Mild subcortical stroke induces widespread astrogliosis independent of microglia and age

Abstract

Ischemic stroke induces a plethora of pathophysiological changes, including neuroinflammation and chronic cerebrovascular dysfunction. In humans, even small, silent strokes can trigger these pathologies, which can spread to brain regions far beyond the infarct and persist chronically, ultimately worsening prognosis and increasing the risk for vascular dementia and Alzheimers disease. The cause of this extensive pathology is unknown, but reactive astrocytes and microglia are likely contributors. Here, we describe an optimized short-duration middle cerebral artery occlusion model that produces a clinically relevant small stroke confined to subcortical regions, similar to most silent strokes in humans. We termed this model the mild subcortical infarct (MSCI). We then mapped the spatiotemporal extent of reactive astrocytes and microglia during the sub-acute period (1, 3, and 7 days) following MSCI. We observed that reactive astrogliosis develops more rapidly and spreads more extensively, permeating the entire middle cerebral artery territory, compared to the reactive microglial response following this small infarct. Microglial depletion resulted in larger infarct sizes but did not prevent the reactive astrocytes, suggesting that ischemia-driven astrogliosis is largely microglia-independent. Lastly, we show that aging mice exposed to MSCI exhibit a comparably strong response of reactive astrocytes and microglia as young mice. We propose that MSCI is a novel and valuable model for examining the subtle yet highly important chronic effects of stroke. It may be especially useful for investigating the influence of reactive astrogliosis on pathologies like neuroinflammation and cerebrovascular dysfunction in regions distal from the primary injury site.