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.

  • Letter
  • Published:

Age-associated suppression of exploratory activity during sickness is linked to meningeal lymphatic dysfunction and microglia activation

Nature Aging volume 2, pages 704–713 (2022)Cite this article

Subjects

Abstract

Peripheral inflammation triggers a transient, well-defined set of behavioral changes known as sickness behavior1,2,3, but the mechanisms by which inflammatory signals originating in the periphery alter activity in the brain remain obscure. Emerging evidence has established meningeal lymphatic vasculature as an important interface between the central nervous system (CNS) and the immune system, responsible for facilitating brain solute clearance and perfusion by cerebrospinal fluid (CSF)4,5. Here, we demonstrate that meningeal lymphatics both assist microglial activation and support the behavioral response to peripheral inflammation. Ablation of meningeal lymphatics results in a heightened behavioral response to IL-1β-induced inflammation and a dampened transcriptional and morphological microglial phenotype. Moreover, our findings support a role for microglia in tempering the severity of sickness behavior with specific relevance to aging-related meningeal lymphatic dysfunction. Transcriptional profiling of brain myeloid cells shed light on the impact of meningeal lymphatic dysfunction on microglial activation. Furthermore, we demonstrate that experimental enhancement of meningeal lymphatic function in aged mice is sufficient to reduce the severity of exploratory abnormalities but not pleasurable consummatory behavior. Finally, we identify dysregulated genes and biological pathways, common to both experimental meningeal lymphatic ablation and aging, in microglia responding to peripheral inflammation that may result from age-related meningeal lymphatic dysfunction.

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: Meningeal lymphatic ablation exacerbates sickness behavior.
Fig. 2: Meningeal lymphatic ablation worsens sickness behavior through microglia.
Fig. 3: Enhancement of meningeal lymphatic function in aged mice improves exploratory behavior during sickness.

Similar content being viewed by others

Data availability

Single-cell RNA-sequencing data are accessible at the Gene Expression Omnibus under the accession number GSE168756. The data underlying the findings in this study are available as source data published alongside as XLSX files. Genetic material used for this paper are available from the authors upon reasonable request.

Code availability

Computer code used for analysis are available from the authors upon reasonable request.

References

  1. Dantzer, R. Neuroimmune interactions: from the brain to the immune system and vice versa. Physiol. Rev. 98, 477–504 (2018).

    Article  CAS  PubMed  Google Scholar 

  2. Kirsten, K., Soares, S. M., Koakoski, G., Carlos Kreutz, L. & Barcellos, L. J. G. Characterization of sickness behavior in zebrafish. Brain Behav. Immun. 73, 596–602 (2018).

    Article  CAS  PubMed  Google Scholar 

  3. Liu, X. et al. Cell-type-specific interleukin 1 receptor 1 signaling in the brain regulates distinct neuroimmune activities. Immunity 50, 317–333.e316 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Da Mesquita, S. et al. Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 560, 185–191 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Konsman, J. P., Kelley, K. & Dantzer, R. Temporal and spatial relationships between lipopolysaccharide-induced expression of Fos, interleukin-1beta and inducible nitric oxide synthase in rat brain. Neuroscience 89, 535–548 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Bluthé, R. M., Dantzer, R. & Kelley, K. W. Interleukin-1 mediates behavioural but not metabolic effects of tumor necrosis factor alpha in mice. Eur. J. Pharmacol. 209, 281–283 (1991).

    Article  PubMed  Google Scholar 

  8. Cremona, S., Goujon, E., Kelley, K. W., Dantzer, R. & Parnet, P. Brain type I but not type II IL-1 receptors mediate the effects of IL-1 beta on behavior in mice. Am. J. Physiol. 274, R735–R740 (1998).

    CAS  PubMed  Google Scholar 

  9. Ellul, P., Boyer, L., Groc, L., Leboyer, M. & Fond, G. Interleukin-1 β-targeted treatment strategies in inflammatory depression: toward personalized care. Acta Psychiatr. Scand. 134, 469–484 (2016).

    Article  CAS  PubMed  Google Scholar 

  10. Dantzer, R. Cytokine, sickness behavior, and depression. Neurol Clin 24, 441–460 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Lu, S. et al. Elevated specific peripheral cytokines found in major depressive disorder patients with childhood trauma exposure: a cytokine antibody array analysis. Compr. Psychiatry 54, 953–961 (2013).

    Article  PubMed  Google Scholar 

  12. Koo, J. W. & Duman, R. S. Evidence for IL-1 receptor blockade as a therapeutic strategy for the treatment of depression. Curr. Opin. Investig. Drugs 10, 664–671 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Mota, R. et al. Interleukin-1β is associated with depressive episode in major depression but not in bipolar disorder. J. Psychiatr. Res. 47, 2011–2014 (2013).

    Article  PubMed  Google Scholar 

  14. Walker, A. K., Wing, E. E., Banks, W. A. & Dantzer, R. Leucine competes with kynurenine for blood-to-brain transport and prevents lipopolysaccharide-induced depression-like behavior in mice. Mol. Psychiatry 24, 1523–1532 (2019).

    Article  CAS  PubMed  Google Scholar 

  15. Ching, S. et al. Endothelial-specific knockdown of interleukin-1 (IL-1) type 1 receptor differentially alters CNS responses to IL-1 depending on its route of administration. J. Neurosci. 27, 10476–10486 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bluthé, R. M., Michaud, B., Kelley, K. W. & Dantzer, R. Vagotomy blocks behavioural effects of interleukin-1 injected via the intraperitoneal route but not via other systemic routes. Neuroreport 7, 2823–2827 (1996).

    Article  PubMed  Google Scholar 

  17. Godbout, J. P. et al. Aging exacerbates depressive-like behavior in mice in response to activation of the peripheral innate immune system. Neuropsychopharmacology 33, 2341–2351 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Godbout, J. P. et al. Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J. 19, 1329–1331 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Abraham, J. & Johnson, R. W. Central inhibition of interleukin-1beta ameliorates sickness behavior in aged mice. Brain Behav. Immun. 23, 396–401 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Holmes, C. et al. Systemic infection, interleukin 1beta, and cognitive decline in Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatry 74, 788–789 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wilson, J. E. et al. Delirium. Nat Rev Dis Primers 6, 90 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Lampe, I. K., Kahn, R. S. & Heeren, T. J. Apathy, anhedonia, and psychomotor retardation in elderly psychiatric patients and healthy elderly individuals. J Geriatr Psychiatry Neurol 14, 11–16 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. JW., L. & V., B. Tables of Summary Health Statistics for the U.S. Population: 2018 National Health Interview Survey. National Center for Health Statistics, (Centers for Disease Control and Prevention, 2019).

  24. Pavon, J. M. et al. Accelerometer-measured hospital physical activity and hospital-acquired disability in older adults. J. Am. Geriatr. Soc. 68, 261–265 (2020).

    Article  PubMed  Google Scholar 

  25. Louveau, A. et al. CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature. Nat. Neurosci. 21, 1380–1391 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rustenhoven, J. et al. Functional characterization of the dural sinuses as a neuroimmune interface. Cell 184, 1000–1016.e1027 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ding, X. B. et al. Impaired meningeal lymphatic drainage in patients with idiopathic Parkinson’s disease.Nat. Med. 27, 411–418 (2021).

    Article  CAS  PubMed  Google Scholar 

  28. Arnone, D. et al. Role of Kynurenine pathway and its metabolites in mood disorders: A systematic review and meta-analysis of clinical studies. Neurosci. Biobehav. Rev. 92, 477–485 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Banks, W. A., Ortiz, L., Plotkin, S. R. & Kastin, A. J. Human interleukin (IL) 1 alpha, murine IL-1 alpha and murine IL-1 beta are transported from blood to brain in the mouse by a shared saturable mechanism. J. Pharmacol. Exp. Ther. 259, 988–996 (1991).

    CAS  PubMed  Google Scholar 

  30. Dantzer, R. Cytokine, sickness behavior, and depression. Immunol. Allergy Clin. North Am. 29, 247–264 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Zhu, L. et al. Interleukin-1 causes CNS inflammatory cytokine expression via endothelia-microglia bi-cellular signaling. Brain Behav. Immun. 81, 292–304 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zeisel, A. et al. Molecular architecture of the mouse nervous system. Cell 174, 999–1014 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kettenmann, H., Hanisch, U. K., Noda, M. & Verkhratsky, A. Physiology of microglia. Physiol. Rev. 91, 461–553 (2011).

    Article  CAS  PubMed  Google Scholar 

  34. Marsh, S. E. et al. Dissection of artifactual and confounding glial signatures by single-cell sequencing of mouse and human brain. Nat. Neurosci. 25, 306–316 (2022).

    Article  CAS  PubMed  Google Scholar 

  35. Elmore, M. R. et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82, 380–397 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lei, F. et al. CSF1R inhibition by a small-molecule inhibitor is not microglia specific; affecting hematopoiesis and the function of macrophages. Proc. Natl Acad. Sci. U S A 117, 23336–23338 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kokona, D., Ebneter, A., Escher, P. & Zinkernagel, M. S. Colony-stimulating factor 1 receptor inhibition prevents disruption of the blood-retina barrier during chronic inflammation. J. Neuroinflammation 15, 340 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Vichaya, E. G. et al. Microglia depletion fails to abrogate inflammation-induced sickness in mice and rats. J. Neuroinflammation 17, 172 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Da Mesquita, S. et al. Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy. Nature 593, 255–260 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Song, E. et al. VEGF-C-driven lymphatic drainage enables immunosurveillance of brain tumours. Nature 577, 689–694 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bonsall, D. R. et al. Suppression of locomotor activity in female C57Bl / 6J mice treated with interleukin-1\beta: investigating a method for the study of fatigue in laboratory animals. PLoS One 10, e0140678 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Merali, Z., Brennan, K., Brau, P. & Anisman, H. Dissociating anorexia and anhedonia elicited by interleukin-1beta: antidepressant and gender effects on responding for “free chow” and “earned” sucrose intake. Psychopharmacology (Berl.) 165, 413–418 (2003).

    Article  CAS  Google Scholar 

  43. Johnston, M., Wakeling, A., Graham, N. & Stokes, F. Cognitive impairment, emotional disorder and length of stay of elderly patients in a district general hospital. Br J Med Psychol 60, 133–139 (1987).

    Article  PubMed  Google Scholar 

  44. Abdi, S., Spann, A., Borilovic, J., de Witte, L. & Hawley, M. Understanding the care and support needs of older people: a scoping review and categorisation using the WHO international classification of functioning, disability and health framework (ICF). BMC Geriatr. 19, 195 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Herrera-Pérez, J. J., Martínez-Mota, L. & Fernández-Guasti, A. Aging increases the susceptibility to develop anhedonia in male rats. Prog. Neuropsychopharmacol. Biol. Psychiatry 32, 1798–1803 (2008).

    Article  PubMed  Google Scholar 

  46. Onaolapo, O. J. et al. Exogenous testosterone, aging, and changes in behavioral response of gonadally intact male mice. J. Exp. Neurosci. 10, 59–70 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bonsall, D. R. et al. Suppression of locomotor activity in female C57Bl/6J mice treated with interleukin-1β: investigating a method for the study of fatigue in laboratory animals. PLoS One 10, e0140678 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Malatynska, E. et al. Anhedonic-like traits and lack of affective deficits in 18-month-old C57BL/6 mice: implications for modeling elderly depression. Exp. Gerontol. 47, 552–564 (2012).

    Article  CAS  PubMed  Google Scholar 

  49. Liu, M. Y. et al. Sucrose preference test for measurement of stress-induced anhedonia in mice. Nat. Protoc. 13, 1686–1698 (2018).

    Article  CAS  PubMed  Google Scholar 

  50. Körbelin, J. et al. A brain microvasculature endothelial cell-specific viral vector with the potential to treat neurovascular and neurological diseases. EMBO Mol. Med. 8, 609–625 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Cronk, J. C. et al. Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia. J. Exp. Med. 215, 1627–1647 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lun, A. T. L. et al. EmptyDrops: distinguishing cells from empty droplets in droplet-based single-cell RNA sequencing data. Genome Biol. 20, 63 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Van den Berge, K. et al. Observation weights unlock bulk RNA-seq tools for zero inflation and single-cell applications. Genome Biol. 19, 24 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2010).

    Article  CAS  PubMed  Google Scholar 

  55. Blighe, K., Rana, S. & Lewis, M. EnhancedVolcano: Publication-Ready Volcano Plots with Enhanced Colouring and Labeling. R package version 1.14.0; https://github.com/kevinblighe/EnhancedVolcano (2020).

  56. Hong, G., Zhang, W., Li, H., Shen, X. & Guo, Z. Separate enrichment analysis of pathways for up- and downregulated genes. J. R. Soc. Interface 11, 20130950 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Yu, G., Wang, L. G., Han, Y. & He, Q. Y. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 16, 284–287 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank S. Smith for editing the manuscript and E. Griffin and N. Al-Hamadani for animal care and colony maintenance. We thank all members of the Kipnis laboratory for their valuable comments during numerous discussions of this work and the University of Virginia Genome Analysis and Technology Core for single-cell sequencing and consultation on experimental design. This work was funded by the National Institutes of Health grants DP1AT010416 and R37AG034113 to J.K. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Authors and Affiliations

  1. Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO, USA

    Dylan H. Goldman, Taitea Dykstra, Igor Smirnov, Susan M. Blackburn, Jonathan Kipnis & Jasmin Herz

  2. Department of Pathology & Immunology, Washington University in St. Louis, St. Louis, MO, USA

    Dylan H. Goldman, Taitea Dykstra, Igor Smirnov, Susan M. Blackburn, Jonathan Kipnis & Jasmin Herz

  3. Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, USA

    Dylan H. Goldman & Jonathan Kipnis

  4. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA

    Sandro Da Mesquita

Authors
  1. Dylan H. Goldman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Taitea Dykstra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Igor Smirnov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Susan M. Blackburn
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sandro Da Mesquita
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jonathan Kipnis
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jasmin Herz
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

D.H.G. primarily responsible for design and/or execution of experiments, analysis, and interpretation. T.D. performed analysis, interpretation of RNA-sequencing data, and design of figures. I.S. performed intra-cisterna magna injections and blinded experimenter. S.B. assisted with immunohistochemistry and ELISA and bred the mice. S.M. assisted with general experimental design, Visudyne ablation and AAV VEGF-C treatments. J.K. conceived project and advised overall work. J.H. assisted with experimental planning, design and execution; data discussion and interpretation; design of figures; and supervised revision and revised the manuscript. D.H.G, T.D. and J.H. wrote the manuscript.

Corresponding author

Correspondence to Jasmin Herz.

Ethics declarations

Competing interests

J.K. is a member of a scientific advisory group for PureTech Heath. The other authors declare no competing interests.

Peer review

Peer review information

Nature Structural and Molecular Biology thanks Niccolo Terrando 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.

Extended data

Extended Data Fig. 1 Off-target effects of Visudyne do not contribute to behavioral response to peripheral IL-1β.

a, Schematic view of dorsal skull. Crosses mark the location of photoactivation with non-thermal laser. Off-target sites were chosen for their lack of meningeal vasculature. b, Locomotor activity one week following artificial cerebrospinal fluid (aCSF) and targeted photoablation, or Visudyne and off-target photoactivation. Mice were injected with 1 ug IL-1β or saline intraperitoneally 1 h before repeated open field assessment (n = 8 mice per group, 2 outliers removed in aCSF – IL-1b by ROUT Q = 0.5%). Data presented as mean ± s.e.m. b, Three-way ANOVA. Data in b resulted from a single experiment.

Source data

Extended Data Fig. 2 IL-1β signaling on endothelial cells, neurons, astrocytes and microglia is not required for behavioral response to peripheral IL-1β.

a–d, Locomotor activity following saline (left) or IL-1β i.p. injection (right) in conditional knockout mice. a, Brain endothelium was targeted by injection of AAV-BR1-GFP or AAV1-BR1-Cre into IL-1Rfl/fl mice (n = 7 per group), or (b-d) by crossing floxed mice to cell specific Cre lines: b, neurons (Syn1Cre, n = 8 mice per group), c, astrocytes (n = 6 GfapCreER- and n = 10 GfapCreER+ mice for saline, n = 15 GfapCreER- and n = 13 GfapCreER+ mice for IL-1β), and d, myeloid (n = 6 Cx3cr1CreER- and n = 5 Cx3cr1CreER+ mice for saline, n = 17 Cx3cr1CreER- and n = 11 Cx3cr1CreER+ for IL-1β). Data presented as mean ± s.e.m.. Two-way ANOVA. The experiments in a–d were repeated in duplicates, and one experimental set of data is presented. No significant difference was found between groups.

Source data

Extended Data Fig. 3 Gene expression analysis by single-cell sequencing of microglia after IL-1β induced sickness.

a, UMAP representation for brain CD11b+ cells highlighting the different clusters with and without lymphatic ablation and injected with saline or IL-1β. b, Dot plot of cell type marker expression by cluster. c, Heatmap of mean expression of genes used to define inflammatory microglia. d, Features plot depicts the distribution of Socs3 expression. e, UMAP representation of CD11b+ sequenced cells from 24-month-old aged mice 2 h following saline or IL-1β i.p. injection. f, Cluster distribution compared between saline and IL-1β treatment.

Supplementary information

Reporting Summary

Supplementary Table 1

Supplementary Table 1. List of DEGs and enriched pathways in microglia (clusters 0, 1, 2, 3 and 6) between sham and lymphatic ablation conditions in response to IL-1β or saline i.p. injection. DEGs were identified using a two-tailed F-test with adjusted degrees of freedom based on weights calculated per gene with a zero-inflation model. Pathway analysis was performed with one-tailed Fisher’s exact test. P value adjustment with Benjamini–Hochberg. Supplementary Table 2. DEGs and enriched pathways in aged microglia (clusters 0, 1, 2, 3 and 6) responding to peripheral IL-1β versus saline injection. DEGs were identified using a two-tailed F-test with adjusted degrees of freedom based on weights calculated per gene with a zero-inflation model. Pathway analysis was performed with one-tailed Fisher’s exact test. P value adjustment with Benjamini–Hochberg. Supplementary Table 3. This table depicts the log2(fold change) and adjusted P values and enriched pathways in microglia for comparisons between sham versus IL-1β, meningeal lymphatic ablation versus IL-1β, or aged versus IL-1β groups for each cluster. One-tailed Fisher’s exact test and P value adjustment with Benjamini–Hochberg.

Source data

Source Data Fig. 1

Behavioral raw data (open field, food consumption, sucrose preference), ELISA reads and statistical analysis.

Source Data Fig. 2

Microscopy image analysis measurements, behavioral raw data (open field) and statistical analysis.

Source Data Fig. 3

Microscopy image analysis measurements, behavioral raw data (open field, food consumption, sucrose preference) and statistical analysis.

Source Data Extended Data Fig. 1

Behavioral raw data (open field) and statistical analysis.

Source Data Extended Data Fig. 2

Behavioral raw data (open field) and statistical analysis.

Rights and permissions

Springer Nature or its licensor 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

Goldman, D.H., Dykstra, T., Smirnov, I. et al. Age-associated suppression of exploratory activity during sickness is linked to meningeal lymphatic dysfunction and microglia activation. Nat Aging 2, 704–713 (2022). https://doi.org/10.1038/s43587-022-00268-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s43587-022-00268-y

This article is cited by

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