The brain accounts for around 2 % of human adult bodyweight but consumes 20 % of the resting oxygen available to the whole body. The brain is dependent on a constant supply of oxygen to tissue, transported from the heart via the vasculature and carried in blood. An interruption to flow can lead to ischaemia (a reduced oxygen supply) and prolonged interruption may result in tissue death, and permanent brain damage. The cerebral vasculature consists of many, densely packed, micro-vessels with a very large total surface area. Oxygen dissolved in blood enters tissue by passive diffusion through the micro-vessel walls. Imaging shows bursts of metabolic activity and flow in localised brain areas coordinated with brain activity (such as raising a hand). An appropriate level of oxygenation, according to physiological demand, is maintained via autoregulation; a set of response pathways in the brain which cause upstream or downstream vessels to expand or contract in diameter as necessary to provide sufficient oxygen to every region of the brain. Further, autoregulation is also evident in the response to pressure changes in the vasculature: the perfusing pressure can vary over a wide range from the basal-state with only a small effect on flow due to the constriction or dilation of vessels. Presented here is a new vasculature model where diameter and length are calculated in order to match the data available for flow velocity and blood pressure in different sized vessels. These vessels are arranged in a network of 6 generations each of bifurcating arterioles and venules, and a set of capillary beds. The input pressure and number of generations are the only specifications required to describe the network. The number of vessels, and therefore vessel geometry, is governed by how many generations are chosen and this can be altered in order to create more simple or complex networks. The flow, geometry and oxygen concentrations are calculated based on the vessel resistance due to flow from geometry based on Kirchoff circuit laws. The passive and active length-tension characteristics of the vasculature are established using an approximation of the network at upper and lower autoregulation limits. An activation model is described with an activation factor which governs the contributions of elastic andmuscle tension to the total vessel tension. This tension balances with the circumferential tension due to pressure and diameter and the change in activation sets the vessel diameter. The mass transport equation for oxygen is used to calculate the concentration of oxygen at every point in the network using data for oxygen saturation to establish a relationship between the permeability of the vessel wall to oxygen and the geometry and flow in individual vessels. A tissue compartment is introduced which enables the modelling of metabolic control. There is evidence for a coordinated response by surrounding vessels to local changes. A signal is proposed based on oxygen demand which can be conducted upstream. This signal decays exponentially with vessel length but also accumulates with the signal added from other vessels. The activation factor is therefore set by weighted signals proportional to changes in tissue concentration, circumferential tension, shear stress and conducted oxygen demand. The model is able to reproduce the autoregulation curve whereby a change in pressure has only a small effect on flow. The model is also able to replicate experimental results of diameter and tissue concentration following an increase in oxygen demand.

It is emerging that the brain’s vasculature consists of a highly spatially heterogeneous network; however, information on how various vascular characteristics differ between brain regions is still lacking. Furthermore, aging studies rarely acknowledge regional differences in the changes of vascular features. The density of the capillary bed is one vascular feature that is important for the adequate delivery of nutrients to brain tissue. Additionally, capillary density may influence regional cerebral blood flow, a parameter that has been repeatedly correlated to cognitive-behavioural performance. Age-related decline in capillary density has been widely reported in various animal models, yet important questions remain concerning whether there are regional vulnerabilities and what mechanisms could account for these regional differences, if they exist. Here we used confocal microscopy combined with a fluorescent dye-filling approach to label the vasculature, and subsequently quantified vessel length, tortuosity and diameter 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 gray matter regions, while some regions (visual cortex, amygdala, insular cortex) showed little decline with aging. Changes in capillary density are determined by a balance of pruning and sprouting events. Previous research showed that capillaries are naturally prone to plugging and prolonged obstructions often lead to vessel pruning without subsequent compensatory vessel sprouting. We therefore 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. Although the relationship between obstruction density and vessel loss was strong, it was clear obstruction rates were insufficient to explain vessel loss on their own. For that reason, we subsequently used in vivo two-photon microscopy to track microsphere-induced capillary obstructions and vascular network changes over 24 days in two areas of cortex that showed different magnitudes of vessel loss and obstruction densities: visual and retrosplenial cortex. Surprisingly, we did not find evidence for differences in vessel pruning rates between areas, as we would have expected. Instead, we observed brain region-specific differences in recanalization times and rates of angiogenesis. These findings indicate that age-related vessel loss is region specific and that regional susceptibilities to capillary plugging and angiogenesis must be considered to explain these differences. Altogether, this work supports the overarching hypothesis that regional differences in vascular structure and function contribute to a regionally heterogeneous phenotype in the aging brain. / Graduate