The Role of Astrocytes in Neurovascular Coupling at the Capillary and Arteriole Level in the Retina and Brain

Seminar | May 23 | 12-1:30 p.m. | 489 Minor Hall

 Anusha Mishra, University College London, UK

 Neuroscience Institute, Helen Wills

Neuronal activity evokes a spatially and temporally localized increase in blood flow to power the information processing carried out by the neurons, a phenomenon that underlies BOLD fMRI signals. This neurovascular coupling occurs both in the brain and the retina.

In the retina, both light- and glial-stimulation evoke pronounced arteriole dilations (30.8±3.7% and 23.5±4.1%, respectively). This dilation depends on O2: high O2 inhibits dilation and promotes constriction. Retinal neurovascular coupling is decreased in diabetic patients, and I found that this deficit (~60%) can also be detected in an animal model of diabetes before any overt loss of neuronal function. These retinas displayed signs of glial reactivity and an upregulation of inducible nitric oxide synthase (iNOS). Inhibiting iNOS function in diabetic retinas restored normal neurovascular coupling both in vitro and in vivo.

In the cerebral cortex, neuronal activity dilates arterioles and capillaries via two separate signaling pathways. Neuronal activity in cortical slices evoked a capillary dilation of 14.7±0.5% and an arteriole dilation of 7.1±0.7%. Stimulation-evoked capillary dilation was reduced by 64% when [Ca2+]i in nearby astrocytes was buffered, but arteriole dilations were unchanged. Capillary dilation was dependent on the ATP-gated ion channel P2X1 and subsequent synthesis and release of vasoactive prostaglandin E2. Arteriole dilation, on the other hand, depended upon NMDA receptor driven production of nitric oxide.

These findings reveal a novel dichotomy in the molecular and cellular signaling cascades that regulate CNS blood flow in different vascular compartments, provide insight into the mechanisms underlying the BOLD signal, and demonstrate how disease-induced alterations of NO signaling can alter blood flow. Furthermore, they suggest that restoring neurovascular coupling, which is altered in many CNS disorders, could provide novel therapeutic targets.