Abstract
The cellular mechanisms underlying functional hyperemia—the coupling of neuronal activation to cerebral blood vessel responses—are not yet known. Here we show in rat cortical slices that the dilation of arterioles triggered by neuronal activity is dependent on glutamate-mediated [Ca2+]i oscillations in astrocytes. Inhibition of these Ca2+ responses resulted in the impairment of activity-dependent vasodilation, whereas selective activation—by patch pipette—of single astrocytes that were in contact with arterioles triggered vessel relaxation. We also found that a cyclooxygenase product is centrally involved in this astrocyte-mediated control of arterioles. In vivo blockade of glutamate-mediated [Ca2+]i elevations in astrocytes reduced the blood flow increase in the somatosensory cortex during contralateral forepaw stimulation. Taken together, our findings show that neuron-to-astrocyte signaling is a key mechanism in functional hyperemia.
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Change history
09 December 2002
corrected spelling of Dr. Hossmann's name
Notes
Note: In the AOP version of this article, Dr. Hossmann's name was misspelled. The correct spelling should be Konstantin-A. Hossmann. This mistake has been corrected in the HTML version and will appear correctly in print. The PDF version available online has been appended.
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Acknowledgements
We thank P. Magalhães for comments on the manuscript and C. Montecucco for the supply of purified tetanus neurotoxin. M.C.A. was supported by the Human Frontier Science Program Organization (HFSPO). This work was supported by grants from the Armenise Harvard University Foundation, the Italian University and Health Ministries, the Italian Association for Cancer Research (AIRC), the Human Frontier Science Program (RG520/95), the ST/Murst 'Neuroscienze' to G.C., Telethon-Italy (845 and 850 to T.P.; 1095 to G.C.), and the European Community (QLG3-CT-2000-00934).
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Supplementary information
Supplementary Fig. 1.
(a, b) Pseudocolour images of the same cortical field shown in Figure 1d of the manuscript, illustrating the [Ca2+]i increases in somata and endfeet of the astrocytes in contact with the arteriole, upon a second (a) and a third (b) neuronal stimulation. The response to the first stimulation was illustrated in figure 1d. Acquisition rate, 2 s. Scale bar, 10 μm. (c, d) Kinetics of [Ca2+]i changes at soma and endfeet of the astrocytes present in the field, including that already shown in Figure 1 of the manuscript, upon the second (c) and the third (d) stimulation. The asteriscs mark the time points corresponding to the images in a and b. The protocol of 4 min of neuronal afferent stimulation was applied (see methods). R corresponds to R405/485. (JPG 187 kb)
Supplementary Fig. 2.
Time course of the change in arteriole diameter in the sectors A and B, indicated in Movies 1a (a) and 1b (b). The timing of the movies is reported on the X axis. (GIF 18 kb)
Supplementary Fig. 3.
Time course of the change in arteriole diameter in the sectors A and B, indicated in Movie 2. The timing of the movie is reported on the X axis. (GIF 9 kb)
Supplementary Fig. 4.
Changes in LDF signal induced by successive episodes of electrical forepaw stimulation in an adult rat under control conditions (black line) and after sistemical infusion of MPEP and LY367385 (red line). (GIF 14 kb)
Supplementary Movie 1a.
Time-lapse movies of the change in arteriole diameter reported in Figure 2c of the manuscript. Neuronal afferent stimulation was performed in absence (movie 1a) and presence (movie 1b) of 50 μM MPEP and 100 μM LY367385, group I mGluR antagonists. The red filled circle marks the onset and duration of the applied stimulus. Acquisition rate, 5 s. (MOV 618 kb)
Supplementary Movie 1b.
Time-lapse movies of the change in arteriole diameter reported in Figure 2c of the manuscript. Neuronal afferent stimulation was performed in absence (movie 1a) and presence (movie 1b) of 50 μM MPEP and 100 μM LY367385, group I mGluR antagonists. The red filled circle marks the onset and duration of the applied stimulus. Acquisition rate, 5 s. (MOV 487 kb)
Supplementary Movie 2.
Time-lapse movie of the change in arteriole diameter reported in Figure 3d of the manuscript, during stimulation with 100 μM t-ACPD. The yellow filled circle indicates the onset and duration of the applied stimulus. Acquisition rate, 5 s. (MOV 886 kb)
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Zonta, M., Angulo, M., Gobbo, S. et al. Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci 6, 43–50 (2003). https://doi.org/10.1038/nn980
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DOI: https://doi.org/10.1038/nn980
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