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Opportunities and challenges of single-cell and spatially resolved genomics methods for neuroscience discovery

Nature Neuroscience volume 27, pages 2292–2309 (2024)Cite this article

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An Author Correction to this article was published on 16 December 2024

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Abstract

Over the past decade, single-cell genomics technologies have allowed scalable profiling of cell-type-specific features, which has substantially increased our ability to study cellular diversity and transcriptional programs in heterogeneous tissues. Yet our understanding of mechanisms of gene regulation or the rules that govern interactions between cell types is still limited. The advent of new computational pipelines and technologies, such as single-cell epigenomics and spatially resolved transcriptomics, has created opportunities to explore two new axes of biological variation: cell-intrinsic regulation of cell states and expression programs and interactions between cells. Here, we summarize the most promising and robust technologies in these areas, discuss their strengths and limitations and discuss key computational approaches for analysis of these complex datasets. We highlight how data sharing and integration, documentation, visualization and benchmarking of results contribute to transparency, reproducibility, collaboration and democratization in neuroscience, and discuss needs and opportunities for future technology development and analysis.

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Fig. 1: Biological considerations: cellular architecture and research questions.
Fig. 2: Outline of key considerations involved in designing high-throughput single-cell and ST studies.
Fig. 3: Outline of computational design of high-throughput single-cell or single-nucleus and spatial omics studies.
Fig. 4: Epigenomic technologies.

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Acknowledgements

We thank I. Adameyko, R. Awatramani, T. Bakken, H. S. Bateup, A. Bhaduri, C. R. Cadwell, E. Caglayan, J. L. Chen, C. Chhatbar, M. G. Filbin, D. Gate, J. Gillis, H. Hochgerner, M. Kampmann, C. N. Kim, F. Krienen, J. Krull, G. La Manno, S. Marsh, M. Monje, Q. Li, Sten Linnarsson, Q. Ma, C. Mayer, V. Menon, P. Nano, M. R O’Dea, R. Patani, A. Pollen, M. Prinz, S. Quake, F. J. Quintana, M. Scavuzzo, M. Schmitz, S. Sloan, P. Tesar, J. Tollkuhn, M. Antonietta Tosches, M. E. Urbanek, C. Walsh, J. Werner and J. Yang for the insightful feedback on this work. G.C.-B. was supported by the Swedish Research Council (grant 2019-01360), Knut and Alice Wallenberg Foundation (grants 2019-0107 and 2019-0089), The Swedish Brain Foundation (FO2023-0032), The Swedish Society for Medical Research (SSMF, grant JUB2019) and the Göran Gustafsson Foundation for Research in Natural Sciences and Medicine. We acknowledge National Institutes of Health (NIH) grants U01AG072573, P01AG073082 and UM1HG012076 (to M.R.C.) and U01DA052713, RF1AG079557, RF1NS128908 and R01AG079291 (to Y.S.). We also acknowledge NIH awards R01MH125516, R01NS123263, R01MH128364 and U01MH130962, the Esther A & Joseph Klingenstein Fund (to T.J.N.), the Shurl and Kay Curci Foundation (T.J.N.) and the Sontag Foundation (to T.J.N.) and a gift from the William K. Bowes Jr Foundation. T.J.N. is a New York Stem Cell Foundation Robertson Neuroscience Investigator. We acknowledge awards from the James S. McDonnell Foundation 21st Century Science Initiative in Understanding Human Cognition (220020467), the Simons Foundation (947591), NHGRI (HG011641), NINDS (NS115821, NS126143) and NIMH (MH126481, MH103517) to G.K. M.H. received a JPB Foundation Picower Institute Innovation Fund award. Work in the group of B.B. was supported by the Helmholtz Center Munich, DFG priority program SPP2202 (BO 5516/1-1), ERA-NET Neuron (MOSAIC) and European Research Council Consolidator grant to B.B. (EpiCortex, 101044469). M.N. acknowledges support from the Israel Science Foundation (grant no. 1079/21), and the European Union (ERC, DecodeSC, 101040660). O.A.B. acknowledges Wellcome Sanger core and Wellcome LEAP funding. J.F. acknowledges support from the National Institute of General Medical Sciences of the NIH under award number R35-GM142889. We acknowledge NINDS Intramural funds through 1ZIA NS003153 (to A.J.L.). K.R.M. acknowledges support from the Lieber Institute for Brain Development and NIH (R01DA055823). L.S. acknowledges support from the European Research Council (ERC StG ‘DecOmPress’, 950584), the National Multiple Sclerosis Society (PA-2022-36405 and RFA-2203-39300) and the German Research Foundation through collaborative research projects (SPP 2395, FOR 2690 and GRK 2727), individual research grants (SCHI 1330/4-1 and SCHI 1330/10-1) and a Heisenberg Fellowship (SCHI 1330/6-1). N.H. acknowledges support from the Israel Science Foundation research grant no. 1709/19 and the European Research Council grant 853409. S.A.L. acknowledges support from the NIH (R01EY033353), the Cure Alzheimer’s Fund, the Belfer Neurodegeneration Consortium, HHMI Emerging Pathogens Initiative and the Carol and Gene Ludwig Family Foundation.

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Authors and Affiliations

  1. Helmholtz Pioneer Campus, Helmholtz Zentrum München, Neuherberg, Germany

    Boyan Bonev

  2. Physiological Genomics, Biomedical Center, Ludwig-Maximilians-Universität München, Munich, Germany

    Boyan Bonev

  3. Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

    Gonçalo Castelo-Branco

  4. The Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Fei Chen, Manolis Kellis, Na Sun, Xiao Wang & Evan Macosko

  5. Moleculent, Stockholm, Sweden

    Simone Codeluppi

  6. Gladstone Institute of Neurological Disease, San Francisco, CA, USA

    M. Ryan Corces

  7. Gladstone Institute of Data Science and Biotechnology, San Francisco, CA, USA

    M. Ryan Corces & Vijay Ramani

  8. Department of Neurology, University of California, San Francisco, San Francisco, CA, USA

    M. Ryan Corces & Yin Shen

  9. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA

    Jean Fan

  10. Department of Brain and Cognitive Sciences, MIT, Cambridge, MA, USA

    Myriam Heiman

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

    Myriam Heiman

  12. UCL Queen Square Institute of Neurology, University College London, London, UK

    Kenneth Harris

  13. Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan

    Fumitaka Inoue

  14. Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA, USA

    Manolis Kellis & Na Sun

  15. Spinal Circuits and Plasticity Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA

    Ariel Levine

  16. Institute of Computational Biology, Helmholtz Center Munich – German Research Center for Environmental Health, Neuherberg, Germany

    Mo Lotfollahi

  17. Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK

    Mo Lotfollahi & Fabian Theis

  18. Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA

    Chongyuan Luo & Fabian Theis

  19. Lieber Institute for Brain Development, Baltimore, MD, USA

    Kristen R. Maynard

  20. Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Kristen R. Maynard

  21. Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Kristen R. Maynard

  22. School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel

    Mor Nitzan

  23. Racah Institute of Physics, The Hebrew University of Jerusalem, Jerusalem, Israel

    Mor Nitzan

  24. Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel

    Mor Nitzan

  25. Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA

    Vijay Ramani

  26. Bakar Computational Health Sciences Institute, San Francisco, CA, USA

    Vijay Ramani

  27. New York Genome Center, New York, NY, USA

    Rahul Satijia

  28. Center for Genomics and Systems Biology, New York University, New York, NY, USA

    Rahul Satijia

  29. Department of Neurology, Mannheim Center for Translational Neuroscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    Lucas Schirmer

  30. Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA

    Yin Shen

  31. Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA

    Yin Shen & Tomasz J. Nowakowski

  32. The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel

    Gilad S. Green & Naomi Habib

  33. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA

    Xiao Wang

  34. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Xiao Wang & Evan Macosko

  35. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA

    Joshua D. Welch

  36. German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

    Ozgun Gokce

  37. Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany

    Ozgun Gokce

  38. Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX, USA

    Genevieve Konopka

  39. Peter O’Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA

    Genevieve Konopka

  40. Neuroscience Institute, NYU Grossman School of Medicine, New York, NY, USA

    Shane Liddelow

  41. Department of Neuroscience & Physiology, NYU Grossman School of Medicine, New York, NY, USA

    Shane Liddelow

  42. Parekh Center for Interdisciplinary Neurology, NYU Grossman School of Medicine, New York, NY, USA

    Shane Liddelow

  43. Department of Ophthalmology, NYU Grossman School of Medicine, New York, NY, USA

    Shane Liddelow

  44. Department of Neurobiology, Harvard Medical School, Boston, MA, USA

    Evan Macosko

  45. Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

    Evan Macosko

  46. Wellcome Sanger Institute, Hinxton, UK

    Omer Ali Bayraktar

  47. Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA

    Tomasz J. Nowakowski

  48. Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA

    Tomasz J. Nowakowski

  49. Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA, USA

    Tomasz J. Nowakowski

  50. The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA

    Tomasz J. Nowakowski

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Corresponding authors

Correspondence to Ozgun Gokce, Genevieve Konopka, Shane Liddelow, Evan Macosko, Omer Ali Bayraktar, Naomi Habib or Tomasz J. Nowakowski.

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S.A.L. declares a financial interest in AstronauTx and Synapticure. All other authors declare no competing interests.

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

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Bonev, B., Castelo-Branco, G., Chen, F. et al. Opportunities and challenges of single-cell and spatially resolved genomics methods for neuroscience discovery. Nat Neurosci 27, 2292–2309 (2024). https://doi.org/10.1038/s41593-024-01806-0

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