Date of Award

2015

Embargo Period

8-1-2024

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Andy Shih

Second Advisor

DeAnna Adkins

Third Advisor

Narayan Bhat

Fourth Advisor

Truman Brown

Fifth Advisor

Prakash Kara

Abstract

Cerebral microinfarcts (CMI), microscopic brain lesions caused by blockade of small blood vessels, have recently emerged as a potential determinant of cognitive decline. Though small in size, our recent work demonstrated that a single, strategically placed CMI was sufficient to disrupt sensory input in a behavioral task. However, the means by which such small lesions disrupt brain function remain poorly understood. We imaged vascular function in awake, head-fixed mice using two-photon microscopy to examine the impact of CMI on neurovascular coupling. CMI were generated in cortex by photothrombotic occlusion of single penetrating vessels through a thinned-skull cranial window. Vibrissa-evoked dilation of individual arteries and arterioles within the primary vibrissa cortex were tracked over four time periods: pre-occlusion, acute (2-3 days post-occlusion), subacute (7-9 days) and chronic (14-21 days). In the acute phase, dilatory responses were markedly attenuated compared to pre-occlusion (2.2 ± 0.5% mean dilation over baseline vs. 11.2 ± 0.8%, p < 0.001). Dilatory responses during the subacute (7.8 ± 1.1%) and chronic (6.5 ± 1.1%) phases partially recovered but remained significantly attenuated in magnitude and time to dilation compared to pre-occlusion (p < 0.01). Critically, vascular dysfunction was observed well beyond the borders of the CMI, as infarcts with an average radius of 0.19 ± 0.05 mm generated deficits in dilation at distances exceeding 1 mm away from the vessel targeted for occlusion. Analysis of dilations in a separate cohort of mice during the hyperacute time period (0-3 hours post-occlusion), revealed that the dilatory deficit is first expressed in the immediate vicinity of the stroke and then propagates outward from the occlusion site. While unresponsive to sensory stimulation, vasodilation could be evoked by isoflurane inhalation, albeit attenuated in the subacute phase (156.7 ± 5.3% of pre-stroke levels vs. 134.6 ± 4.3% subacute, p = 0.02). Expression of c-Fos following an extended period of vibrissa stimulation was reduced in the peri-infarct tissue in the acute time period, with gradual recovery initiating distal to the stroke apparent in subacute and chronic mice. This indicated that loss of sensory-evoked vasodilation is attributed to a combination of altered vascular mechanical properties and a deficit in neural connectivity and/or activity. Thus, CMI disrupt brain function well beyond the regions of overt tissue infarction and this effect, combined with their widespread distribution in the aged brain, may contribute to the pathogenesis of CMI in vascular dementia.

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