Dynamic connectivity maps of pericytes and endothelial cells mediate neurovascular coupling in health and disease

Functional hyperemia, or matching blood flow to activity, is spatially accurate to direct the oxygen and nutrients to regionally firing neurons. The underlying signaling mechanisms of neurovascular coupling remain unclear, but are critical for brain function and establish the diagnostic power of BOLD-fMRI. Here, we described a mosaic of pericytes, the vasomotor capillary cells in the living retina. We then tested if this symmetric net of pericytes and surrounding neuroglia predicted a connectivity map in response to sensory stimuli. Surprisingly, we found that these connections were not only discriminatory across cell types, but also highly asymmetric spatially. First, pericytes connected predominantly to other neighboring pericytes and endothelial cells, and less to arteriolar smooth muscle cells, and not to surrounding neurons or glia. Second, focal, but not global stimulation evoked a directional vasomotor response by strengthening connections along the feeding vascular branch. This activity required local NO signaling and occurred by means of direct coupling via gap-junctions. By contrast, bath application of NO or diabetes, a common microvascular pathology, not only weakened the vascular signaling but also abolished its directionality. We conclude that the discriminatory nature of neurovascular interactions may thus establish spatial accuracy of blood delivery with the precision of the neuronal receptive field size, and is disrupted early in microvascular disease.\n\nHighlightsO_LIWithin a structurally symmetric mosaic, pericytes form discriminatory connections\nC_LIO_LIPericyte connectome tunes with a precision matching a neuronal receptive field\nC_LIO_LIFocal but not global input evokes a vasomotor response by strengthening the gap-junction mediated signaling towards a feeding vascular branch\nC_LIO_LIDisrupted functional connectivity map triggers loss of the functional hyperemia in diabetic neuropathy\nC_LI