Vessel loss in the aging brain is commonly reported, yet important questions remain concerning whether there are regional vulnerabilities and what mechanisms could account for these regional differences, if they exist. Here we imaged and quantified vessel length, tortuosity and width in 15 brain regions in young adult and aged mice. Our data indicate that vessel loss was most pronounced in white matter followed by cortical, then subcortical grey matter regions, while some regions (visual cortex, amygdala, thalamus) showed no decline with aging. Regions supplied by the anterior cerebral artery were more vulnerable to loss than those supplied by middle or posterior cerebral arteries. Vessel width and tortuosity generally increased with age but neither reliably predicted regional vessel loss. Since capillaries are naturally prone to plugging and prolonged obstructions often lead to vessel pruning, we hypothesized that regional susceptibilities to plugging could help predict vessel loss. By mapping the distribution of microsphere-induced capillary obstructions, we discovered that regions with a higher density of persistent obstructions were more likely to show vessel loss with aging and vice versa. These findings indicate that age-related vessel loss is region specific and can be explained, at least partially, by regional susceptibilities to capillary plugging.

The capillaries of the brain, owing to their small diameter and low perfusion pressure, are vulnerable to interruptions in blood flow. These tiny occlusions can have outsized consequences on angioarchitecture and brain function; especially when exacerbated by disease states or accumulate with aging. A distinctive feature of the brain’s microvasculature is the ability for active neurons to recruit local blood flow. The coupling of neural activity to blood flow could play an important role in recanalizing obstructed capillaries. To investigate this idea, we experimentally induced capillary obstructions in mice by injecting fluorescent microspheres and then manipulated neural activity levels though behavioral or pharmacologic approaches. We show that engaging adult and aged mice with 12 h exposure to an enriched environment (group housing, novel objects, exercise wheels) was sufficient to significantly reduce the density of obstructed capillaries throughout the forebrain. In order to more directly manipulate neural activity, we pharmacologically suppressed or increased neuronal activity in the somatosensory cortex. When we suppressed cortical activity, recanalization was impaired given the density of obstructed capillaries was significantly increased. Conversely, increasing cortical activity improved capillary recanalization. Since systemic cardiovascular factors (changes in heart rate, blood pressure) could explain these effects on recanalization, we demonstrate that unilateral manipulations of neural activity through whisker trimming or injection of muscimol, still had significant and hemisphere specific effects on recanalization, even in mice exposed to enrichment where cardiovascular effects would be evident in both hemispheres. In summary, our studies reveal that neural activity bi-directionally regulates the recanalization of obstructed capillaries. Further, we show that stimulating brain activity through behavioral engagement (i.e., environmental enrichment) can promote vascular health throughout the lifespan.