iBet uBet web content aggregator. Adding the entire web to your favor.
iBet uBet web content aggregator. Adding the entire web to your favor.



Link to original content: https://www.nature.com/articles/s41586-022-05483-6
Filopodia are a structural substrate for silent synapses in adult neocortex | Nature
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:

Filopodia are a structural substrate for silent synapses in adult neocortex

Nature volume 612, pages 323–327 (2022)Cite this article

Subjects

Abstract

Newly generated excitatory synapses in the mammalian cortex lack sufficient AMPA-type glutamate receptors to mediate neurotransmission, resulting in functionally silent synapses that require activity-dependent plasticity to mature. Silent synapses are abundant in early development, during which they mediate circuit formation and refinement, but they are thought to be scarce in adulthood1. However, adults retain a capacity for neural plasticity and flexible learning that suggests that the formation of new connections is still prevalent. Here we used super-resolution protein imaging to visualize synaptic proteins at 2,234 synapses from layer 5 pyramidal neurons in the primary visual cortex of adult mice. Unexpectedly, about 25% of these synapses lack AMPA receptors. These putative silent synapses were located at the tips of thin dendritic protrusions, known as filopodia, which were more abundant by an order of magnitude than previously believed (comprising about 30% of all dendritic protrusions). Physiological experiments revealed that filopodia do indeed lack AMPA-receptor-mediated transmission, but they exhibit NMDA-receptor-mediated synaptic transmission. We further showed that functionally silent synapses on filopodia can be unsilenced through Hebbian plasticity, recruiting new active connections into a neuron’s input matrix. These results challenge the model that functional connectivity is largely fixed in the adult cortex and demonstrate a new mechanism for flexible control of synaptic wiring that expands the learning capabilities of the mature brain.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1: Filopodia account for a large fraction of dendritic protrusions in L5 and L2/3 pyramidal neurons of adult mouse primary visual cortex.
Fig. 2: Filopodia exhibit AMPAR-immunonegative and NMDAR-immunopositive synapses.
Fig. 3: Filopodia lack AMPAR- but exhibit NMDAR-mediated transmission and release-competent presynaptic partners.
Fig. 4: Silent synapses at filopodia can be unsilenced by Hebbian pairing.

Similar content being viewed by others

Data availability

The data generated and analysed in the current study are available from the corresponding author upon reasonable request. Source data are provided with this paper.

Code availability

Code for image analysis can be accessed at https://github.com/harnett/FilopodiaStructuralSubstrateSilentSynapses.

References

  1. Hanse, E., Seth, H. & Riebe, I. AMPA-silent synapses in brain development and pathology. Nat. Rev. Neurosci. 14, 839–850 (2013).

    Article  CAS  Google Scholar 

  2. Katz, L. C. & Shatz, L. C. Synaptic activity and the construction of cortical circuits. Science 274, 1133–1138 (1996).

    Article  ADS  CAS  Google Scholar 

  3. Magee, J. C. & Grienberger, C. Synaptic plasticity forms and functions. Annu. Rev. Neurosci. 43, 95–117 (2020).

    Article  CAS  Google Scholar 

  4. Trachtenberg, J. T. et al. Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex. Nature 420, 788–794 (2002).

    Article  ADS  CAS  Google Scholar 

  5. Knott, G. W., Holtmaat, A., Wilbrecht, L., Welker, E. & Svoboda, K. Spine growth precedes synapse formation in the adult neocortex in vivo. Nat. Neurosci. 9, 1117–1124 (2006).

    Article  CAS  Google Scholar 

  6. Grutzendler, J., Kasthuri, N. & Gan, W. B. Long-term dendritic spine stability in the adult cortex. Nature 420, 812–816 (2002).

    Article  ADS  CAS  Google Scholar 

  7. Holtmaat, A. J. G. D. et al. Transient and persistent dendritic spines in the neocortex in vivo. Neuron 45, 279–291 (2005).

    Article  CAS  Google Scholar 

  8. Fusi, S. & Abbott, L. F. Limits on the memory storage capacity of bounded synapses. Nat. Neurosci. 10, 485–493 (2007).

    Article  CAS  Google Scholar 

  9. Poirazi, P. & Mel, B. W. Impact of active dendrites and structural plasticity on the memory capacity of neural tissue. Neuron 29, 779–796 (2001).

    Article  CAS  Google Scholar 

  10. Durand, G. M., Kovalchuk, Y. & Konnerth, A. Long-term potentiation and functional synapse induction in developing hippocampus. Nature 381, 71–75 (1996).

    Article  ADS  CAS  Google Scholar 

  11. Huang, X. et al. Progressive maturation of silent synapses governs the duration of a critical period. Proc. Natl Acad. Sci. USA 112, E3131–E3140 (2015).

    Article  CAS  Google Scholar 

  12. Busetto, G., Higley, M. J. & Sabatini, B. L. Developmental presence and disappearance of postsynaptically silent synapses on dendritic spines of rat layer 2/3 pyramidal neurons. J. Physiol. 586, 1519–1527 (2008).

    Article  CAS  Google Scholar 

  13. Isaac, J. T. R., Crair, M. C., Nicoll, R. A. & Malenka, R. C. Silent synapses during development of thalamocortical inputs. Neuron 18, 269–280 (1997).

    Article  CAS  Google Scholar 

  14. Anastasiades, P. G. & Butt, S. J. B. A role for silent synapses in the development of the pathway from layer 2/3 to 5 pyramidal cells in the neocortex. J. Neurosci. 32, 13085–13099 (2012).

    Article  CAS  Google Scholar 

  15. Park, J. et al. Epitope-preserving magnified analysis of proteome (eMAP). Sci. Adv. 7, eabf6589–eabf6589 (2021).

  16. Fiala, J. C., Feinberg, M., Popov, V. & Harris, K. M. Synaptogenesis via dendritic filopodia in developing hippocampal area CA1. J. Neurosci. 18, 8900–8911 (1998).

    Article  CAS  Google Scholar 

  17. Zuo, Y., Lin, A., Chang, P. & Gan, W. B. Development of long-term dendritic spine stability in diverse regions of cerebral cortex. Neuron 46, 181–189 (2005).

    Article  CAS  Google Scholar 

  18. Dunaevsky, A., Tashiro, A., Majewska, A., Mason, C. & Yuste, R. Developmental regulation of spine motility in the mammalian central nervous system. Proc. Natl Acad. Sci. USA 96, 13438–13443 (1999).

    Article  ADS  CAS  Google Scholar 

  19. Berry, K. P. & Nedivi, E. Spine dynamics: are they all the same? Neuron 96, 43–55 (2017).

    Article  CAS  Google Scholar 

  20. Gundelfinger, E. D., Reissner, C. & Garner, C. C. Role of Bassoon and Piccolo in assembly and molecular organization of the active zone. Front. Synaptic Neurosci. 7, 19 (2016).

    Article  Google Scholar 

  21. Nusser, Z. et al. Cell type and pathway dependence of synaptic AMPA receptor number and variability in the hippocampus. Neuron 21, 545–559 (1998).

    Article  CAS  Google Scholar 

  22. Kharazia, V. N. & Weinberg, R. J. Immunogold localization of AMPA and NMDA receptors in somatic sensory cortex of albino rat. J. Comp. Neurol. 412, 292–302 (1999).

    Article  CAS  Google Scholar 

  23. Holler, S., Köstinger, G., Martin, K. A. C., Schuhknecht, G. F. P. & Stratford, K. J. Structure and function of a neocortical synapse. Nature 591, 111–116 (2021).

    Article  ADS  CAS  Google Scholar 

  24. Liao, D., Scannevin, R. H. & Huganir, R. Activation of silent synapses by rapid activity-dependent synaptic recruitment of AMPA receptors. J. Neurosci. 21, 6008–6017 (2001).

    Article  CAS  Google Scholar 

  25. Isaac, J. T. R., Nicoll, R. A. & Malenka, R. C. Evidence for silent synapses: implications for the expression of LTP. Neuron 15, 427–434 (1995).

    Article  CAS  Google Scholar 

  26. Mainen, Z. F., Malinow, R. & Svoboda, K. Synaptic calcium transients in single spines indicate that NMDA receptors are not saturated. Nature 399, 151–155 (1999).

    Article  ADS  CAS  Google Scholar 

  27. Oertner, T. G., Sabatini, B. L., Nimchinsky, E. A. & Svoboda, K. Facilitation at single synapses probed with optical quantal analysis. Nat. Neurosci. 5, 657–664 (2002).

    Article  CAS  Google Scholar 

  28. Kerchner, G. A. & Nicoll, R. A. Silent synapses and the emergence of a postsynaptic mechanism for LTP. Nat. Rev. Neurosci. 9, 813–825 (2008).

    Article  CAS  Google Scholar 

  29. Lisman, J. E., Raghavachari, S. & Tsien, R. W. The sequence of events that underlie quantal transmission at central glutamatergic synapses. Nat. Rev. Neurosci. 8, 597–609 (2007).

    Article  CAS  Google Scholar 

  30. Liao, D., Hessler, N. A. & Malinow, R. Activation of postsynaptically silent synapses during pairing-induced LTP in CA1 region of hippocampal slice. Nature 375, 400–404 (1995).

    Article  ADS  CAS  Google Scholar 

  31. Zhu, J. J., Esteban, J. A., Hayashi, Y. & Malinow, R. Postnatal synaptic potentiation: delivery of GluR4-containing AMPA receptors by spontaneous activity. Nat. Neurosci. 3, 1098–1106 (2000).

    Article  CAS  Google Scholar 

  32. Tazerart, S., Mitchell, D. E., Miranda-Rottmann, S. & Araya, R. A spike-timing-dependent plasticity rule for dendritic spines. Nat. Commun. 11, 4276 (2020).

    Article  ADS  Google Scholar 

  33. Wassie, A. T., Zhao, Y. & Boyden, E. S. Expansion microscopy: principles and uses in biological research. Nat. Methods 16, 33–41 (2019).

    Article  CAS  Google Scholar 

  34. Ofer, N., Berger, D. R., Kasthuri, N., Lichtman, J. W. & Yuste, R. Ultrastructural analysis of dendritic spine necks reveals a continuum of spine morphologies. Dev. Neurobiol. 81, 746–757 (2021).

  35. Kullmann, D. M. Amplitude fluctuations of dual-component EPSCs in hippocampal pyramidal cells: implications for long-term potentiation. Neuron 12, 1111–1120 (1994).

    Article  CAS  Google Scholar 

  36. Wright, W. J. et al. Silent synapses dictate cocaine memory destabilization and reconsolidation. Nat. Neurosci. 23, 32–46 (2020).

    Article  CAS  Google Scholar 

  37. Takumi, Y., Ramírez-León, V., Laake, P., Rinvik, E. & Ottersen, O. P. Different modes of expression of AMPA and NMDA receptors in hippocampal synapses. Nat. Neurosci. 2, 618–624 (1999).

    Article  CAS  Google Scholar 

  38. Benna, M. K. & Fusi, S. Computational principles of synaptic memory consolidation. Nat. Neurosci. 19, 1697–1706 (2016).

    Article  CAS  Google Scholar 

  39. Fusi, S., Drew, P. J. & Abbott, L. F. Cascade models of synaptically stored memories. Neuron 45, 599–611 (2005).

    Article  CAS  Google Scholar 

  40. Aitchison, L. et al. Synaptic plasticity as Bayesian inference. Nat. Neurosci. 24, 565–571 (2021).

    Article  CAS  Google Scholar 

  41. Feng, G. et al. Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron 28, 41–51 (2000).

    Article  CAS  Google Scholar 

  42. Yang, G., Chang, P. C., Bekker, A., Blanck, T. J. J. & Gan, W. B. Transient effects of anesthetics on dendritic spines and filopodia in the living mouse cortex. Anesthesiology 115, 718–726 (2011).

    Article  CAS  Google Scholar 

  43. Ji, N., Magee, J. C. & Betzig, E. High-speed, low-photodamage nonlinear imaging using passive pulse splitters. Nat. Methods 5, 197–202 (2008).

    Article  CAS  Google Scholar 

  44. Harnett, M. T., Xu, N. L., Magee, J. C. & Williams, S. R. Potassium channels control the interaction between active dendritic integration compartments in layer 5 cortical pyramidal neurons. Neuron 79, 516–529 (2013).

    Article  CAS  Google Scholar 

  45. Matsuzaki, M., Honkura, N., Ellis-Davies, G. C. R. & Kasai, H. Structural basis of long-term potentiation in single dendritic spines. Nature 255, 243–244 (2004).

    Google Scholar 

  46. Weber, J. P. et al. Location-dependent synaptic plasticity rules by dendritic spine cooperativity. Nat. Commun. 7, 11380 (2016).

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank D. H. Yun for technical assistance with eMAP, K. Tsimring and A. Krol for technical assistance with perfusions, and C. Yaeger, M. Tadross, E. Nedivi and M. Bear for constructive criticism of the manuscript. We thank H. Umemori for the donation of Thy1-GFP-M+ mouse pups. Financial support was provided by the Boehringer Ingelheim Fonds (D.V.), National Institutes of Health RO1NS106031 (M.T.H.), the James W. and Patricia T. Poitras Fund at MIT (M.T.H.), a Klingenstein-Simons Fellowship (M.T.H.), a Vallee Foundation Scholarship (M.T.H.) and a McKnight Scholarship (M.T.H.).

Author information

Authors and Affiliations

  1. McGovern Institute for Brain Research, MIT, Cambridge, MA, USA

    Dimitra Vardalaki & Mark T. Harnett

  2. Department of Brain & Cognitive Sciences, MIT, Cambridge, MA, USA

    Dimitra Vardalaki, Kwanghun Chung & Mark T. Harnett

  3. Picower Institute for Learning and Memory, MIT, Cambridge, MA, USA

    Kwanghun Chung

  4. Institute for Medical Engineering and Science, MIT, Cambridge, MA, USA

    Kwanghun Chung

  5. Department of Chemical Engineering, MIT, Cambridge, MA, USA

    Kwanghun Chung

  6. Broad Institute of Harvard University and MIT, Cambridge, MA, USA

    Kwanghun Chung

Authors
  1. Dimitra Vardalaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kwanghun Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark T. Harnett
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

D.V. performed all experiments, analysed all data and prepared the figures. K.C. provided eMAP resources. M.T.H supervised all aspects of the project and wrote the manuscript with D.V.

Corresponding author

Correspondence to Mark T. Harnett.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature thanks Bernardo Sabatini 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 figures and tables

Extended Data Fig. 1 Morphological measurements of dendritic protrusions.

a, Illustration of a dendritic protrusion and corresponding measurements: head diameter. (dhead), neck diameter (dneck), length (l). b–d, Population histograms of morphological characteristics across all dendritic protrusions (n = 2234). e, Population histogram of the relationship between dhead and dneck. Shaded area indicates a ratio below 1.3, the first criterion used to classify filopodia versus spines. f, Population histogram of dhead/l for protrusions with dhead/dneck below 1.3 (shaded area in e). Protrusions with dhead/l above 3 were classified as filopodia, those below 3 were likely short stubby spines and were not analyzed further (shaded area= (dhead /dneck < 1.3) ∩ (l/ dhead>3)). g, Same as e but for each of the 4 mice. h, Fraction of dendritic protrusions classified as filopodia per mouse (n = 527, 944, 435, 328 dendritic protrusions and 30, 47, 25, 21 dendritic branches for mouse 1, 2, 3, 4 respectively). Box plot represents median and IQR with whiskers extending to the most extreme points not considered outliers. ns P = 0.093, Kruskal-Wallis test.

Source data

Extended Data Fig. 2 Filopodia in L2/3 pyramidal neurons exhibit AMPAR immune-negative and NMDAR immune-positive synapses.

a, Example confocal image of a V1 L2/3 neuron (green arrowhead) expressing GFP after viral transfection in V1 in an originally 45 μm thick slice. Scale bar: 100 μm expanded/ 59 μm original. Image was taken after reshrinking the tissue from 4x expansion to 1.7x expansion. b, Box plot (left) and kernel density estimate (right) of signal intensity in Bassoon (blue), NMDAR (yellow), and AMPAR (red) channels for L2/3 pyramidal neuron spines (n = 275). Box plot represents median and IQR with whiskers extending to the most extreme points not considered outliers. Signal in each channel is shown for all dendritic protrusions, each represented by one dot. c, As in b, but for filopodia (n = 134).

Source data

Extended Data Fig. 3 Anti-Bassoon signal intensity threshold for presence of presynaptic partner.

a, Cumulative density function of Bassoon signal intensity in spines (red) and filopodia (yellow). Vertical line at the choosen threshold (anti-Bassoon signal = 0). b, Magnified plot of a around 0. c-d, Example filopodia with anti-Bassoon signal intensities below above the threshold. Scale bar: 5 μm expanded/1.25 μm original.

Source data

Extended Data Fig. 4 Representatitive examples of eMAP at dendritic protrusions.

Example four channel images of dendritic protrusions with different dhead/dneck values (increasing from left to right). From top to bottom: cell-filling GFP stained with Alexa Fluor 488 (green) at lower magnification to show full protrusion shape, presynaptic protein Bassoon stained Alexa Fluor 405 (blue), NMDAR subunit NR1(GluN1) stained with Alexa Fluor 555 (yellow), and AMPAR subunit GluR1(GluA1) stained with Alexa Fluor 647 (red), all at higher magnifiaction to show synaptic localization. Scale bar: 2 μm expanded/0.5 μm original.

Extended Data Fig. 5 Anti-GluA1 signal increases with spine size.

a, Anti-GluA1 signal intensity as a function of head diameter for spines (red) and filopodia (yellow). b, Correlation between head diameter and anti-GluA1 signal intensity for spines. The data are fitted with a line of slope 421+/−22 using linear regression. c, Correlation between diameter of filopodium head and anti-GluaA1 signal intensity. The data are fitted with a line of slope 95+/−39 using linear regression. Correlation coefficients (r) and p-values were obtained from a two-tailed, non-parametric Spearman correlation.

Source data

Extended Data Fig. 6 Spatial resolution of two-photon MNI-glutamate uncaging at adult mouse cortical protrusions.

a, Left: Two-photon z-stack of a V1 L5 pyramidal neuron filled with Alexa-488 via somatic patch pipette. Basal branch segment of interest indicated by yellow box. Right: Magnified view of basal branch of interest. b, (top) Voltage response for the spine at lateral uncaging locations shown in a. (bottom) plot of lateral uncaging resolution. Continuous line is the Gaussian fit of the amplitudes of two-photon glutamate uncaging along lateral steps (circles). c, (top) Voltage response for the spine at axial locations shown in a. Each voltage trace is an average of the voltage traces evoked at a specific axial step above and below of the spine. (bottom) plot of axial uncaging resolution (see b). d, Magnified view of a filopodium of a basal branch of a L5 pyramidal neuron. All uncaging experiments shown in e and f were performed in Mg2+ free ASCF with AMPA blocked (DNQX, 20 μM). e, As in b, for the filopodium shown in d. f, As in c, for the filopodium shown in d.

Source data

Extended Data Fig. 7 Responses to focal extracellular synaptic stimulation for the filopodium shown in Fig. 3e.

a, Superimposed traces of somatic voltage recordings (left) and corresponding changes in local Ca2+ (measured via Fluo-4 fluorescence; ΔF/F) at the parent dendritic branch (middle) and at the tip of the filopodium (right) in response to focal extracellular synaptic stimulation in Mg2+-free aCSF with AMPA blocked (via DNQX, 20 μΜ). All synaptic stimulation successes and failures for the filopodium in Fig. 3e are shown. Synaptic stimulation driven backpropagating action potential (bAP) shown in red. b, Same as in a with traces spaced apart. Grey dashed line indicates the onset of synaptic stimulation.

Source data

Extended Data Fig. 8 Length of protrusions before and after induction protocols.

Length of protrusions before (grey) and after (red) induction in filopodia and spines. Three different induction protocols were tested in filopodia: i- Pairing protocol (n = 15 filopodia from 13 slices and 10 mice); ii- Somatic action potentials without any caged glutamate present (Post alone; n = 7 filopodia from 7 slices and 6 mice); iii- Glutamate uncaging without somatic action potential (Pre alone; n = 7 filopodia from 7 slices and 6 mice); ns P > 0.15. Two-sided Wilcoxon signed-rank test. Box plot represents median and IQR with whiskers extending to the most extreme points not considered outliers.

Source data

Extended Data Fig. 9 Spiny synapses do not exhibit changes in synaptic strength or length in response to the STDP protocol.

a, Schematic of the experiment. A control spine on a different branch than the branch of the test spine was always present. 40 and 90 repetitions of the pairing protocol were used for spines. b, Relative change of peak somatic uEPSP amplitude after pairing. P = 0.5781 (40 repetitions, n = 7 test and 7 control spines from 7 slices and 4 mice), P = 0.9375 (90 repetitions, n = 7 test and 7 control spines from 7 slices and 3 mice), two-sided Wilcoxon signed-rank test. Box plot represents median and IQR with whiskers extending to the 95% CI. c, Relative change of spine length after pairing. P = 0.4688 (40 repetitions, n = 7 test and 7 control spines from 7 slices and 4 mice), P = 0.8125 (90 repetitions, n = 7 test and 7 control spines from 7 slices and 3 mice), two-sided Wilcoxon signed-rank test. Box plot represents median and IQR with whiskers extending to the 95% CI.

Source data

Extended Data Fig.10 Super-resolution characterization of synapses in developing mouse visual cortex.

a, Example confocal image of a postnatal day (P) 13 Thy1- GFP-M+ L5 pyramidal neuron dendritic segment after 4x expansion. Scale bar: 10 μm expanded/2.5 μm original. b, Fraction of dendritic protrusions classified as filopodia in P13 L5 PNs (n = 371 dendritic protrusion, 18 dendritic branches, 3 mice). Box plot represents median and IQR with whiskers extending to the most extreme points not considered outliers. c, Fraction of total synapses in the three dendritic locations in P13 L5 PNs (n = 397 synapses, 18 dendritic branches, 3 mice). Box plot represents median and IQR with whiskers extending to the most extreme points not considered outliers. d, (left) Box plot and individual data for signal intensity in Bassoon (blue), NMDAR (yellow), and AMPAR (red) channels for spines (n = 236). (right) example four channel images of a representative spine. Box plot represents median and IQR with whiskers extending to the most extreme points not considered outliers. Scale bar: 5 μm expanded/1.25 μm original (GFP), 1 μm expanded/0.25 μm original (Bassoon). e, As in b, but for filopodia (n = 79). f, As in b, but for shaft synapses (n = 82). Example images show a shaft synapse that lacks AMPARs (top) and a shaft synapse that exhibits AMPARs (bottom). g, Comparison of dendritic protrusion types in P13 (n = 371) and adult mice (n = 2234). h, Comparison of synapse distribution in P13 (n = 397) and adult mice (n = 2188).

Source data

Supplementary information

Source data

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

Vardalaki, D., Chung, K. & Harnett, M.T. Filopodia are a structural substrate for silent synapses in adult neocortex. Nature 612, 323–327 (2022). https://doi.org/10.1038/s41586-022-05483-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41586-022-05483-6

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