Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation

This article has been updated

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Neuronal afferent stimulation mediates dilation of cerebral arterioles and [Ca2+]i elevations in astrocyte somata and endfeet.
Figure 2: The blockade of [Ca2+]i elevations in astrocytes by mGluR antagonists impairs neuronal activity–dependent vasodilation.
Figure 3: Stimulation with t-ACPD induces [Ca2+]i increases in astrocytes and dilation of cerebral arterioles.
Figure 4: Direct stimulation of an individual astrocyte results in arteriole dilation.
Figure 5: The action of astrocytes depends mainly on a COX product.
Figure 6: The mGluR antagonists MPEP and LY367385 reduce the hyperemic response in the somatosensory cortex in vivo.

Similar content being viewed by others

Change history

  • 09 December 2002

    corrected spelling of Dr. Hossmann's name

Notes

  1. 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.

References

  1. Roy, C.S. & Sherrington, C. On the regulation of the blood supply of the brain. J. Physiol. 11, 85–108 (1890).

    Article  CAS  Google Scholar 

  2. Reinhard, J.F. Jr., Liebmann, J.E., Schlosberg, A.J. & Moskowitz, M.A. Serotonin neurons project to small blood vessels in the brain. Science 206, 85–87 (1979).

    Article  CAS  Google Scholar 

  3. Vaucher, E. & Hamel, E. Cholinergic basal forebrain neurons project to cortical microvessels in the rat: electron microscopic study with anterogradely transported Phaseolus vulgaris leucoagglutinin and choline acetyltransferase immunocytochemistry. J. Neurosci. 15, 7427–7441 (1995).

    Article  CAS  Google Scholar 

  4. Krimer, L.S., Muly, E.C., Williams, G.V. & Goldman-Rakic, P.S. Dopaminergic regulation of cerebral cortical microcirculation. Nat. Neurosci. 1, 286–289 (1998).

    Article  CAS  Google Scholar 

  5. Paspalas, C.D. & Papadopoulos, G.C. Ultrastructural evidence for combined action of noradrenaline and vasoactive intestinal polypeptide upon neurons, astrocytes, and blood vessels of the rat cerebral cortex. Brain Res. Bull. 45, 247–259 (1998).

    Article  CAS  Google Scholar 

  6. Yang, G., Huard, J.M., Beitz, A.J., Ross, M.E. & Iadecola, C. Stellate neurons mediate functional hyperemia in the cerebellar molecular layer. J. Neurosci. 20, 6968–6973 (2000).

    Article  CAS  Google Scholar 

  7. Faraci, F.M. & Heistad, D.D. Regulation of the cerebral circulation: role of endothelium and potassium channels. Physiol. Rev. 78, 53–97 (1998).

    Article  CAS  Google Scholar 

  8. Golgi, C. Sulla fina anatomia degli organi centrali del sistema nervoso. Riv. Sper. Fremiat. Med. Leg. Alienazioni Ment. 11, 72–123 (1885).

    Google Scholar 

  9. Peters, A., Palay, S.L. & Webster, H.d.F. in The Fine Structure of the Central Nervous System: Neurons and Their Supportive Cells (ed. Press, O.U.) 276–295 (Oxford Univ. Press, New York, 1991).

    Google Scholar 

  10. Ventura, R. & Harris, K.M. Three-dimensional relationships between hippocampal synapses and astrocytes. J. Neurosci. 19, 6897–6906 (1999).

    Article  CAS  Google Scholar 

  11. Porter, J.T. & McCarthy, K.D. Hippocampal astrocytes in situ respond to glutamate released from synaptic terminals. J. Neurosci. 16, 5073–5081 (1996).

    Article  CAS  Google Scholar 

  12. Pasti, L., Volterra, A., Pozzan, T. & Carmignoto, G. Intracellular calcium oscillations in astrocytes: a highly plastic, bidirectional form of communication between neurons and astrocytes in situ. J. Neurosci. 17, 7817–7830 (1997).

    Article  CAS  Google Scholar 

  13. Kang, J., Jiang, L., Goldman, S.A. & Nedergaard, M. Astrocyte-mediated potentiation of inhibitory synaptic transmission. Nat. Neurosci. 1, 683–692 (1998).

    Article  CAS  Google Scholar 

  14. Alkayed, N.J. et al. Role of P-450 arachidonic acid epoxygenase in the response of cerebral blood flow to glutamate in rats. Stroke 28, 1066–1072 (1997).

    Article  CAS  Google Scholar 

  15. Bezzi, P. et al. Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature 391, 281–285 (1998).

    Article  CAS  Google Scholar 

  16. Sagher, O. et al. Live computerized videomicroscopy of cerebral microvessels in brain slices. J. Cereb. Blood Flow Metab. 13, 676–682 (1993).

    Article  CAS  Google Scholar 

  17. Fergus, A., Jin, Y., Thai, Q.A., Kassell, N.F. & Lee, K.S. Vasodilatory actions of calcitonin gene-related peptide and nitric oxide in parenchymal microvessels of the rat hippocampus. Brain Res. 694, 78–84 (1995).

    Article  CAS  Google Scholar 

  18. Farber, N.E. et al. Region-specific and agent-specific dilation of intracerebral microvessels by volatile anesthetics in rat brain slices. Anesthesiology 87, 1191–1198 (1997).

    Article  CAS  Google Scholar 

  19. Gasparini, F. et al. 2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology 38, 1493–1503 (1999).

    Article  CAS  Google Scholar 

  20. Garthwaite, J., Charles, S.L. & Chess-Williams, R. Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature 336, 385–388 (1988).

    Article  CAS  Google Scholar 

  21. Garthwaite, J. Glutamate, nitric oxide and cell-cell signaling in the nervous system. Trends Neurosci. 14, 60–67 (1991).

    Article  CAS  Google Scholar 

  22. Iadecola, C. Regulation of the cerebral microcirculation during neural activity: is nitric oxide the missing link? Trends Neurosci. 16, 206–214 (1993).

    Article  CAS  Google Scholar 

  23. Fergus, A. & Lee, K.S. Regulation of cerebral microvessels by glutamatergic mechanisms. Brain Res. 754, 35–45 (1997).

    Article  CAS  Google Scholar 

  24. Fagni, L., Chavis, P., Ango, F. & Bockaert, J. Complex interactions between mGluRs, intracellular Ca2+ stores and ion channels in neurons. Trends Neurosci. 23, 80–88 (2000).

    Article  CAS  Google Scholar 

  25. Skeberdis, V.A. et al. mGluR1-mediated potentiation of NMDA receptors involves a rise in intracellular calcium and activation of protein kinase C. Neuropharmacology 40, 856–865 (2001).

    Article  CAS  Google Scholar 

  26. Schiavo, G. et al. Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin. Nature 359, 832–835 (1992).

    Article  CAS  Google Scholar 

  27. Parpura, V. et al. Glutamate-mediated astrocyte-neuron signalling. Nature 369, 744–747 (1994).

    Article  CAS  Google Scholar 

  28. Monn, J.A. et al. Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0] hexane- 2,6-dicarboxylic acid (LY354740): identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors. J. Med. Chem. 42, 1027–1040 (1999).

    Article  CAS  Google Scholar 

  29. Schmitz, B., Bottiger, B.W. & Hossmann, K.A. Functional activation of cerebral blood flow after cardiac arrest in rat. J. Cereb. Blood Flow Metab. 17, 1202–1209 (1997).

    Article  CAS  Google Scholar 

  30. White, R.P., Deane, C., Vallance, P. & Markus, H.S. Nitric oxide synthase inhibition in humans reduces cerebral blood flow but not the hyperemic response to hypercapnia. Stroke 29, 467–472 (1998).

    Article  CAS  Google Scholar 

  31. Lindauer, U., Megow, D., Matsuda, H. & Dirnagl, U. Nitric oxide: a modulator, but not a mediator, of neurovascular coupling in rat somatosensory cortex. Am. J. Physiol. 277, 799–811 (1999).

    Google Scholar 

  32. Iadecola, C., Zhang, F. & Xu, X. Role of nitric oxide synthase-containing vascular nerves in cerebrovasodilation elicited from cerebellum. Am. J. Physiol. 264, 738–746 (1993).

    Google Scholar 

  33. Yang, G., Chen, G., Ebner, T.J. & Iadecola, C. Nitric oxide is the predominant mediator of cerebellar hyperemia during somatosensory activation in rats. Am. J. Physiol. 277, 1760–1770 (1999).

    Article  Google Scholar 

  34. Golanov, E.V. & Reis, D.J. Nitric oxide and prostanoids participate in cerebral vasodilation elicited by electrical stimulation of the rostral ventrolateral medulla. J. Cereb. Blood Flow Metab. 14, 492–502 (1994).

    Article  CAS  Google Scholar 

  35. Bakalova, R., Matsuura, T. & Kanno, I. The cyclooxygenase inhibitors indomethacin and Rofecoxib reduce regional cerebral blood flow evoked by somatosensory stimulation in rats. Exp. Biol. Med. 227, 465–473 (2002).

    Article  CAS  Google Scholar 

  36. Niwa, K., Araki, E., Morham, S.G., Ross, M.E. & Iadecola, C. Cyclooxygenase-2 contributes to functional hyperemia in whisker-barrel cortex. J. Neurosci. 20, 763–770 (2000).

    Article  CAS  Google Scholar 

  37. Brinker, G. et al. Simultaneous recording of evoked potentials and T2*-weighted MR images during somatosensory stimulation of rat. Magn. Reson. Med. 41, 469–473 (1999).

    Article  CAS  Google Scholar 

  38. Carmignoto, G. Reciprocal communication systems between astrocytes and neurones. Prog. Neurobiol. 62, 561–581 (2000).

    Article  CAS  Google Scholar 

  39. Haydon, P.G. GLIA: listening and talking to the synapse. Nat. Rev. Neurosci. 2, 185–193 (2001).

    Article  CAS  Google Scholar 

  40. Robitaille, R. Modulation of synaptic efficacy and synaptic depression by glial cells at the frog neuromuscular junction. Neuron 21, 847–855 (1998).

    Article  CAS  Google Scholar 

  41. Araque, A., Sanzgiri, R.P., Parpura, V. & Haydon, P.G. Calcium elevation in astrocytes causes an NMDA receptor-dependent increase in the frequency of miniature synaptic currents in cultured hippocampal neurons. J. Neurosci. 18, 6822–6829 (1998).

    Article  CAS  Google Scholar 

  42. Parri, H.R., Gould, T.M. & Crunelli, V. Spontaneous astrocytic Ca2+ oscillations in situ drive NMDAR-mediated neuronal excitation. Nat. Neurosci. 4, 803–812 (2001).

    Article  CAS  Google Scholar 

  43. de la Torre, J.C. Alzheimer disease as a vascular disorder: nosological evidence. Stroke 33, 1152–1162 (2002).

    Article  CAS  Google Scholar 

  44. Raichle, M.E. Cognitive neuroscience. Bold insights. Nature 412, 128–130 (2001).

    Article  CAS  Google Scholar 

  45. Fox, P.T., Raichle, M.E., Mintun, M.A. & Dence, C. Nonoxidative glucose consumption during focal physiologic neural activity. Science 241, 462–464 (1988).

    Article  CAS  Google Scholar 

  46. Logothetis, N.K., Pauls, J., Augath, M., Trinath, T. & Oeltermann, A. Neurophysiological investigation of the basis of the fMRI signal. Nature 412, 150–157 (2001).

    Article  CAS  Google Scholar 

  47. Pellerin, L. & Magistretti, P.J. Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc. Natl. Acad. Sci. USA 91, 10625–10629 (1994).

    Article  CAS  Google Scholar 

  48. Carmignoto, G. & Vicini, S. Activity-dependent decrease in NMDA receptor responses during development of the visual cortex. Science 258, 1007–1011 (1992).

    Article  CAS  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Giorgio Carmignoto.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

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)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn980

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing