UCLA

White matter stroke (WMS) is a debilitating disorder, characterized by the formation of ischemic lesions along the white matter tracts in the brain. The accumulation of these white matter lesions leads to vascular dementia, which is the second leading cause of dementia, and accelerates the pathology of Alzheimer’s Disease [11]. Currently, there are no therapy options available to halt the progression of vascular dementia. Hence, we wanted to better understand the molecular mechanisms and behavioral outcomes that may result as a consequence of multiple strokes happening within the white matter region of the brain. We created a two-stroke protocol in which an initial large white matter stroke was induced in C57BL/6J mice models, then 1-month later, a small white matter stroke was induced contralaterally. This models the progressive nature of ischemic white matter damage, which is a core feature of the human condition. We measured the recovery of these cohorts through motor behavior tests (grid-walking and pole test) and cognitive tests (fear conditioning and novel object recognition) at baseline, 1-month, 2-month, and 3-month timepoints. Our data indicates that for the grid-walking test, the Large WMS mice have significantly more foot faults at the 1-month and 2-month timepoints, and then plateau at the 3-month timepoint, when compared to the Large WMS + Small WMS. In the pole test at the 3-month timepoint, the Large WMS mice have shorter t-turn times when compared to the Large WMS + Small WMS cohort. During the fear conditioning test, the Large WMS mice had higher freeze times across all timepoints when compared to the Large WMS + Small WMS mice. Overall, this data suggests that the Large WMS + Small WMS mice have more difficulty performing fine motor tasks, such as the pole test, at a later timepoint and have hindered memory and recall ability when compared to the Large WMS only cohort.