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Translating Thought into Blood Flow in the Brain: Capillaries as Sensors of Neural Activity

Wednesday, October 14, 2020 - 3:00pm to 4:00pm


Mark T. Nelson, Ph.D.
University Distinguished Professor and Chair, Department of Pharmacology
University of Vermont


Healthy brain function depends on the finely tuned spatial and temporal delivery of blood-borne nutrients to active neurons via the vast, dense capillary network. Cerebral small vessel diseases (SVDs) are a central link between stroke and dementia—two co-morbidities that rank among the most pressing human health issues {Pantoni:2010hf}. Despite the emerging consensus that SVDs are initiated in the endothelium, the early molecular mechanisms remain largely unknown and no specific treatments are yet available. Deficits in on-demand delivery of blood to active brain regions (functional hyperemia) have been identified as early manifestations of the underlying pathogenesis. The strong inward-rectifier K+ channel (Kir2.1) in capillary endothelial cells, which senses neuronal activity and initiates a propagating electrical signal that dilates upstream arterioles (Longden et al., Nature Neuroscience, 2017), is a cornerstone of this functional hyperemia mechanism. However, whether this mechanism is targeted in SVDs and how resulting signaling deficits might be rescued remains unknown. Here, using a genetic mouse model of the most common hereditary SVD (CADASIL, Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), we show that impaired functional hyperemia is caused by a complete loss of capillary-to-arteriole electrical signaling due to diminished capillary endothelial Kir2.1 channel activity. We further linked Kir2.1 deactivation to depletion of phosphatidylinositol 4,5-bisphosphate (PIP2), a membrane phospholipid essential for Kir2.1 activity. Strikingly, systemic injection of soluble PIP2 rapidly restored functional hyperemia in SVD, suggesting a possible strategy for rescuing functional hyperemia in brain disorders in which blood flow is disturbed.

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