectively, these data imply that microinfarcts likely contribute to cognitive decline. Strategies that have received limited success in the treatment of ischemic injury, which include therapeutics against excitotoxicity, may be successful against the progressive nature of vascular dementia.

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Figure 1: Similarity between human and rat cortical microinfarcts.
Figure 2: Topology and flow dynamics of cortical vasculature.
Figure 3: Acute neuropathology and growth of microinfarcts.
Figure 4: Chronic nature of microinfarcts caused by occlusion of penetrating arterioles and venules in rat cortex.
Figure 5: Reduction in the volume of isolated microinfarcts by administration of NMDAR antagonists.
Figure 6: Cognitive deficit following single penetrating vessel occlusion in vibrissa primary sensory cortex.
Figure 7: Reduction in cognitive deficit following single penetrating vessel occlusion by administration of the NMDAR antagonist memantine.
Figure 8: Potential coalescence of multiple, single penetrating vessel microinfarcts into an extended infarct.

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Acknowledgements

We thank A. Schweitzer for constructing the behavioral apparatus, S.E. Black, M. Deschênes, M.E. Diamond, F.F. Ebner, E.E. Smith and R. Swanson for discussions, and C. Mateo for comments on an early version of the manuscript. This work was supported by the American Heart Association (Post-doctoral fellowship to A.Y.S.) and the US National Institutes of Health (MH085499, EB003832 and OD006831 to D.K.), which further supported the University of California, San Diego Neuroscience Shared Microscopy Core (NS047101), which was used to image histological tissue.

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A.Y.S., B.F., P.D.L. and D.K. designed the study. A.Y.S. and G.S. carried out the experiments. A.Y.S., P.B. and P.S.T. analyzed the data. A.Y.S., B.F. and D.K. wrote the manuscript.

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Correspondence to David Kleinfeld.

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Shih, A., Blinder, P., Tsai, P. et al. The smallest stroke: occlusion of one penetrating vessel leads to infarction and a cognitive deficit. Nat Neurosci 16, 55–63 (2013). https://doi.org/10.1038/nn.3278

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