Understanding the impact of capillary obstructions on brain angio-architecture and function

点击翻译按钮获取中文摘要

Background. Capillaries are the primary site of nutrient and gas exchange and the brain contains kilometers of capillaries to meet its energetically demanding needs. Capillary networks are assumed to be critical for maintaining brain function since decrements in cognition that occur with aging and certain neurodegenerative diseases correlate with the loss of brain capillaries. One underappreciated aspect of the brain's capillary network is that it is prone to obstruction, even in healthy animals. Recent studies have shown that at any given moment, a small fraction of capillaries are obstructed. This is not surprising since capillaries are inherently narrow, low pressure tubes that must pass relatively large blood cells. While the majority of these obstructions clear within seconds to minutes, a fraction of capillaries remain obstructed for much longer. We have recently shown that 30% of capillaries with persistent obstructions are pruned over 21 day period and are not compensated for by sprouting new capillaries. This led to a prolonged perturbation in local flow blood. Using this information, we were able to model and predict capillary loss with aging in healthy mice which fell closely in line with empirical data. In light of these new findings, we still do not have a good mechanistic understanding of how these capillary obstructions are cleared, or even what impact they have on brain function. Preliminary findings and general hypothesis. Pilot data from my lab indicate that increasing neural activity through environmental enrichment or pharmacology enhances obstruction clearance and reduces capillary loss. Based on these findings, we hypothesize that bouts of increased neural activity, through an as of yet understood circuit or molecular mechanism, is critical for clearing obstructions and maintaining capillary blood flow in the brain. Methodological approach. We will image naturally occurring capillary obstructions or induce them with injection of fluorescent microspheres, which blocks a small fraction of capillaries and do not lead to detectable cell death. The mouse brain will be imaged in vivo or post-mortem in brain sections to assess obstruction clearance and capillary pruning rates. We will use pharmacological, genetic (viruses, Cre-Lox mice), optical and chemo-genetic approaches to test our 3 broad aims: Aim 1: Define the role of neuronal activity in clearing capillary obstructions and what specific neural circuits are involved. Aim 2: Understand how neural activity dislodges obstructions by influencing capillary tone and blood flow. Aim 3: Determine the impact/significance of capillary obstructions on brain function. Significance. This research will provide fundamental knowledge regarding the impact of micro-circulatory obstructions on brain function and the mechanisms that regulate their removal, so that new strategies can be devised to maintain a healthy microcirculatory system and preserve brain function throughout life.