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.

  • Perspective
  • Published:

A conceptual framework for astrocyte function

Nature Neuroscience volume 26, pages 1848–1856 (2023)Cite this article

Subjects

Abstract

The participation of astrocytes in brain computation was hypothesized in 1992, coinciding with the discovery that these cells display a form of intracellular Ca2+ signaling sensitive to neuroactive molecules. This finding fostered conceptual leaps crystalized around the idea that astrocytes, once thought to be passive, participate actively in brain signaling and outputs. A multitude of disparate roles of astrocytes has since emerged, but their meaningful integration has been muddied by the lack of consensus and models of how we conceive the functional position of these cells in brain circuitry. In this Perspective, we propose an intuitive, data-driven and transferable conceptual framework we coin ‘contextual guidance’. It describes astrocytes as ‘contextual gates’ that shape neural circuitry in an adaptive, state-dependent fashion. This paradigm provides fresh perspectives on principles of astrocyte signaling and its relevance to brain function, which could spur new experimental avenues, including in computational space.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Astrocyte networks are cued by contextual signals to guide neural circuits.
Fig. 2: Astrocytes reconfigure circuits in a context-dependent fashion.
Fig. 3: In contextual guidance, astrocytes are a gate for modulatory inputs.
Fig. 4: Astrocytes provide context adaptation and stability to recurrent neural networks: proof of principle.

Similar content being viewed by others

Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author upon request.

Code availability

Codes and mathematical algorithms used in Fig. 4 will be made available upon publication.

References

  1. Cornell-Bell, A. H., Finkbeiner, S. M., Cooper, M. S. & Smith, S. J. Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling. Science 247, 470–473 (1990).

    Article  CAS  PubMed  Google Scholar 

  2. Smith, S. J. Do astrocytes process neural information? Prog. Brain Res. 94, 119–136 (1992).

    Article  CAS  PubMed  Google Scholar 

  3. Verkhratsky, A. & Nedergaard, M. Physiology of astroglia. Physiol. Rev. 98, 239–389 (2018).

    Article  CAS  PubMed  Google Scholar 

  4. 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  PubMed Central  PubMed  Google Scholar 

  5. Smith, S. J. Neural signalling. Neuromodulatory astrocytes. Curr. Biol. 4, 807–810 (1994).

    Article  CAS  PubMed  Google Scholar 

  6. Araque, A., Parpura, V., Sanzgiri, R. P. & Haydon, P. G. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci. 22, 208–215 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Nagai, J. et al. Behaviorally consequential astrocytic regulation of neural circuits. Neuron 109, 576–596 (2021).

    Article  CAS  PubMed  Google Scholar 

  8. Aten, S. et al. Ultrastructural view of astrocyte arborization, astrocyte-astrocyte and astrocyte-synapse contacts, intracellular vesicle-like structures, and mitochondrial network. Prog. Neurobiol. 213, 102264 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Bushong, E. A., Martone, M. E., Jones, Y. Z. & Ellisman, M. H. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J. Neurosci. 22, 183–192 (2002).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Salmon, C. K. et al. Organizing principles of astrocytic nanoarchitecture in the mouse cerebral cortex. Curr. Biol. 33, 957–972 (2023).

    Article  CAS  PubMed  Google Scholar 

  11. Hösli, L. et al. Direct vascular contact is a hallmark of cerebral astrocytes. Cell Rep. 39, 110599 (2022).

    Article  PubMed  Google Scholar 

  12. Endo, F. et al. Molecular basis of astrocyte diversity and morphology across the CNS in health and disease. Science 378, eadc9020 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Semyanov, A. & Verkhratsky, A. Astrocytic processes: from tripartite synapses to the active milieu. Trends Neurosci. 44, 781–792 (2021).

    Article  CAS  PubMed  Google Scholar 

  14. Díaz-Castro, B., Robel, S. & Mishra, A. Astrocyte endfeet in brain function and pathology: open questions. Annu. Rev. Neurosci. 46, 101–121 (2023).

    Article  PubMed  Google Scholar 

  15. Gourine, A. V. et al. Astrocytes control breathing through pH-dependent release of ATP. Science 329, 571–575 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Xie, L. et al. Sleep drives metabolite clearance from the adult brain. Science 342, 373–377 (2013).

    Article  CAS  PubMed  Google Scholar 

  17. Wang, F. et al. Astrocytes modulate neural network activity by Ca²+-dependent uptake of extracellular K+. Sci. Signal. 5, ra26 (2012).

    Article  PubMed Central  PubMed  Google Scholar 

  18. Henneberger, C., Papouin, T., Oliet, S. H. & Rusakov, D. A. Long-term potentiation depends on release of d-serine from astrocytes. Nature 463, 232–236 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Ding, F. et al. Changes in the composition of brain interstitial ions control the sleep-wake cycle. Science 352, 550–555 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Tønnesen, J., Inavalli, V. V. G. K. & Nägerl, U. V. Super-resolution imaging of the extracellular space in living brain tissue. Cell 172, 1108–1121 (2018).

    Article  PubMed  Google Scholar 

  21. Murphy-Royal, C. et al. Stress gates an astrocytic energy reservoir to impair synaptic plasticity. Nat. Commun. 11, 2014 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Kasymov, V. et al. Differential sensitivity of brainstem versus cortical astrocytes to changes in pH reveals functional regional specialization of astroglia. J. Neurosci. 33, 435–441 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Khakh, B. S. & Deneen, B. The emerging nature of astrocyte diversity. Annu. Rev. Neurosci. 42, 187–207 (2019).

    Article  CAS  PubMed  Google Scholar 

  24. Lanjakornsiripan, D. et al. Layer-specific morphological and molecular differences in neocortical astrocytes and their dependence on neuronal layers. Nat. Commun. 9, 1623 (2018).

    Article  PubMed Central  PubMed  Google Scholar 

  25. Bayraktar, O. A. et al. Astrocyte layers in the mammalian cerebral cortex revealed by a single-cell in situ transcriptomic map. Nat. Neurosci. 23, 500–509 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Batiuk, M. Y. et al. Identification of region-specific astrocyte subtypes at single cell resolution. Nat. Commun. 11, 1220 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Chai, H. et al. Neural circuit-specialized astrocytes: transcriptomic, proteomic, morphological, and functional evidence. Neuron 95, 531–549 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Rusakov, D. A., Bard, L., Stewart, M. G. & Henneberger, C. Diversity of astroglial functions alludes to subcellular specialisation. Trends Neurosci. 37, 228–242 (2014).

    Article  CAS  PubMed  Google Scholar 

  29. Papouin, T., Dunphy, J. M., Tolman, M., Dineley, K. T. & Haydon, P. G. Septal cholinergic neuromodulation tunes the astrocyte-dependent gating of hippocampal NMDA receptors to wakefulness. Neuron 94, 840–854 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Ameroso, D. et al. Astrocytic BDNF signaling within the ventromedial hypothalamus regulates energy homeostasis. Nat. Metab. 4, 627–643 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Zuend, M. et al. Arousal-induced cortical activity triggers lactate release from astrocytes. Nat. Metab. 2, 179–191 (2020).

    Article  CAS  PubMed  Google Scholar 

  32. Tran, C. H. T., Peringod, G. & Gordon, G. R. Astrocytes integrate behavioral state and vascular signals during functional hyperemia. Neuron 100, 1133–1148 (2018).

    Article  CAS  PubMed  Google Scholar 

  33. Morquette, P. et al. An astrocyte-dependent mechanism for neuronal rhythmogenesis. Nat. Neurosci. 18, 844–854 (2015).

    Article  CAS  PubMed  Google Scholar 

  34. Lee, J. H. et al. Astrocytes phagocytose adult hippocampal synapses for circuit homeostasis. Nature 590, 612–617 (2021).

    Article  CAS  PubMed  Google Scholar 

  35. Panatier, A. et al. Glia-derived d-serine controls NMDA receptor activity and synaptic memory. Cell 125, 775–784 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Paukert, M. et al. Norepinephrine controls astroglial responsiveness to local circuit activity. Neuron 82, 1263–1270 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Bojarskaite, L. et al. Astrocytic Ca2+ signaling is reduced during sleep and is involved in the regulation of slow wave sleep. Nat. Commun. 11, 3240 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Burda, J. E. et al. Divergent transcriptional regulation of astrocyte reactivity across disorders. Nature 606, 557–564 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Heiman, M. G. & Shaham, S. Ancestral roles of glia suggested by the nervous system of Caenorhabditis elegans. Neuron Glia Biol. 3, 55–61 (2007).

    Article  PubMed  Google Scholar 

  40. Stobart, J. L. et al. Cortical circuit activity evokes rapid astrocyte calcium signals on a similar timescale to neurons. Neuron 98, 726–735 (2018).

    Article  CAS  PubMed  Google Scholar 

  41. Vardjan, N., Parpura, V. & Zorec, R. Loose excitation-secretion coupling in astrocytes. Glia 64, 655–667 (2016).

    Article  PubMed  Google Scholar 

  42. Bindocci, E. et al. Three-dimensional Ca2+ imaging advances understanding of astrocyte biology. Science 356, eaai8185 (2017).

    Article  PubMed  Google Scholar 

  43. Wu, Y. W. et al. Spatiotemporal calcium dynamics in single astrocytes and its modulation by neuronal activity. Cell Calcium 55, 119–129 (2014).

    Article  CAS  PubMed  Google Scholar 

  44. Lines, J., Martin, E. D., Kofuji, P., Aguilar, J. & Araque, A. Astrocytes modulate sensory-evoked neuronal network activity. Nat. Commun. 11, 3689 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Robin, L. M. et al. Astroglial CB1 receptors determine synaptic d-serine availability to enable recognition memory. Neuron 98, 935–944 (2018).

    Article  CAS  PubMed  Google Scholar 

  46. Martín, R., Bajo-Grañeras, R., Moratalla, R., Perea, G. & Araque, A. Circuit-specific signaling in astrocyte–neuron networks in basal ganglia pathways. Science 349, 730–734 (2015).

    Article  PubMed  Google Scholar 

  47. Takano, T. et al. Chemico-genetic discovery of astrocytic control of inhibition in vivo. Nature 588, 296–302 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Matos, M. et al. Astrocytes detect and upregulate transmission at inhibitory synapses of somatostatin interneurons onto pyramidal cells. Nat. Commun. 9, 4254 (2018).

    Article  PubMed Central  PubMed  Google Scholar 

  49. Deemyad, T., Lüthi, J. & Spruston, N. Astrocytes integrate and drive action potential firing in inhibitory subnetworks. Nat. Commun. 9, 4336 (2018).

    Article  PubMed Central  PubMed  Google Scholar 

  50. Stefanelli, T., Bertollini, C., Lüscher, C., Muller, D. & Mendez, P. Hippocampal somatostatin interneurons control the size of neuronal memory ensembles. Neuron 89, 1074–1085 (2016).

    Article  CAS  PubMed  Google Scholar 

  51. Mariotti, L. et al. Interneuron-specific signaling evokes distinctive somatostatin-mediated responses in adult cortical astrocytes. Nat. Commun. 9, 82 (2018).

    Article  PubMed Central  PubMed  Google Scholar 

  52. Kohro, Y. et al. Spinal astrocytes in superficial laminae gate brainstem descending control of mechanosensory hypersensitivity. Nat. Neurosci. 23, 1376–1387 (2020).

    Article  CAS  PubMed  Google Scholar 

  53. Pankratov, Y. & Lalo, U. Role for astroglial α1-adrenoreceptors in gliotransmission and control of synaptic plasticity in the neocortex. Front. Cell. Neurosci. 9, 230 (2015).

    Article  PubMed Central  PubMed  Google Scholar 

  54. Wahis, J. et al. Astrocytes mediate the effect of oxytocin in the central amygdala on neuronal activity and affective states in rodents. Nat. Neurosci. 24, 529–541 (2021).

    Article  CAS  PubMed  Google Scholar 

  55. Takata, N. et al. Astrocyte calcium signaling transforms cholinergic modulation to cortical plasticity in vivo. J. Neurosci. 31, 18155–18165 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Poskanzer, K. E. & Molofsky, A. V. Dynamism of an astrocyte in vivo: perspectives on identity and function. Annu. Rev. Physiol. 80, 143–157 (2018).

    Article  CAS  PubMed  Google Scholar 

  57. Gau, Y. A. et al. Multicore fiber optic imaging reveals that astrocyte calcium activity in the cerebral cortex is modulated by internal motivational state. Preprint at bioRxiv https://doi.org/10.1101/2023.05.18.541390 (2023).

  58. Suthard, R. L. et al. Basolateral amygdala astrocytes are engaged by the acquisition and expression of a contextual fear memory. J. Neurosci. 43, 4997–5013 (2022).

    Article  Google Scholar 

  59. Adedipe, I. I. et al. Astrocyte glucocorticoid signaling mediates cognitive impairment induced by early-life stress. Preprint at bioRxiv https://doi.org/10.1101/2022.12.11.519598 (2022).

  60. Sapkota, D. et al. Activity-dependent translation dynamically alters the proteome of the perisynaptic astrocyte process. Cell Rep. 41, 111474 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Di Castro, M. A. & Volterra, A. Astrocyte control of the entorhinal cortex-dentate gyrus circuit: relevance to cognitive processing and impairment in pathology. Glia 70, 1536–1553 (2022).

    Article  PubMed  Google Scholar 

  62. Oe, Y. et al. Distinct temporal integration of noradrenaline signaling by astrocytic second messengers during vigilance. Nat. Commun. 11, 471 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Armbruster, M. et al. Neuronal activity drives pathway-specific depolarization of peripheral astrocyte processes. Nat. Neurosci. 25, 607–616 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Giaume, C., Koulakoff, A., Roux, L., Holcman, D. & Rouach, N. Astroglial networks: a step further in neuroglial and gliovascular interactions. Nat. Rev. Neurosci. 11, 87–99 (2010).

    Article  CAS  PubMed  Google Scholar 

  65. Longden, T. A. et al. Local IP3 receptor-mediated Ca2+ signals compound to direct blood flow in brain capillaries. Sci. Adv. 7, eabh0101 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. García-Cáceres, C. et al. Astrocytic insulin signaling couples brain glucose uptake with nutrient availability. Cell 166, 867–880 (2016).

    Article  PubMed Central  PubMed  Google Scholar 

  67. Kim, J. G. et al. Leptin signaling in astrocytes regulates hypothalamic neuronal circuits and feeding. Nat. Neurosci. 17, 908–910 (2014).

    Article  CAS  PubMed  Google Scholar 

  68. Fuente-Martín, E. et al. Ghrelin regulates glucose and glutamate transporters in hypothalamic astrocytes. Sci. Rep. 6, 23673 (2016).

    Article  PubMed Central  PubMed  Google Scholar 

  69. Crosby, K. M. et al. Cholecystokinin switches the plasticity of GABA synapses in the dorsomedial hypothalamus via astrocytic ATP release. J. Neurosci. 38, 8515–8525 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  70. Zerbi, V. et al. Rapid reconfiguration of the functional connectome after chemogenetic locus coeruleus activation. Neuron 103, 702–718 (2019).

    Article  CAS  PubMed  Google Scholar 

  71. Pacholko, A. G., Wotton, C. A. & Bekar, L. K. Astrocytes—the ultimate effectors of long-range neuromodulatory networks? Front. Cell. Neurosci. 14, 581075 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Hirase, H., Iwai, Y., Takata, N., Shinohara, Y. & Mishima, T. Volume transmission signalling via astrocytes. Philos. Trans. R. Soc. Lond. B Biol. Sci. 369, 20130604 (2014).

    Article  PubMed Central  PubMed  Google Scholar 

  73. Rurak, G. M. et al. Sex differences in developmental patterns of neocortical astroglia: a mouse translatome database. Cell Rep. 38, 110310 (2022).

    Article  CAS  PubMed  Google Scholar 

  74. Richards, B., Tsao, D. & Zador, A. The application of artificial intelligence to biology and neuroscience. Cell 185, 2640–2643 (2022).

    Article  CAS  PubMed  Google Scholar 

  75. Parisi, G. I., Kemker, R., Part, J. L., Kanan, C. & Wermter, S. Continual lifelong learning with neural networks: a review. Neural Netw. 113, 54–71 (2019).

    Article  PubMed  Google Scholar 

  76. Yu, Y., Si, X., Hu, C. & Zhang, J. A review of recurrent neural networks: LSTM cells and network architectures. Neural Comput. 31, 1235–1270 (2019).

    Article  PubMed  Google Scholar 

  77. Corkrum, M. et al. Dopamine-evoked synaptic regulation in the nucleus accumbens requires astrocyte activity. Neuron 105, 1036–1047 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  78. Mu, Y. et al. Glia accumulate evidence that actions are futile and suppress unsuccessful behavior. Cell 178, 27–43 (2019).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

C.M.-R. was supported by a Canadian Institutes of Health Research Project Grant (478629), an NSERC Discovery Grant (RGPIN-2021-03211), Fonds de Recherche du Québec – Santé (296562 & 309889) and the Brain & Behavior Research Foundation (NARSAD Young Investigator Award 28589). S.C. was supported by the Department of Defense (DoD; W911NF-21-1-0312) and the National Science Foundation (1653589). T.P. was supported by the National Institutes of Health (1R01MH127163-01), the DoD (W911NF-21-1-0312), the Brain & Behavior Research Foundation (NARSAD Young Investigator Award 28616), the Whitehall Foundation (2020-08-35) and the McDonnell Center for Cellular and Molecular Neurobiology Award (22-3930-26275U). The authors thank J. Dunphy for critical feedback. We apologize that the work of many of our colleagues and peers could not be cited owing to strict space limitations and the abundance of papers published during the publication process. Figure 4 was created with BioRender.com.

Author information

Authors and Affiliations

  1. Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM) & Département de Neurosciences, Université de Montréal, Montréal, Quebec, Canada

    Ciaran Murphy-Royal

  2. Electrical and Systems Engineering, Washington University in St. Louis, St. Louis, MO, USA

    ShiNung Ching

  3. Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, USA

    Thomas Papouin

Authors
  1. Ciaran Murphy-Royal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. ShiNung Ching
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas Papouin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T.P. wrote the first drafts and created the figures, box and supplementary tables. C.M.-R. and S.C. contributed to sections along lines of expertise. C.M.-R. expanded and revised the manuscript. S.C. generated Fig. 4. T.P. assembled comments from all authors, wrote the final version and performed revisions.

Corresponding author

Correspondence to Thomas Papouin.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Neuroscience thanks Inbal Goshen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Tables 1 and 2

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Murphy-Royal, C., Ching, S. & Papouin, T. A conceptual framework for astrocyte function. Nat Neurosci 26, 1848–1856 (2023). https://doi.org/10.1038/s41593-023-01448-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41593-023-01448-8

Search

Advanced 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