Connectomic comparison of mouse and human cortex
Abstract
The human cerebral cortex houses 1000 times more neurons than that of the cerebral cortex of a mouse, but the possible differences in synaptic circuits between these species are still poorly understood. We used three-dimensional electron microscopy of mouse, macaque, and human cortical samples to study their cell type composition and synaptic circuit architecture. The 2.5-fold increase in interneurons in humans compared with mice was compensated by a change in axonal connection probabilities and therefore did not yield a commensurate increase in inhibitory-versus-excitatory synaptic input balance on human pyramidal cells. Rather, increased inhibition created an expanded interneuron-to-interneuron network, driven by an expansion of interneuron-targeting interneuron types and an increase in their synaptic selectivity for interneuron innervation. These constitute key neuronal network alterations in the human cortex.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The preference of glutamatergic axons for spines and GABAergic axons for shafts is often misinterpreted as implying that synapses on dendritic shafts are mostly SS.
“However, this characteristic is often misinterpreted as implying that synapses on dendritic shafts are mostly SS (Motta et al., 2019; Karimi et al., 2020; Loomba et al., 2022).”
From Unambiguous identification of asymmetric and symmetric synapses using volume electron microscopy (2024) · cites this paper as Loomba et al., 2022
Cites
The human brain in numbers: a linearly scaled-up primate brain
Herculano-Houzel, S. (2009) · Frontiers in Human Neuroscience · doi:10.3389/neuro.09.031.2009 · Cited by 1,778 · cited 2× · see citing works
“T he human brain, with its 86 billion nerve cells (1) forming a network of unparalleled complexity, is of special interest for neuroscience.”
BackgroundConserved cell types with divergent features in human versus mouse cortex
Hodge, R. D., Bakken, T. E., Miller, J. A., Smith, K. A., Barkan, E. R., Graybuck, L. T., Close, J. L., Long, B., Johansen, N., Penn, O., et al. (2019) · Nature · doi:10.1038/s41586-019-1506-7 · Cited by 1,775 · see citing works
Shared and distinct transcriptomic cell types across neocortical areas
Tasic, B., Yao, Z., Graybuck, L. T., Smith, K. A., Nguyen, T. N., Bertagnolli, D., Goldy, J., Garren, E., Economo, M. N., Viswanathan, S., et al. (2018) · Nature · doi:10.1038/s41586-018-0654-5 · Cited by 1,746 · see citing works
Serial Block-Face Scanning Electron Microscopy to Reconstruct Three-Dimensional Tissue Nanostructure
Denk, W., & Horstmann, H. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020329 · Cited by 1,644 · see citing works
Cortex: Statistics and Geometry of Neuronal Connectivity
Braitenberg, V., & Schüz, A. (1998) · doi:10.1007/978-3-662-03733-1 · Cited by 1,178 · see citing works
von Bartheld, C. S., Bahney, J., & Herculano‐Houzel, S. (2016) · Journal of Comparative Neurology · doi:10.1002/cne.24040 · Cited by 1,063 · see citing works
The excitatory neuronal network of the C2 barrel column in mouse primary somatosensory cortex
Lefort, S., Tomm, C., Floyd Sarria, J.-C., & Petersen, C. C. H. (2009) · Neuron · doi:10.1016/j.neuron.2008.12.020 · Cited by 875 · see citing works
A disinhibitory microcircuit for associative fear learning in the auditory cortex
Letzkus, J. J., Wolff, S. B. E., Meyer, E. M. M., Tovote, P., Courtin, J., Herry, C., & Lüthi, A. (2011) · Nature · doi:10.1038/nature10674 · Cited by 840 · see citing works
Innovations present in the primate interneuron repertoire
Krienen, F. M., Goldman, M., Zhang, Q., C. H. del Rosario, R., Florio, M., Machold, R., Saunders, A., Levandowski, K., Zaniewski, H., Schuman, B., et al. (2020) · Nature · doi:10.1038/s41586-020-2781-z · Cited by 381 · see citing works
Innovations in Primate Interneuron Repertoire
Krienen, F. M., Goldman, M., Zhang, Q., del Rosario, R., Florio, M., Machold, R., Saunders, A., Levandowski, K., Zaniewski, H., Schuman, B., et al. (2019) · doi:10.1101/709501 · Cited by 372 · see citing works
Dense connectomic reconstruction in layer 4 of the somatosensory cortex
Motta, A., Berning, M., Boergens, K. M., Staffler, B., Beining, M., Loomba, S., Hennig, P., Wissler, H., & Helmstaedter, M. (2019) · Science · doi:10.1126/science.aay3134 · Cited by 333 · see citing works
Self-citationTranscriptomic and morphophysiological evidence for a specialized human cortical GABAergic cell type
Boldog, E., Bakken, T. E., Hodge, R. D., Novotny, M., Aevermann, B. D., Baka, J., Bordé, S., Close, J. L., Diez-Fuertes, F., Ding, S.-L., et al. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0205-2 · Cited by 291 · see citing works
Mohan, H., Verhoog, M. B., Doreswamy, K. K., Eyal, G., Aardse, R., Lodder, B. N., Goriounova, N. A., Asamoah, B., B. Brakspear, A. B. C., Groot, C., et al. (2015) · Cerebral Cortex · doi:10.1093/cercor/bhv188 · Cited by 280 · see citing works
Inhibitory interneurons in a cortical column form hot zones of inhibition in layers 2 and 5A
Meyer, H. S., Schwarz, D., Wimmer, V. C., Schmitt, A. C., Kerr, J. N. D., Sakmann, B., & Helmstaedter, M. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1113648108 · Cited by 254 · see citing works
Self-citationSomogyi, P., & Cowey, A. (1981) · Journal of Comparative Neurology · doi:10.1002/cne.901950402 · Cited by 234 · see citing works
DeFelipe, J., Hendry, S. H. C., Hashikawa, T., Molinari, M., & Jones, E. G. (1990) · Neuroscience · doi:10.1016/0306-4522(90)90097-n · Cited by 231 · see citing works
Synapses of double bouquet cells in monkey cerebral cortex visualized by calbindin immunoreactivity
DeFelipe, J., Hendry, S. H. C., & Jones, E. G. (1989) · Brain Research · doi:10.1016/0006-8993(89)91702-2 · Cited by 226 · see citing works
Cortical area and species differences in dendritic spine morphology
Benavides-Piccione, R., Ballesteros-Yáñez, I., DeFelipe, J., & Yuste, R. (2002) · Journal of Neurocytology · doi:10.1023/a:1024134312173 · Cited by 207 · see citing works
Complex Events Initiated by Individual Spikes in the Human Cerebral Cortex
Molnár, G., Oláh, S., Komlósi, G., Füle, M., Szabadics, J., Varga, C., Barzó, P., & Tamás, G. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060222 · Cited by 197 · see citing works
Kirov, S. A., Petrak, L. J., Fiala, J. C., & Harris, K. M. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.04.053 · Cited by 172 · see citing works
Ren, J. Q., Aika, Y., Heizmann, C. W., & Kosaka, T. (1992) · Experimental Brain Research · doi:10.1007/bf00230378 · Cited by 148 · see citing works
De Lima, A. D., & Morrison, J. H. (1989) · Journal of Comparative Neurology · doi:10.1002/cne.902830205 · Cited by 91 · see citing works
Three-dimensional synaptic Organization of Layer III of the human temporal neocortex
Cano-Astorga, N., DeFelipe, J., & Alonso-Nanclares, L. (2021) · Cerebral Cortex · doi:10.1093/cercor/bhab120 · Cited by 49 · see citing works
A Subtype of Inhibitory Interneuron with Intrinsic Persistent Activity in Human and Monkey Neocortex
Wang, B., Yin, L., Zou, X., Ye, M., Liu, Y., He, T., Deng, S., Jiang, Y., Zheng, R., Wang, Y., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.02.018 · Cited by 40 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Neuronal wiring diagram of an adult brain
Dorkenwald, S., Matsliah, A., Sterling, A. R., Schlegel, P., Yu, S.-C., McKellar, C. E., Lin, A., Costa, M., Eichler, K., Yin, Y., et al. (2024) · Nature · doi:10.1038/s41586-024-07558-y · Cited by 570 · see citing works
“In recent years, this approach has been applied to chunks of brains to reconstruct local connectivity maps that are highly informative 1–6 , but nevertheless inadequate for understanding brain function more globally.”
BackgroundMethodMathys, H., Peng, Z., Boix, C. A., Victor, M. B., Leary, N., Babu, S., Abdelhady, G., Jiang, X., Ng, A. P., Ghafari, K., et al. (2023) · Cell · doi:10.1016/j.cell.2023.08.039 · Cited by 495 · see citing works
A petavoxel fragment of human cerebral cortex reconstructed at nanoscale resolution
Shapson-Coe, A., Januszewski, M., Berger, D. R., Pope, A., Wu, Y., Blakely, T., Schalek, R. L., Li, P. H., Wang, S., Maitin-Shepard, J., et al. (2024) · Science · doi:10.1126/science.adk4858 · Cited by 361 · see citing works
Neuronal wiring diagram of an adult brain
Dorkenwald, S., Matsliah, A., Sterling, A. R., Schlegel, P., Yu, S.-C., McKellar, C. E., Lin, A., Costa, M., Eichler, K., Yin, Y., et al. (2023) · doi:10.1101/2023.06.27.546656 · Cited by 149 · see citing works
A cross-species proteomic map reveals neoteny of human synapse development
Wang, L., Pang, K., Zhou, L., Cebrián-Silla, A., González-Granero, S., Wang, S., Bi, Q., White, M. L., Ho, B., Li, J., et al. (2023) · Nature · doi:10.1038/s41586-023-06542-2 · Cited by 82 · see citing works
A cross-species proteomic map reveals neoteny of human synapse development
Wang, L., Pang, K., Zhou, L., Cebrián-Silla, A., González-Granero, S., Wang, S., Bi, Q., White, M. L., Ho, B., Li, J., et al. (2022) · doi:10.1101/2022.10.24.513541 · Cited by 82 · see citing works
Isochronic development of cortical synapses in primates and mice
Wildenberg, G., Li, H., Sampathkumar, V., Sorokina, A., & Kasthuri, N. (2023) · Nature Communications · doi:10.1038/s41467-023-43088-3 · Cited by 31 · see citing works
Lappalainen, J. K., Tschopp, F. D., Prakhya, S., McGill, M., Nern, A., Shinomiya, K., Takemura, S.-Y., Gruntman, E., Macke, J. H., & Turaga, S. C. (2023) · doi:10.1101/2023.03.11.532232 · Cited by 31 · see citing works
Unambiguous identification of asymmetric and symmetric synapses using volume electron microscopy
Cano-Astorga, N., Plaza-Alonso, S., Turegano-Lopez, M., Rodrigo-Rodríguez, J., Merchan-Perez, A., & DeFelipe, J. (2024) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2024.1348032 · Cited by 17 · see citing works
“Alternatively, several other articles classify synapses as excitatory and inhibitory based on their postsynaptic targets (i.e., dendritic spines and dendritic shafts) (Motta et al., 2019; Karimi et al., 2020; Loomba et al., 2022).”
BackgroundMultilevel visual motion opponency in Drosophila
Ammer, G., Serbe-Kamp, E., Mauss, A. S., Richter, F. G., Fendl, S., & Borst, A. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01443-z · Cited by 17 · see citing works
- Authors
- Loomba, S., Straehle, J., Gangadharan, V., Heike, N., Khalifa, A., Motta, A., Ju, N., Sievers, M., Gempt, J., Meyer, H. S., & Helmstaedter, M.
- Affiliations
- Radboud University Nijmegen (NL)
- Max Planck Institute for Brain Research (DE)
- Department of Connectomics, Max Planck Institute for Brain Research, Frankfurt, Germany.
- TUM Klinikum (DE)
- Corresponding author
- Loomba, Sahil
- Straehle, Jakob
- Gangadharan, Vijayan
- Heike, Natalie
- Motta, Alessandro
- Helmstaedter, Moritz
- ORCID
- Venue
- Science
- Published
- 2022-07-08
- Volume
- 377
- Issue
- 6602
- Pages
- eabo0924-eabo0924
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W4283328497
- Cited by
- 242
- References
- 24
- Citations by year
- 2026: 41 · 2025: 75 · 2024: 70 · 2023: 48 · 2022: 8
- FWCI
- 22.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- cerebral cortex, interneurons, synaptic circuits, excitation-inhibition balance, pyramidal neurons, macaque cortex, 3D electron microscopy
- MeSH terms
- Animals, Cerebral Cortex, Humans, Interneurons, Macaca, Pyramidal Cells, Mice, Connectome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review