Single Cortical Microinfarcts Lead to Widespread Microglia/Macrophage Migration Along the White Matter

Abstract

Loss of cognitive function with aging is a complex and poorly understood process. Recently, clinical research has linked the occurrence of cortical microinfarcts to cognitive decline. Cortical microinfarcts form following the occlusion of penetrating vessels and are considered to be restricted to the proximity of the occluded vessel. Whether and how such local events propagate and affect remote brain regions remain unknown. To this end, we combined histological analysis and longitudinal diffusion tensor imaging (DTI), following the targeted-photothrombotic occlusion of single cortical penetrating vessels. Occlusions resulted in distant tissue reorganization across the mouse brain. This remodeling co-occurred with the formation of a microglia/macrophage migratory path along subcortical white matter tracts, reaching the contralateral hemisphere through the corpus callosum and leaving a microstructural signature detected by DTI-tractography. CX3CR1-deficient mice exhibited shorter trail lengths, differential remodeling, and only ipsilateral white matter tract changes. We concluded that microinfarcts lead to brain-wide remodeling in a microglial CX3CR1-dependent manner.

Post-Stroke Cognitive Impairment and Dementia

“…Microinfarcts are considered the most abundant form of silent brain infarction and their accrual over time can significantly impact brain structure and function by disrupting connected areas beyond the actual visible lesion boundaries. 95–98…”

Intravital imaging of cerebral microinfarct reveals an astrocyte reaction led to glial scar

“…However, unfortunately, neither a reduction in the size of microinfarct lesion nor a recovery of astrocyte loss in the microinfarct was achieved (Fig 7A ) and a noticeable amount of collagen still remained in the microinfarct (Fig 7B and C). These limited improvements in pathological features with KDS2010 treatment could be attributed to the infiltrated immune cells such as CX3CR1 + immune cells reported to be highly accumulated in the microinfarct after photothrombotic occlusion (Lubart, Benbenishty et al, 2021) or myelin debris engulfment of endothelial cells (Zhou, Zheng et al, 2019) and proliferative CNS fibroblasts (Dorrier et al, 2021). Additional intervention strategies targeting other scar-forming factors would be needed to further decrease the fibrous scar formation after the onset of microinfarct and improve pathological features.…”

Long-term Microglial Phase-specific Dynamics During Single Vessel Occlusion and Recanalization

“…Vascular occlusion, as one of the primary causes of disability, is implicated in multiple disease factors (Cruz Hernandez et al, 2019;Tennant & Brown, 2013;Zhang et al, 2020). Previous studies suggest that vascular occlusion leads to neural de cits, infarction and cognitive dysfunctions (Lubart et al, 2021;Shih et al, 2013;Summers et al, 2017). Vascular occlusion evokes in ammation response in the brain (Chamorro, Dirnagl, Urra, & Planas, 2016;Moskowitz, Lo, & Iadecola, 2010;S.…”

“…However, the mechanism of the interaction between the vascular occlusion and in ammation response is not fully elucidated. As the main effectors of the innate in ammatory response in the central nervous system (CNS), microglia have been extensively studied in vascular occlusion-related diseases (Cortes-Canteli et al, 2019;Fernandez-Lopez et al, 2016;Liu et al, 2021;Lubart et al, 2021;Mastorakos et al, 2021;Neumann et al, 2015;Szalay et al, 2016;Zhou et al, 2017).…”

“…The function of microglia in extending processes is impaired with P2RY12 receptors inhibition (Mastorakos et al, 2021). Microglia migrate to the contralateral hemisphere through the corpus callosum after cortical microinfarcts in a CX3CR1-dependent manner to affect remote brain regions reorganization (Lubart et al, 2021). Moreover, microglia form clusters following genetic ablation to achieve repopulation (Bruttger et al, 2015).…”