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Astrocyte-mediated control of cerebral blood flow

Abstract

Local increase in blood flow during neural activity forms the basis for functional brain imaging, but its mechanism remains poorly defined. Here we show that cortical astrocytes in vivo possess a powerful mechanism for rapid vasodilation. We imaged the activity of astrocytes labeled with the calcium (Ca2+)-sensitive indicator rhod-2 in somatosensory cortex of adult mice. Photolysis of caged Ca2+ in astrocytic endfeet ensheathing the vessel wall was associated with an 18% increase in arterial cross-section area that corresponded to a 37% increase in blood flow. Vasodilation occurred with a latency of only 1–2 s, and both indomethacin and the cyclooxygenase-1 inhibitor SC-560 blocked the photolysis-induced hyperemia. These observations implicate astrocytes in the control of local microcirculation and suggest that one of their physiological roles is to mediate vasodilation in response to increased neural activity.

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Figure 1: Photolysis of caged Ca2+ in astrocytic endfeet triggers vasodilation.
Figure 2: Photolysis-induced vasodilation is a function of the amplitude of endfoot Ca2+ and does not occur in veins or capillaries.
Figure 3: Astrocytes trigger rapid vasodilation.
Figure 4: Astrocyte-mediated vasodilation requires COX-1 activity.
Figure 5: Increased neuronal activity triggers astrocytic Ca2+ signaling and indomethacin-sensitive vasodilation.

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Acknowledgements

We thank M. Lauritzen, B. Zlokovic and L. Bekar for comments on the manuscript; M. Schwartzman and K. O'Banion for discussions; and J.R. Falck for supplying us with MS-PPOH. This work was sponsored by the US National Institutes of Health and National Institute of Neurological Disorders and Stroke.

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Correspondence to Takahiro Takano.

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Supplementary information

Supplementary Fig. 1

Rhod-2/am staining co-localizes with GFP expression in the cortex of a transgenic mouse expressing green fluorescent protein (GFP) under the GFAP promotor. (PDF 1092 kb)

Supplementary Fig. 2

Spontaneous astrocytic Ca2+ oscillations as a function of 2-photon laser power and inter-frame interval. (PDF 469 kb)

Supplementary Video 1

Photolysis of caged Ca2+ compound caused Ca2+ increase in astrocytic endfeet and vasodilation of a penetrating artery. Time-course images of cross-section of an artery were taken at 15 sec interval. The movie was presented as 5 fps. Astrocytes were loaded with the Ca2+ indicator dye, rhod-2/am (red) and DMNP-EDTA/am, whereas the vasculature was stained with FITC-dextran (green). (MOV 292 kb)

Supplementary Video 2

Vessel diameter and endfeet Ca2+ did not change in the absence of stimulation. Time-course images of cross-section of an artery were taken at 15 sec interval. The movie was presented as 5 fps. Astrocytes were loaded with the Ca2+ indicator dye, rhod-2/am (red) and DMNP-EDTA/am, whereas the vasculature was stained with FITC-dextran (green). (MOV 249 kb)

Supplementary Video 3

Photostimulation failed to trigger Ca2+ increases or vasodilation in mice not loaded with caged Ca2+. Time-course images of cross-section of an artery were taken at 15 sec interval. The movie was presented as 5 fps. Astrocytes were loaded with the Ca2+ indicator dye, rhod-2/am (red) but not DMNP-EDTA/am, whereas the vasculature was stained with FITC-dextran (green). (MOV 257 kb)

Supplementary Video 4

Photolysis of caged Ca2+ triggered Ca2+ increase in an astrocytic endfoot adjacent to a vein, but failed to evoke vasodilation. Time-course images of cross-section of an artery were taken at 15 sec interval. The movie was presented as 5 fps. Astrocytes were loaded with the Ca2+ indicator dye, rhod-2/am (red) and DMNP-EDTA/am, whereas the vasculature was stained with FITC-dextran (green). (MOV 351 kb)

Supplementary Video 5

Photolysis of caged Ca2+ triggered Ca2+ increase in astrocytic endfeet but not vasodilation of artery in the presence of indomethacin (500 μM). Time-course images of cross-section of an artery were taken at 15 sec interval. The movie was presented as 5 fps. Astrocytes were loaded with the Ca2+ indicator dye, rhod-2/am (red) and DMNP-EDTA/am, whereas the vasculature was stained with FITC-dextran (green). (MOV 268 kb)

Supplementary Video 6

Photolysis of caged Ca2+ caused Ca2+ increase in astrocytic endfeet but not arterial vasodilation in the presence of SC-560 (500 μM). Time-course images of cross-section of an artery were taken at 15 sec interval. The movie was presented as 5 fps. Astrocytes were loaded with the Ca2+ indicator dye, rhod-2/am (red) and DMNP-EDTA/am, whereas the vasculature was stained with FITC-dextran (green). (MOV 243 kb)

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Takano, T., Tian, GF., Peng, W. et al. Astrocyte-mediated control of cerebral blood flow. Nat Neurosci 9, 260–267 (2006). https://doi.org/10.1038/nn1623

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