Brain Drain: In Vivo Optical Interrogation of Venular Function in Gray and White Matter

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PROJECT SUMMARY Much of our understanding of how cerebrovascular disease contribute to dementia focuses on the pathology of brain arterioles. However, whether pathology of cerebral venules also contribute to impairment of cerebral perfusion remains highly understudied. Preclinical and clinical studies have demonstrated marked alterations in venule tortuosity and vascular wall composition in small vessel diseases that underlie Vascular contributions to Cognitive Impairment and Dementia (VCID) and Alzheimer’s disease. Yet, the fundamentals of how brain venous networks are organized, and how their deterioration contributes to dementia, remain obscure. The goal of this project is to leverage recent advances in multi-photon imaging to investigate age-related impairment of venous drainage in deep gray and white matter of mouse brain in vivo. Cerebral white matter resides in deep brain regions and is particularly sensitive to blood flow deficit in early stages of dementia. It is challenging to access this tissue in vivo such that the etiology of white matter deficits can be better understood. Our approach overcomes this issue by using a combination of in vivo deep two-photon imaging with long wavelength excitation/emission and three-photon imaging to study microvasculature at the cortical gray-white matter interface and in deeper white matter, respectively. In preliminary studies, we found that blood drainage from deeper tissues rely exclusively on rare ascending venules, termed principle cortical venules (PCVs). PCVs collect blood by extending massive branching networks with long, tortuous draining capillaries. Critically, deep microvascular networks of PCVs were selectively constricted, reduced in vascular density, and more poorly perfused in aged mice (18-24 months) compared to adult mice (6-9 months). Our over-arching hypothesis is that deterioration of PCV structure and function is the basis for age-related blood flow impairment in deep gray and white matter. In Aim 1 of this project, we will test the hypothesis that PCVs exhibit brain region-specific deterioration in structure and function during aging, as white matter is more distant from arteriolar input in regions with thicker cortex. In Aim 2, we will test the hypothesis that dysfunction of capillary pericytes contributes to deterioration of PCV networks. In Aim 3, we will test the hypothesis that vasoconstriction and flow impairment in PCV networks can be alleviated by fasudil, a clinically-used drug that can reduce contractile tone in capillaries in addition to arterioles. A genetic strategy to remove fasudil’s target, rho kinase, specifically in brain capillary pericytes will complement the pharmacological approach. This project is significant because it will: (1) Advance novel imaging technologies to study the microvascular basis of white matter degeneration in mouse models of VCID and Alzheimer’s disease. (2) Provide insight into the structure and function of PCVs, which are an uncharacterized and essential drainage system for white matter. (3) Provide insight on how age-related pericyte dysfunction contributes to blood flow impairment, and whether they are a therapeutic target. (4) Yield data on whether age-related flow impairment in white matter is amenable to therapeutic modulation.