A KATP channel-Dependent Electrical Signaling Network Links Capillary Pericytes to Arterioles During Neurovascular Coupling

Abstract

The brain has evolved mechanisms to dynamically modify local blood flow, thus enabling the timely delivery of energy substrates and the rapid clearance of byproducts in response to the highly fluctuating metabolic demands of cognition and behavior. Several such neurovascular coupling mechanisms have been identified, but vascular signal transduction and transmission mechanisms that enable acute dilation of penetrating arterioles remote from sites of increased neuronal activity are unclear. Given the exponential relationship between vessel diameter and blood flow, tight control of arteriole membrane potential and diameter is a crucial aspect of neurovascular coupling. However, the relatively sparse spatial arrangement of arterioles contrasts with the vast plexus of capillaries, and recent evidence suggests that capillaries play a major role in sensing neural activity and transmitting signals to modify the contractile state of mural cells on upstream vessels. Thin-strand pericyte processes cover around 90% of the capillary bed but their specific contributions to blood flow control are not understood. We hypothesized that thin-strand pericytes could play a role in sensing and transmitting blood flow control signals from neurons back to the electromechanical controller of blood flow , upstream PA and contractile pericytes. We first wondered whether we could probe for the existence of a functional vascular relay between pericytes and arterioles using focal optogenetics. To do this we developed a mouse line expressing ArchT-EGFP optically driven proton pump in mural cells (shown below). We targted pericytes in this mouse with focal 561 nm laser to excite ArchT while monitoring the feeding PA for dynamics. After observing evidence for a functional electrical network coupling pericyte-ArchT activation to PA dilation we moved on to determine if this system operated in a physiological scenario. We assayed neurovascular coupling in several mouse models, including awake mice receiving whisker stimulus and anesthetized Thy1-ChR2-EYFP mice where we excited the cortex with 488 nm point-scanning. We found using a conditional expressed dominant negative KATP channel in mural cells (pericytes and smooth muscle cells) that the initial phase of the bi-phasic response to sensory stimulation was diminished. Next we physically disrupted pericytes via laser ablation, which reduced the PA dilation associated with an optogenetic impulse in neural activity. The effect of laser ablation was lost with the inclusion of glibenclamide in the agar, implicating the pericyte KATP channel specifically in mediating a component of neurovascular coupling in mouse cortex